02960nas a2200409 4500008004100000022001400041245015100055210006900206260001300275300001100288490000700299520170300306653003902009653000902048653001902057653002802076653004002104653001102144653001902155653001102174653001702185653000902202653002602211653003402237653002702271653001802298100002302316700002302339700001902362700001902381700002002400700002202420700002402442700002402466700002502490856003502515 2002 eng d a0895-706100aAngiotensin II type 1 receptor polymorphisms in the cardiovascular health study: relation to blood pressure, ethnicity, and cardiovascular events.0 aAngiotensin II type 1 receptor polymorphisms in the cardiovascul c2002 Dec a1050-60 v153 a
BACKGROUND: The angiotensin II type 1 receptor A1166C polymorphism has been associated with increased risks of hypertension and myocardial infarction in several small studies. We examined the association between this polymorphism and new-onset hypertension, blood pressure (BP) control, and incident cardiovascular events in a large population-based cohort of older adults.
METHODS: Eight hundred self-identified African Americans and 1,371 randomly selected white participants in the Cardiovascular Health Study were genotyped. The median duration of follow-up was 8.1 years.
RESULTS: The A1166C polymorphism was not associated with new-onset hypertension, with BP control, or with incident cardiovascular events in the overall population. In white participants, the CC genotype was associated with higher baseline systolic BP and pulse pressure, compared to the AC or AA genotype. In whites with treated hypertension at baseline, compared to the AA genotype, the CC genotype was associated with increased risks of incident congestive heart failure (hazard ratio = 2.5, 95% confidence interval [CI] 1.3-4.9) and incident ischemic stroke (hazard ratio = 2.6, 95% CI 1.1-6.0). These associations were not observed among white participants without treated hypertension, but the interaction of genotype with treated hypertension on ischemic stroke and heart failure was only marginally significant.
CONCLUSIONS: On the whole, in this large cohort of older adults, the A1166C polymorphism was not associated with BP control or incident cardiovascular events. The subgroup findings in treated hypertensives need to be confirmed in additional studies.
10aAfrican Continental Ancestry Group10aAged10aBlood Pressure10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aHumans10aHypertension10aMale10aPolymorphism, Genetic10aReceptor, Angiotensin, Type 110aReceptors, Angiotensin10aUnited States1 aHindorff, Lucia, A1 aHeckbert, Susan, R1 aTracy, Russell1 aTang, Zhonghua1 aPsaty, Bruce, M1 aEdwards, Karen, L1 aSiscovick, David, S1 aKronmal, Richard, A1 aNazar-Stewart, Valle uhttps://chs-nhlbi.org/node/71101042nas a2200337 4500008004100000022001400041245008800055210006900143260001300212300001000225490000700235653000900242653002800251653002900279653003200308653002500340653003300365653001100398653001700409653002400426653001700450100002200467700002300489700002400512700002400536700002100560700002200581700002000603710004600623856003500669 2002 eng d a0002-072900aCalcium channel blocker use and gastrointestinal tract bleeding among older adults.0 aCalcium channel blocker use and gastrointestinal tract bleeding c2002 May a217-80 v3110aAged10aAntihypertensive Agents10aCalcium Channel Blockers10aGastrointestinal Hemorrhage10aGeriatric Assessment10aHealth Services for the Aged10aHumans10aHypertension10aProspective Studies10aRisk Factors1 aKaplan, Robert, C1 aHeckbert, Susan, R1 aKoepsell, Thomas, D1 aRosendaal, Frits, R1 aFurberg, Curt, D1 aCooper, Lawton, S1 aPsaty, Bruce, M1 aCardiovascular Health Study Investigators uhttps://chs-nhlbi.org/node/68902765nas a2200373 4500008004100000022001400041245013000055210006900185260001600254300001100270490000800281520168800289653000901977653002101986653001102007653001102018653001402029653000902043653001602052653002602068653003202094653002402126653002302150653001702173653001802190653002202208100002002230700001802250700002302268700002302291700002102314700002102335856003502356 2002 eng d a0003-992600aCardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology.0 aCardiovascular risk factors and venous thromboembolism incidence c2002 May 27 a1182-90 v1623 aBACKGROUND: The association between traditional cardiovascular risk factors and risk of venous thromboembolism (VTE) has not been extensively examined in prospective studies.
METHODS: To determine whether atherosclerotic risk factors are also associated with increased incidence of VTE, we conducted a prospective study of 19 293 men and women without previous VTE in 6 US communities between 1987 and 1998.
RESULTS: There were 215 validated VTE events (1.45 per 1000 person-years) during a median of 8 years of follow-up. The age-adjusted hazard ratio was 1.4 (95% confidence interval [CI], 1.1-1.9) for men vs women, 1.6 (95% CI, 1.2-2.2) for blacks vs whites, and 1.7 (95% CI, 1.5-2.0) per decade of age. Cigarette smoking, hypertension, dyslipidemia, physical inactivity, and alcohol consumption were not associated with risk of VTE. Age-, race-, and sex-adjusted hazard ratios for body mass index categories (calculated as the weight in kilograms divided by the height in meters squared) of less than 25, 25 to less than 30, 30 to less than 35, 35 to less than 40, and 40 or more were 1.0, 1.5, 2.2, 1.5, and 2.7, respectively (P<.001 for the trend). Diabetes was also associated with an increased risk of VTE (adjusted hazard ratio, 1.5 [95% CI, 1.0-2.1]).
CONCLUSIONS: Our data showing no relationship of some arterial risk factors with VTE corroborate the view that the etiology of VTE differs from atherosclerotic cardiovascular disease. In addition, the findings suggest a hypothesis that avoidance of obesity and diabetes or vigilance in prophylaxis in patients with those conditions may prevent some venous thromboses.
10aAged10aArteriosclerosis10aFemale10aHumans10aIncidence10aMale10aMiddle Aged10aMultivariate Analysis10aProportional Hazards Models10aProspective Studies10aPulmonary Embolism10aRisk Factors10aUnited States10aVenous Thrombosis1 aTsai, Albert, W1 aCushman, Mary1 aRosamond, Wayne, D1 aHeckbert, Susan, R1 aPolak, Joseph, F1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/69103319nas a2200481 4500008004100000022001400041245014200055210006900197260001600266300001100282490000800293520191900301653000902220653001502229653003002244653002302274653001902297653002502316653001502341653001102356653001502367653001102382653002702393653002502420653000902445653001602454653002602470653002402496653002002520653001702540653003202557653002002589653002202609653002602631100002002657700001802677700002302695700002302718700002202741700001802763700002102781856003502802 2002 eng d a0002-934300aCoagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE).0 aCoagulation factors inflammation markers and venous thromboembol c2002 Dec 01 a636-420 v1133 aPURPOSE: We sought to assess prospectively whether higher levels of blood coagulation factors and inflammation markers are risk factors for venous thromboembolism.
SUBJECTS AND METHODS: In two pooled population-based cohort studies, we measured levels of factor VII, factor VIII, von Willebrand factor, fibrinogen, and C-reactive protein, and white blood cell count, in samples obtained from 19,237 adults with no baseline history of venous thromboembolism, cancer, or warfarin use. The endpoint was validated venous thromboembolism during follow-up (median, 7.8 years).
RESULTS: A total of 159 venous thromboembolism events occurred. Factor VIII and von Willebrand factor were linearly associated with increased risk of venous thromboembolism (P for trend <0.0001). As compared with those in the lowest quartile, the multivariate-adjusted hazard ratio (HR) of venous thromboembolism was 2.6 (95% confidence interval [CI]: 1.6 to 4.3) for factor VIII levels in the highest quartile and 3.8 (95% CI: 2.0 to 7.2) for the highest fifth percentile. For von Willebrand factor, the hazard ratios in middle-aged subjects were 4.6 (95% CI: 2.2 to 9.2) for the highest quartile and 7.6 (95% CI: 3.1 to 18) for the highest fifth percentile. Factor VII levels above the 95th percentile, as compared with the lowest quartile, also conveyed a higher risk of venous thromboembolism (HR = 2.4; 95% CI: 1.2 to 4.8). In contrast, there was no association of venous thromboembolism with fibrinogen or C-reactive protein levels, or white cell count.
CONCLUSIONS: In this prospective study, elevated factor VIII and von Willebrand factor levels were common, independent, and dose-dependent risk factors for venous thromboembolism, and an elevated factor VII level was a possible risk factor. Venous thromboembolism, unlike arterial disease, was not related to inflammatory markers.
10aAged10aBiomarkers10aBlood Coagulation Factors10aC-Reactive Protein10aCohort Studies10aConfidence Intervals10aFactor VII10aFemale10aFibrinogen10aHumans10aInflammation Mediators10aLongitudinal Studies10aMale10aMiddle Aged10aMultivariate Analysis10aProspective Studies10aRisk Assessment10aRisk Factors10aSensitivity and Specificity10aThromboembolism10aVenous Thrombosis10avon Willebrand Factor1 aTsai, Albert, W1 aCushman, Mary1 aRosamond, Wayne, D1 aHeckbert, Susan, R1 aTracy, Russell, P1 aAleksic, Nena1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/71603016nas a2200397 4500008004100000022001400041245015200055210006900207260001600276300001100292490000800303520182700311653000902138653001802147653002802165653001202193653001102205653002702216653001102243653000902254653002602263653003002289653003202319653002002351653001102371100002302382700002402405700002102429700002102450700002302471700002102494700002402515700002402539700002002563856003502583 2002 eng d a0003-992600aFasting and 2-hour postchallenge serum glucose measures and risk of incident cardiovascular events in the elderly: the Cardiovascular Health Study.0 aFasting and 2hour postchallenge serum glucose measures and risk c2002 Jan 28 a209-160 v1623 aBACKGROUND: The contributions of fasting and 2-hour postchallenge glucose level to cardiovascular events remain ill-defined, especially for nondiabetic adults. This study examined the relative predictive power of fasting and 2-hour glucose level on cardiovascular event risk.
METHODS: A total of 4014 community-dwelling adults 65 years or older who participated in the baseline visit of the Cardiovascular Health Study and who were without treated diabetes or previous myocardial infarction or stroke were eligible for analyses. Participants with treated diabetes at baseline were excluded. Incident myocardial infarction or stroke, or coronary death, was the outcome of interest. Age-, sex-, and race-adjusted proportional hazards regression models described individual and joint associations between baseline measures of fasting and 2-hour postchallenge glucose level and event risk.
RESULTS: There were 764 incident cardiovascular events during 8.5 years of follow-up. Fasting glucose level of 115 mg/dL (6.4 mmol/L) or more was associated with an increased cardiovascular risk (hazard ratio [HR], 1.66 [95% confidence interval (CI), 1.39-1.98]) in adjusted analyses compared with fasting glucose level less than 115 mg/dL. Two-hour glucose level was associated with a linear risk (HR, 1.02 [95% CI, 1.00-1.04] per 10 mg/dL [0.6 mmol/L]) that included an additional increase in risk for 2-hour glucose level of 154 mg/dL (8.5 mmol/L) or more (HR, 1.29 [95% CI, 1.04-1.59]) in adjusted analyses. In joint fasting and 2-hour glucose models, only 2-hour glucose level remained predictive of event risk.
CONCLUSIONS: Two-hour glucose level was better than fasting glucose level alone at identifying older adults at increased risk of major incident cardiovascular events.
10aAged10aBlood Glucose10aCardiovascular Diseases10aFasting10aFemale10aGlucose Tolerance Test10aHumans10aMale10aMyocardial Infarction10aPredictive Value of Tests10aProportional Hazards Models10aRisk Assessment10aStroke1 aSmith, Nicholas, L1 aBarzilay, Joshua, I1 aShaffer, Douglas1 aSavage, Peter, J1 aHeckbert, Susan, R1 aKuller, Lewis, H1 aKronmal, Richard, A1 aResnick, Helaine, E1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/67503238nas a2200397 4500008004100000022001400041245013200055210006900187260001300256300001100269490000700280520209000287653001602377653000902393653001802402653001902420653002802439653002102467653002802488653002702516653002202543653001102565653001102576653000902587653001502596653002402611653001702635100002302652700002102675700002302696700002402719700002102743700002102764700002002785856003502805 2002 eng d a0002-861400aGlucose, blood pressure, and lipid control in older people with and without diabetes mellitus: the Cardiovascular Health Study.0 aGlucose blood pressure and lipid control in older people with an c2002 Mar a416-230 v503 aOBJECTIVES: To determine the prevalence of cardiovascular risk-factor treatment and control in older adults with normal fasting glucose, impaired fasting glucose, and diabetes mellitus and whether those with diabetes mellitus had better risk factor control than older adults with normal fasting glucose.
DESIGN: Secondary analysis of data from population-based, prospective cohort study of risk factors for cardio-vascular and cerebrovascular disease in older people (Cardiovascular Health Study).
SETTING: Community-based.
PARTICIPANTS: Community-dwelling adults aged 65 and older.
MEASUREMENTS: Fasting plasma glucose, serum cholesterol and its subfractions, systolic and diastolic blood pressures, and body mass index.
RESULTS: There were 579 (18%) cohort members with diabetes mellitus (77% receiving antidiabetic medication, 23% with fasting glucose > or =126 mg/dL and no treatment), 213 (6%) with impaired fasting glucose, and 2,582 (77%)with normal fasting glucose. Of diabetic participants, 12% had recommended fasting glucose levels of less than 110 mg/dL. Of participants with hypertension, a larger proportion of diabetic participants than nondiabetic participants (89% versus 75%, P < .01) was treated with antihypertensive agents, but a smaller proportion of diabetic participants had recommended blood pressure levels of 129/85 mmHg or lower than nondiabetic participants had recommended blood pressure levels of 139/89 mmHg or lower (27% vs 48%, P < .01). Diabetic dyslipidemic participants were treated less often with lipid-lowering therapy (26% versus 55%, P < .01) and achieved recommended low-density lipoprotein goals less often (8%versus 54%, P < .01) than nondiabetic dyslipidemic participants.
CONCLUSIONS: Overall, treatment and control of cardiovascular risk factors were suboptimal in this older population, especially among those with diabetes mellitus. Optimizing risk-factor control can improve health outcomes in older adults with and without diabetes mellitus.
10aAge Factors10aAged10aBlood Glucose10aBlood Pressure10aCardiovascular Diseases10aCholesterol, LDL10aCross-Sectional Studies10aDiabetes Complications10aDiabetes Mellitus10aFemale10aHumans10aMale10aPrevalence10aProspective Studies10aRisk Factors1 aSmith, Nicholas, L1 aSavage, Peter, J1 aHeckbert, Susan, R1 aBarzilay, Joshua, I1 aBittner, Vera, A1 aKuller, Lewis, H1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/68502290nas a2200409 4500008004100000022001400041245015000055210006900205260001300274300001100287490000700298520107500305653003901380653001601419653000901435653002501444653004001469653001301509653001101522653001401533653001601547653001501563653003601578653002401614653001601638653001501654653002001669653001701689653002001706653001801726100002101744700001801765700002101783700002301804700001801827856003501845 2002 eng d a0361-860900aProspective study of the G20210A polymorphism in the prothrombin gene, plasma prothrombin concentration, and incidence of venous thromboembolism.0 aProspective study of the G20210A polymorphism in the prothrombin c2002 Dec a285-900 v713 aCase-control studies have indicated increased risk of venous thrombosis associated with the prothrombin gene G20210A polymorphism and with elevated plasma prothrombin levels. We sought to confirm these results in a prospective population-based study of 21,690 persons. We measured G20210A and prothrombin antigen on pre-event blood samples of 302 participants who developed venous thromboembolism (VTE) and 626 participants who remained free of VTE. Approximately 4.0% of cases and 2.4% of controls carried the G20210A polymorphism, but only one of 137 African Americans did. The odds ratio in whites was 1.87 (95% CI = 0.85, 4.11)--higher for those who reported a prior history of VTE (OR = 5.44) than those reporting no VTE history (OR = 1.41) and in those with idiopathic VTE (OR = 2.51) than those with secondary VTE (OR = 1.38). There was no association between venous thromboembolism and plasma prothrombin antigen level. We estimated that the G20210A polymorphism may account for approximately 2.5% of venous thromboembolism events in United States whites.
10aAfrican Continental Ancestry Group10aAge Factors10aAged10aCase-Control Studies10aEuropean Continental Ancestry Group10aGenotype10aHumans10aIncidence10aMiddle Aged10aOdds Ratio10aPolymorphism, Single Nucleotide10aProspective Studies10aProthrombin10aRecurrence10aResearch Design10aRisk Factors10aThromboembolism10aUnited States1 aFolsom, Aaron, R1 aCushman, Mary1 aTsai, Michael, Y1 aHeckbert, Susan, R1 aAleksic, Nena uhttps://chs-nhlbi.org/node/71002750nas a2200433 4500008004100000022001400041245010200055210006900157260001600226300001100242490000700253520153800260653003501798653000901833653001901842653003401861653001301895653001301908653001501921653001101936653001401947653002501961653001601986653001502002653002402017653001702041653002002058653002202078100002102100700001802121700002102139700001802160700002302178700002002201700002002221700001702241700002302258856003502281 2002 eng d a0006-497100aA prospective study of venous thromboembolism in relation to factor V Leiden and related factors.0 aprospective study of venous thromboembolism in relation to facto c2002 Apr 15 a2720-50 v993 aThe aim of this study was to examine the occurrence of venous thromboembolism (VTE) in relation to factor V-related risk factors. Using a nested case-control design combining 2 population-based prospective studies, we measured factor V Leiden, HR2 haplotype, activated protein C (APC) resistance, and plasma factor V antigen in 335 participants who developed VTE during 8 years of follow-up and 688 controls. The overall odds ratio (OR) of VTE was 3.67 (95% CI, 2.20-6.12) in participants carrying factor V Leiden compared with noncarriers. APC resistance measured after predilution with factor V-deficient plasma conferred an OR of 2.58 (95% CI, 1.62-4.10). All 3 participants homozygous for the HR2 haplotype had a VTE, and the OR of VTE for homozygosity was estimated to be 5.5 (95% CI, 2.45-12.5). Carriers of the HR2 haplotype otherwise were not at increased risk of VTE overall (OR = 1.05; 95% CI, 0.64-1.72), but double heterozygotes for HR2 and factor V Leiden carried an OR of idiopathic VTE of 16.3 (95% CI, 1.7-159) compared with noncarriers. Factor V antigen also was not associated with VTE overall, but for participants with the combination of high factor V antigen plus factor V Leiden the OR of idiopathic VTE was 11.5 (95% CI, 4.2-31.4). In the general population, APC resistance and factor V Leiden were important VTE risk factors; homozygosity for the HR2 haplotype may be a risk factor but was rare; otherwise, HR2 haplotype and factor V antigen were not risk factors except in carriers of factor V Leiden.
10aActivated Protein C Resistance10aAged10aCohort Studies10aContinental Population Groups10aFactor V10aGenotype10aHaplotypes10aHumans10aIncidence10aLongitudinal Studies10aMiddle Aged10aOdds Ratio10aProspective Studies10aRisk Factors10aThromboembolism10aVenous Thrombosis1 aFolsom, Aaron, R1 aCushman, Mary1 aTsai, Michael, Y1 aAleksic, Nena1 aHeckbert, Susan, R1 aBoland, Lori, L1 aTsai, Albert, W1 aYanez, David1 aRosamond, Wayne, D uhttps://chs-nhlbi.org/node/68403096nas a2200385 4500008004100000022001400041245019900055210006900254260001600323300001300339490000800352520187000360653000902230653002102239653002102260653001102281653002202292653001102314653005102325653002502376653002502401653001402426653000902440653002602449653003202475653001702507653001802524100002402542700002002566700002302586700002402609700002002633700002202653856003502675 2002 eng d a0003-992600aTherapy with hydroxymethylglutaryl coenzyme a reductase inhibitors (statins) and associated risk of incident cardiovascular events in older adults: evidence from the Cardiovascular Health Study.0 aTherapy with hydroxymethylglutaryl coenzyme a reductase inhibito c2002 Jun 24 a1395-4000 v1623 aBACKGROUND: Recommendations to treat older adults with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) for the primary prevention of coronary heart disease events are supported by a single clinical trial restricted to adults 73 years or younger with low levels of high-density lipoprotein cholesterol.
METHODS: We investigated the association of statin use with incident cardiovascular disease and all-cause mortality during up to 7.3 years' follow-up of 1250 women and 664 men from the Cardiovascular Health Study. Study participants were 65 years and older and free of cardiovascular disease at baseline. They received drug therapy to lower cholesterol levels at baseline or no treatment with a recommendation for therapy according to the National Cholesterol Education Program guidelines. Use of these drugs was assessed annually. We used proportional-hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for confounding variables.
RESULTS: We found 382 incident cardiovascular events (159 myocardial infarctions, 159 strokes, and 64 deaths due to coronary heart disease) and 362 total deaths from June 1, 1989, to May 31, 1997. Compared with no use of drugs to lower cholesterol levels, statin use was associated with decreased risk of cardiovascular events (multivariate HR, 0.44; 95% CI, 0.27-0.71) and all-cause mortality (HR, 0.56; 95% CI, 0.36-0.88). Similar associations were observed among participants 74 years or older at baseline.
CONCLUSIONS: Use of statins was associated with decreased risk of incident cardiovascular events among elderly adults. These findings lend support to the National Cholesterol Education Program guidelines, which recommend therapy for the lowering of cholesterol levels for older adults with hypercholesterolemia.
10aAged10aCholesterol, LDL10aCoronary Disease10aFemale10aFollow-Up Studies10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aHypercholesterolemia10aHypolipidemic Agents10aIncidence10aMale10aMultivariate Analysis10aProportional Hazards Models10aRisk Factors10aUnited States1 aLemaitre, Rozenn, N1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aKronmal, Richard, A1 aNewman, Anne, B1 aBurke, Gregory, L uhttps://chs-nhlbi.org/node/69503826nas a2200433 4500008004100000022001400041245014100055210006900196260001600265300001200281490000800293520256400301653001602865653000902881653002802890653001402918653001902932653001702951653001102968653004202979653001103021653001703032653000903049653002403058653001703082100002003099700002103119700002303140700002303163700002403186700002203210700002003232700001803252700001903270700001503289700002103304710003203325856003503357 2002 eng d a0003-992600aTime trends in high blood pressure control and the use of antihypertensive medications in older adults: the Cardiovascular Health Study.0 aTime trends in high blood pressure control and the use of antihy c2002 Nov 11 a2325-320 v1623 aBACKGROUND: Control of high blood pressure (BP) in older adults is an important part of public health efforts at prevention.
OBJECTIVE: To assess recent time trends in the awareness, treatment, and control of high BP and in the use of medications to treat high BP.
METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline, participants underwent an extensive examination that included the measurement of BP, use of medications, and other risk factors. Participants were followed up with annual visits that assessed BP and medication use from baseline in 1989-1990 through the examination in 1998-1999. The primary outcome measures were control of BP to levels lower than than 140/90 mm Hg and the prevalence of use of various classes of antihypertensive medications.
RESULTS: The awareness, treatment, and control of high BP improved during the 1990s. The proportions aware and treated were higher among blacks than whites, though control prevalences were similar. For both groups combined, the control of high BP to lower than 140/90 mm Hg increased from 37% at baseline to 49% in 1999. The 51% whose BP was not controlled generally had isolated mild to moderate elevations in systolic BP. Among treated persons, the improvement in control was achieved in part by a mean increase of 0.2 antihypertensive medications per person over the course of 9 years. Improved control was also achieved by increasing the proportion of the entire Cardiovascular Health Study population that was treated for hypertension, from 34.5% in 1990 to 51.1% in 1999. Time trends in antihypertensive drug use were pronounced. Among those without coronary disease, the use of low-dose diuretics and beta-blockers decreased, while the use of newer agents, such as calcium channel blockers, angiotensin-converting enzyme inhibitors, and alpha-blockers increased.
CONCLUSIONS: While control of high BP improved in the 1990s, about half the participants with hypertension had uncontrolled BP, primarily mild to moderate elevations in systolic BP. Low-dose diuretics and beta-blockers--the preferred agents since 1993 according to the recommendations of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure--remained underused. More widespread use of these agents will be an important intervention to prevent the devastating complications of hypertension, including stroke, myocardial infarction, and heart failure.
10aAge Factors10aAged10aAntihypertensive Agents10aAwareness10aCohort Studies10aDrug Therapy10aFemale10aHealth Knowledge, Attitudes, Practice10aHumans10aHypertension10aMale10aProspective Studies10aTime Factors1 aPsaty, Bruce, M1 aManolio, Teri, A1 aSmith, Nicholas, L1 aHeckbert, Susan, R1 aGottdiener, John, S1 aBurke, Gregory, L1 aWeissfeld, Joel1 aEnright, Paul1 aLumley, Thomas1 aPowe, Neil1 aFurberg, Curt, D1 aCardiovascular Health Study uhttps://chs-nhlbi.org/node/70802636nas a2200481 4500008004100000022001400041245010300055210006900158260001600227300001100243490000800254520123900262653003901501653000901540653001201549653001901561653002801580653001901608653001601627653002101643653004001664653002201704653001901726653001101745653001401756653002701770653002601797653003401823653002001857653001101877653001801888100002301906700002301929700002201952700002001974700001901994700002402013700001902037700001702056700002402073700002202097856003502119 2003 eng d a1524-453900aBeta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly.0 aBeta2adrenergic receptor polymorphisms and risk of incident card c2003 Apr 22 a2021-40 v1073 aBACKGROUND: Genetic polymorphisms at codons 16 and 27 of the beta2-adrenergic receptor have been associated with altered response to sympathetic stimulation. We examined these polymorphisms in relation to cardiovascular event risk in the Cardiovascular Health Study.
METHODS AND RESULTS: A total of 808 black and 4441 white participants (mean age, 73 years) were genotyped for the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenergic receptor. There were 702 incident coronary events, 438 ischemic strokes, and 1136 combined cardiovascular events during 7 to 10 years of follow-up. Allele frequencies differed by race but not by age or hypertension status. Glu27 carriers had a lower risk of coronary events than Gln27 homozygotes (hazard ratio, 0.82; 95% CI, 0.70 to 0.95), and there was a suggestion of decreased risk among Gly16 carriers compared with Arg16 homozygotes (hazard ratio, 0.88; 95% CI, 0.72 to 1.07). There was no association of beta2-adrenergic receptor genotype with ischemic stroke or combined cardiovascular events.
CONCLUSIONS: The Glu27 allele of the beta2-adrenergic receptor was associated with a lower risk of incident coronary events in this elderly population.
10aAfrican Continental Ancestry Group10aAged10aAlleles10aBrain Ischemia10aCardiovascular Diseases10aCohort Studies10aComorbidity10aCoronary Disease10aEuropean Continental Ancestry Group10aFollow-Up Studies10aGene Frequency10aHumans10aIncidence10aLinkage Disequilibrium10aPolymorphism, Genetic10aReceptors, Adrenergic, beta-210aRisk Assessment10aStroke10aUnited States1 aHeckbert, Susan, R1 aHindorff, Lucia, A1 aEdwards, Karen, L1 aPsaty, Bruce, M1 aLumley, Thomas1 aSiscovick, David, S1 aTang, Zhonghua1 aDurda, Peter1 aKronmal, Richard, A1 aTracy, Russell, P uhttps://chs-nhlbi.org/node/73302781nas a2200421 4500008004100000022001400041245007000055210006800125260001600193300001100209490000800220520163800228653000901866653002001875653001901895653003401914653001301948653001601961653001101977653004301988653001102031653002502042653000902067653001602076653001502092653002402107653001602131653001702147653002202164100001802186700002102204700001302225700001802238700002302256700002202279700002302301856003502324 2003 eng d a0006-497100aFibrin fragment D-dimer and the risk of future venous thrombosis.0 aFibrin fragment Ddimer and the risk of future venous thrombosis c2003 Feb 15 a1243-80 v1013 aPlasma D-dimer concentration rises more than 100-fold during acute deep vein thrombosis, but there are no prospective data concerning D-dimer as a risk factor for incident venous thrombosis in a general population. Incident venous thrombosis was ascertained in 2 prospective observational studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Of 21 690 participants enrolled between 1987 and 1993, after 8 years of follow-up, D-dimer was measured using baseline stored plasma of 307 participants who developed venous thrombosis and 616 who did not. Relative to the first quintile of the distribution of D-dimer, the age-adjusted odds ratios for future venous thrombosis for the second to fifth quintiles of D-dimer were 1.6, 2.3, 2.3, and 4.2, respectively (P for trend <.0001). Following added adjustment for sex, race, body mass index, factor V Leiden, prothrombin 20210A, and elevated factor VIII coagulant activity (factor VIII:c), these odds ratios were 1.5, 2.1, 1.9, and 3.0, respectively (P for trend <.0001). Among those with idiopathic thrombosis or secondary thrombosis unrelated to cancer, the adjusted fifth quintile odds ratios were 3.5 and 4.8, respectively. By contrast, D-dimer in the fifth versus first quintile was not related to occurrence of cancer-associated thrombosis (odds ratio, 1.1). Odds ratios for elevated D-dimer were consistently elevated in subgroups defined by age, sex, race, duration of follow-up, and thrombosis type (deep vein thrombosis or pulmonary embolus). D-dimer is strongly and positively related to the occurrence of future venous thrombosis.
10aAged10aBody Mass Index10aCohort Studies10aContinental Population Groups10aFactor V10aFactor VIII10aFemale10aFibrin Fibrinogen Degradation Products10aHumans10aLongitudinal Studies10aMale10aMiddle Aged10aOdds Ratio10aProspective Studies10aProthrombin10aRisk Factors10aVenous Thrombosis1 aCushman, Mary1 aFolsom, Aaron, R1 aWang, Lu1 aAleksic, Nena1 aRosamond, Wayne, D1 aTracy, Russell, P1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/70603151nas a2200493 4500008004100000022001400041245011600055210006900171260001300240300001100253490000700264520176200271653000902033653002202042653002002064653001902084653003302103653001102136653001802147653001102165653001402176653001502190653001602205653002602221653001202247653003302259653003202292653002402324653000902348653001702357653001802374653001902392100001902411700002002430700002302450700001802473700002002491700001902511700002402530700002302554700002202577700002302599856003502622 2003 eng d a1540-999600aHormone replacement therapy and the risk of incident congestive heart failure: the Cardiovascular Health Study.0 aHormone replacement therapy and the risk of incident congestive c2003 May a341-500 v123 aBACKGROUND: The development of congestive heart failure (CHF) in older persons is related to a variety of mechanisms. Hormone replacement therapy (HRT) affects several of the pathways that may be important in the development of CHF. We hypothesized that HRT would be associated with a decreased risk of incident CHF.
METHODS: Using Cox proportional-hazards regression, we assessed the risk of incident CHF (n = 304) associated with time-dependent past and current use of HRT compared to never use. The Cardiovascular Health Study is a prospective cohort study of community-dwelling adults aged 65 years and older. This analysis included female participants without a history of CHF at baseline (n = 3223).
RESULTS: At baseline, 62% were never users, 26% were past users, and 12% were current users of HRT. Compared with never users, the multivariable relative risk (RR) of CHF was 1.01 (95% confidence interval [95% CI] 0.76,1.34) for past users and 1.34 (0.93,1.94) for current users. Results were similar among most treatment and clinical subgroups, except that the association of current HRT with CHF appeared to depend on body mass index (BMI) or osteoporosis status. The RR was 0.82 (0.43,1.60) for normal weight women, 1.65 (0.95,2.88) for overweight women, and 2.22 (1.06,4.67) for obese women (p = 0.01 for interaction). Similarly, the RR was 0.15 (0.04,0.65) for women with osteoporosis and 1.82 (1.25,2.65) for women without osteoporosis (p = 0.001 for interaction).
CONCLUSIONS: Overall, HRT was not associated with the risk of incident CHF, although BMI and osteoporosis appeared to modify the association of HRT with CHF. The risk of CHF was lower in patients with lower BMI or osteoporosis.
10aAged10aAged, 80 and over10aBody Mass Index10aCohort Studies10aEstrogen Replacement Therapy10aFemale10aHeart Failure10aHumans10aIncidence10aLife Style10aMiddle Aged10aMultivariate Analysis10aObesity10aOsteoporosis, Postmenopausal10aProportional Hazards Models10aProspective Studies10aRisk10aRisk Factors10aUnited States10aWomen's Health1 aRea, Thomas, D1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aCushman, Mary1 aMeilahn, Elaine1 aOlson, Jean, L1 aLemaitre, Rozenn, N1 aSmith, Nicholas, L1 aSotoodehnia, Nona1 aChaves, Paulo, H M uhttps://chs-nhlbi.org/node/74002062nas a2200433 4500008004100000022001400041245007400055210006900129260001300198300001200211490000700223520086300230653000901093653002401102653002801126653001501154653003601169653002501205653001101230653001701241653001701258653001101275653000901286653001601295653001501311653003801326653001401364653002401378653002901402653001701431653002001448653002201468100002101490700001801511700002301529700002301552700001801575856003501593 2003 eng d a0895-435600aProspective study of fibrinolytic markers and venous thromboembolism.0 aProspective study of fibrinolytic markers and venous thromboembo c2003 Jun a598-6030 v563 aPrior research has conflicted on whether increased levels of plasma fibrinolytic factors may identify patients at risk of venous thromboembolism (VTE). We therefore performed a nested case-control study of VTE within two prospective population-based studies. In 308 participants who developed VTE and 640 controls, we measured PAI-1 antigen, tPA/PAI-1 complex, plasmin-alpha 2-antiplasmin (PAP), and the PAI-1 -675 4G/5G promoter polymorphism on pre-event blood samples. There was no overall association between any of these fibrinolytic variables and VTE, after adjustment for age or for multiple VTE risk factors. There was weak evidence for an interaction of PAP with elevated factor VIIIc and elevated D-dimer in augmenting VTE risk. We conclude that, for the most part, these fibrinolytic markers do not identify healthy subjects at risk for VTE.
10aAged10aalpha-2-Antiplasmin10aAntifibrinolytic Agents10aBiomarkers10aCaenorhabditis elegans Proteins10aCase-Control Studies10aFemale10aFibrinolysin10aFibrinolysis10aHumans10aMale10aMiddle Aged10aOdds Ratio10aPlasminogen Activator Inhibitor 110aPrognosis10aProspective Studies10aProtein-Tyrosine Kinases10aRisk Factors10aThromboembolism10aVenous Thrombosis1 aFolsom, Aaron, R1 aCushman, Mary1 aHeckbert, Susan, R1 aRosamond, Wayne, D1 aAleksic, Nena uhttps://chs-nhlbi.org/node/74302477nas a2200481 4500008004100000022001400041245018500055210006900240260001300309300001200322490000700334520104600341653000901387653001001396653001201406653002501418653001901443653001301462653001101475653001301486653001701499653001101516653002501527653000901552653004901561653001601610653001501626653004901641653002601690653002401716653001701740653002201757100002001779700001801799700002101817700002301838700002301861700001801884700001701902700002001919700002101939856003501960 2003 eng d a0361-860900aSerum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE).0 aSerum homocysteine thermolabile variant of methylene tetrahydrof c2003 Mar a192-2000 v723 aWe sought to examine prospectively the association of serum homocysteine and the methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphism with risk of venous thromboembolism (VTE). We studied these relationships in a nested case-control study of 303 VTE cases and 635 matched controls from a population-based cohort of 21,680 adults from six U.S. communities. The highest quintile of serum homocysteine carried a non-statistically significant adjusted odds ratio of 1.55 (95% CI, 0.93-2.58) compared to the lowest quintile in the overall cohort but a significant association among adults aged 45-64 years (OR = 2.05, 95% CI, 1.10-3.83) and an inverse association in those > or = 65 years of age. Carriers of the MTHFR C677T polymorphism were not at higher risk for VTE than those with normal genotype (OR = 0.74, 95% CI = 0.56-0.98). Our prospective data showed, at most, a weak relationship between homocysteine and VTE risk, with associations larger among younger participants. MTHFR C677T was not a risk factor for VTE.
10aAged10aAging10aAnimals10aCase-Control Studies10aCohort Studies10aFactor V10aFemale10aGenotype10aHomocysteine10aHumans10aLongitudinal Studies10aMale10aMethylenetetrahydrofolate Reductase (NADPH2)10aMiddle Aged10aOdds Ratio10aOxidoreductases Acting on CH-NH Group Donors10aPolymorphism, Genetic10aProspective Studies10aRisk Factors10aVenous Thrombosis1 aTsai, Albert, W1 aCushman, Mary1 aTsai, Michael, Y1 aHeckbert, Susan, R1 aRosamond, Wayne, D1 aAleksic, Nena1 aYanez, David1 aPsaty, Bruce, M1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/72602878nas a2200409 4500008004100000022001400041245012400055210006900179260001600248300001000264490000800274520173300282653000902015653002502024653001902049653001102068653002202079653001102101653001402112653000902126653001602135653001402151653002802165653002302193653001502216653001702231653001802248653002202266100001802288700002002306700002202326700002302348700002302371700001802394700002102412856003502433 2004 eng d a0002-934300aDeep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology.0 aDeep vein thrombosis and pulmonary embolism in two cohorts the l c2004 Jul 01 a19-250 v1173 aPURPOSE: To determine the incidence of deep vein thrombosis and pulmonary embolism in two cohorts representing regions of the United States.
METHODS: The sample comprised 21,680 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study. Subjects were aged >/=45 years, resided in six communities, and were followed for 7.6 years. All hospitalizations were identified and thromboses were validated by chart review.
RESULTS: The age-standardized incidence of first-time venous thromboembolism was 1.92 per 1000 person-years. Rates were higher in men than women, and increased with age in both sexes. There was no antecedent trauma, surgery, immobilization, or diagnosis of cancer for 48% (175/366) of events. The 28-day case-fatality rate was 11% (29/265) after a first venous thromboembolism and 25% (17/67) for cancer-associated thrombosis. The recurrence rate 2 years after a first venous thromboembolism was 7.7% per year (95% confidence interval [CI]: 4.5% to 10.9% per year). Cancer was the only factor independently associated with 28-day fatality (relative risk [RR] = 5.2; 95% CI: 1.4 to 19.9) or recurrent thrombosis (RR = 9.2; 95% CI: 2.0 to 41.7).
CONCLUSION: The incidence of venous thromboembolism in this cohort of middle- and older-aged subjects was similar to that observed in more geographically homogeneous samples. Half of cases were idiopathic. Short-term mortality and 2-year recurrence rates were appreciable, especially among subjects with cancer. Based on this study we estimate that 187,000 cases of first-time venous thromboembolism are diagnosed yearly in the United States among those aged 45 years or older.
10aAged10aCase-Control Studies10aCohort Studies10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aMiddle Aged10aNeoplasms10aPopulation Surveillance10aPulmonary Embolism10aRecurrence10aRisk Factors10aSurvival Rate10aVenous Thrombosis1 aCushman, Mary1 aTsai, Albert, W1 aWhite, Richard, H1 aHeckbert, Susan, R1 aRosamond, Wayne, D1 aEnright, Paul1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/79303224nas a2200493 4500008004100000022001400041245017200055210006900227260001300296300001000309490000700319520182100326653002102147653000902168653002202177653001602199653001502215653002002230653001602250653002102266653002802287653002202315653001102337653001102348653001702359653001702376653002002393653000902413653002602422653001502448653001702463653001202480653002002492100002402512700001702536700001802553700002302571700001602594700002002610700002202630700001802652700002502670856003502695 2004 eng d a1523-683800aThe relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study.0 arelationship of cardiovascular risk factors to microalbuminuria c2004 Jul a25-340 v443 aBACKGROUND: Microalbuminuria is a risk factor for coronary heart disease (CHD). It occurs most commonly in the settings of diabetes and hypertension. The mechanisms by which it increases CHD risk are uncertain.
METHODS: We examined the cross-sectional association of microalbuminuria with a broad range of CHD risk factors in 3 groups of adults aged 65 years or older with and without microalbuminuria: those with (1) no diabetes or hypertension (n = 1,098), (2) hypertension only (n = 1,450), and (3) diabetes with or without hypertension (n = 465).
RESULTS: Three factors were related to microalbuminuria in all 3 groups: age, elevated systolic blood pressure, and markers of systemic inflammation. In patients with neither diabetes nor hypertension, increasing C-reactive protein levels were associated with microalbuminuria (odds ratio per 1-mg/L increase, 1.46; 95% confidence interval [CI], 1.15 to 1.84). Among those with diabetes, an increase in white blood cell (WBC) count was associated with microalbuminuria (odds ratio per 1,000-cell/mL increase, 2.57; 95% CI, 1.12 to 5.89). Among those with hypertension, an increase in WBC count (odds ratio per 1,000-cell/mL increase, 1.83; 95% CI, 1.04 to 3.23) and fibrinogen level (odds ratio per 10-mg/dL increase, 1.02; 95% CI, 1.00 to 1.05) were significantly associated with microalbuminuria. In all 3 groups, prevalent CHD was related to an elevated WBC count. In none of the 3 groups was brachial artery reactivity to ischemia, an in vivo marker of endothelial function, related to microalbuminuria.
CONCLUSION: Microalbuminuria is associated with age, systolic blood pressure, and markers of inflammation. These associations reflect potential mechanisms by which microalbuminuria is related to CHD risk.
10aAge Distribution10aAged10aAged, 80 and over10aAlbuminuria10aBiomarkers10aBrachial Artery10aComorbidity10aCoronary Disease10aCross-Sectional Studies10aDiabetes Mellitus10aFemale10aHumans10aHypertension10aInflammation10aLogistic Models10aMale10aMultivariate Analysis10aOdds Ratio10aRisk Factors10aSmoking10aUltrasonography1 aBarzilay, Joshua, I1 aPeterson, Do1 aCushman, Mary1 aHeckbert, Susan, R1 aCao, Jie, J1 aBlaum, Caroline1 aTracy, Russell, P1 aKlein, Ronald1 aHerrington, David, M uhttps://chs-nhlbi.org/node/79402681nas a2200409 4500008004100000022001400041245009100055210006900146260001600215300001100231490000800242520154100250653000901791653002201800653001901822653002801841653001101869653002201880653001801902653001101920653001401931653000901945653001401954653003001968653002201998100002602020700001902046700002302065700002302088700001902111700002402130700002302154700002202177700001702199700002002216856003502236 2004 eng d a0002-926200aSurvival associated with two sets of diagnostic criteria for congestive heart failure.0 aSurvival associated with two sets of diagnostic criteria for con c2004 Oct 01 a628-350 v1603 aCongestive heart failure (CHF) definitions vary across epidemiologic studies. The Framingham Heart Study criteria include CHF signs and symptoms assessed by a physician panel. In the Cardiovascular Health Study, a committee of physicians adjudicated CHF diagnoses, confirmed by signs, symptoms, clinical tests, and/or medical therapy. The authors used data from the Cardiovascular Health Study, a population-based cohort study of 5,888 elderly US adults, to compare CHF incidence and survival patterns following onset of CHF as defined by Framingham and/or Cardiovascular Health Study criteria. They constructed an inception cohort of nonfatal, hospitalized CHF patients. Of 875 participants who had qualifying CHF hospitalizations between 1989 and 2000, 54% experienced a first CHF event that fulfilled both sets of diagnostic criteria (concordant), 31% fulfilled only the Framingham criteria (Framingham only), and 15% fulfilled only the Cardiovascular Health Study criteria (Cardiovascular Health Study only). No significant survival difference was found between the Framingham-only group (hazard ratio = 0.87, 95% confidence interval: 0.71, 1.07) or the Cardiovascular Health Study-only group (hazard ratio = 0.89, 95% confidence interval: 0.68, 1.15) and the concordant group (referent). Compared with Cardiovascular Health Study central adjudication, Framingham criteria for CHF identified a larger group of participants with incident CHF, but all-cause mortality rates were similar across these diagnostic classifications.
10aAged10aAged, 80 and over10aCohort Studies10aDiagnosis, Differential10aFemale10aFollow-Up Studies10aHeart Failure10aHumans10aIncidence10aMale10aPrognosis10aSeverity of Illness Index10aSurvival Analysis1 aSchellenbaum, Gina, D1 aRea, Thomas, D1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aLumley, Thomas1 aRoger, Veronique, L1 aKitzman, Dalane, W1 aTaylor, Herman, A1 aLevy, Daniel1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/80202860nas a2200361 4500008004100000022001400041245013800055210006900193260001300262300001100275490000800286520181600294653003202110653001602142653000902158653002202167653001102189653002202200653001802222653001102240653000902251100002102260700001902281700002302300700002102323700002302344700001902367700001802386700002102404700001802425700002002443856003502463 2005 eng d a1097-674400aAssociation of beta-blocker use with mortality among patients with congestive heart failure in the Cardiovascular Health Study (CHS).0 aAssociation of betablocker use with mortality among patients wit c2005 Sep a464-700 v1503 aBACKGROUND: In clinical trials, beta-blocker therapy reduces all-cause mortality among people with congestive heart failure (CHF) characterized by depressed systolic function, but few trials included large numbers of elderly participants. This study assessed the association between beta-blocker therapy and mortality among community-dwelling older adults with CHF.
METHODS: The Cardiovascular Health Study (CHS) is a longitudinal, population-based study of adults aged > or = 65 years. Recruitment began in 1989 with follow-up extending through June 2000 or death. Cox proportional hazard regression models were used to assess the association between beta-blocker therapy and all-cause mortality among 950 participants who developed new-onset CHF.
RESULTS: beta-Blocker users (n = 157) were more likely than nonusers (n = 793) to have treated hypertension, clinical coronary artery disease, and valvular disease at the time of CHF diagnosis. Death occurred in 67 users and 446 nonusers during a median follow-up of 2.3 years. Compared with nonuse, use of beta-blockers was associated with a multivariable adjusted hazard ratio (HR) of 0.74 (95% CI 0.56-0.98) for all-cause mortality. Among the 520 participants who had left ventricular ejection fraction assessed within 90 days after CHF diagnosis, the risk for all cause mortality associated with beta-blocker use did not differ significantly between those with ejection fraction of < 40% and those with ejection fraction of > or = 40% (HR 0.56, 95% CI 0.27-1.13; HR 0.82, 95% CI 0.56-1.22, respectively; interaction P = .34).
CONCLUSIONS: This observational study suggests that beta-blocker treatment is associated with a reduced risk of all-cause mortality among community-dwelling older adults with CHF.
10aAdrenergic beta-Antagonists10aAge Factors10aAged10aAged, 80 and over10aFemale10aFollow-Up Studies10aHeart Failure10aHumans10aMale1 aChan, Jeannie, D1 aRea, Thomas, D1 aSmith, Nicholas, L1 aSiscovick, David1 aHeckbert, Susan, R1 aLumley, Thomas1 aChaves, Paulo1 aFurberg, Curt, D1 aKuller, Lewis1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/85603325nas a2200421 4500008004100000022001400041245012000055210006900175260001300244300001000257490000700267520209400274653002202368653002802390653002102418653002802439653004002467653001102507653001302518653001502531653001102546653001702557653001402574653000902588653001602597653002602613653003402639653001702673100002302690700002302713700002002736700001902756700002402775700002502799700002202824700002202846856003502868 2005 eng d a0895-706100abeta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the Cardiovascular Health Study.0 abeta2Adrenergic receptor polymorphisms and determinants of cardi c2005 Mar a392-70 v183 aBACKGROUND: Common Arg16Gly and Gln27Glu polymorphisms of the beta(2)-adrenergic receptor (beta(2)AR) have been associated with hypertension and coronary disease. This analysis of older adults in the Cardiovascular Health Study examined whether these polymorphisms were associated with blood pressure (BP), subclinical atherosclerosis, and, among treated hypertensive individuals, differences in coronary disease risk according to antihypertensive drug class.
METHODS: Altogether, 5249 participants (4441 white and 808 African American, median follow-up time 10.2 years) were genotyped for both polymorphisms. Ankle-arm index (AAI), carotid intima-media thickness (IMT), and brachial flow-mediated dilation were measured cross-sectionally. All estimates were adjusted for ethnicity.
RESULTS: Relative to Gln27 homozygotes, carrying the Glu27 allele was not associated with new-onset hypertension (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 0.87 to 1.16), BP control (odds ratio [OR] = 0.97, 95% CI = 0.89 to 1.06), AAI (mean difference 0.0042 +/- 0.0052), carotid IMT (mean difference 0.0044 +/- 0.02 mm), or brachial flow-mediated dilation (mean difference in baseline diameter -0.028 +/- 0.036 mm; the most marked of three measures). Among treated hypertensive individuals, coronary disease risk was similar in Glu27 carriers relative to Gln27 homozygotes in subgroups defined by use of beta-blockers (HR = 1.09, 95% CI = 0.64 to 1.87) or other antihypertensive medications (HR = 1.00, 95% CI = 0.78 to 1.28). Results were similar for the Arg16Gly polymorphism.
CONCLUSIONS: The association of beta(2)AR genotype with coronary disease previously reported in this older adult population is not likely to be explained by BP levels, subclinical atherosclerosis, or antihypertensive treatment. Other measures of vascular response, gene-gene or gene-environment interactions, or characteristics developing earlier in life may mediate the association between beta(2)AR genotype and coronary disease and merit further research.
10aAfrican Americans10aAntihypertensive Agents10aArteriosclerosis10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aFemale10aGenotype10aHomozygote10aHumans10aHypertension10aIncidence10aMale10aMiddle Aged10aPolymorphism, Genetic10aReceptors, Adrenergic, beta-210aRisk Factors1 aHindorff, Lucia, A1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aLumley, Thomas1 aSiscovick, David, S1 aHerrington, David, M1 aEdwards, Karen, L1 aTracy, Russell, P uhttps://chs-nhlbi.org/node/82502874nas a2200409 4500008004100000022001400041245014200055210006900197260001300266300001400279490000700293520165500300653000901955653002201964653004501986653001102031653001802042653001802060653001102078653001702089653000902106653002602115653003602141653002402177653002402201653001802225653001602243100002602259700002302285700002302308700001902331700001902350700002102369700001902390700002002409856003502429 2005 eng d a0002-861400aWeight loss, muscle strength, and angiotensin-converting enzyme inhibitors in older adults with congestive heart failure or hypertension.0 aWeight loss muscle strength and angiotensinconverting enzyme inh c2005 Nov a1996-20000 v533 aOBJECTIVES: To determine whether angiotensin-converting enzyme (ACE) inhibitor use may be associated with weight maintenance and sustained muscle strength (measured by grip strength) in older adults.
DESIGN: Data from the Cardiovascular Health Study (CHS), a community-based prospective cohort study of 5,888 older adults, were used.
SETTING: Subjects were recruited from four U.S. sites beginning in 1989; this analysis included data through 2001.
PARTICIPANTS: CHS participants with congestive heart failure (CHF) or treated hypertension.
MEASUREMENTS: The exposure, current ACE inhibitor use, was ascertained by medication inventory at annual clinic visits; the outcomes were weight change and grip-strength change during the following year. Multivariate linear regression was used, accounting for correlations between observations on the same participant over time.
RESULTS: The average annual weight change was -0.38 kg in 2,834 participants (14,443 person-years) with treated hypertension and -0.62 kg in 342 participants (980 person-years) with CHF. ACE inhibitor use was associated with less annual weight loss after adjustment for potential confounders: a difference of 0.17 kg (95% confidence interval (CI)=0.05-0.29) in those with treated hypertension and 0.29 kg (95% CI=-0.25-0.83) in those with CHF. There was no evidence of association between ACE inhibitor use and grip-strength change.
CONCLUSION: ACE inhibitor use may be associated with weight maintenance, but not maintenance of muscle strength, in older adults with treated hypertension.
10aAged10aAged, 80 and over10aAngiotensin-Converting Enzyme Inhibitors10aFemale10aHand Strength10aHeart Failure10aHumans10aHypertension10aMale10aMultivariate Analysis10aOutcome Assessment, Health Care10aProspective Studies10aStatistics as Topic10aUnited States10aWeight Loss1 aSchellenbaum, Gina, D1 aSmith, Nicholas, L1 aHeckbert, Susan, R1 aLumley, Thomas1 aRea, Thomas, D1 aFurberg, Curt, D1 aLyles, Mary, F1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/86803303nas a2200505 4500008004100000022001400041245008100055210006900136260001600205300001100221490000800232520183100240653003902071653000902110653002502119653002702144653004002171653001102211653001902222653003802241653002202279653001402301653001502315653001502330653001102345653000902356653003602365653003402401653003102435100002202466700002402488700001802512700002002530700002202550700002302572700002402595700001902619700001702638700001902655700002202674700002102696700002202717700002302739856003502762 2006 eng d a1524-453900aBeta2-adrenergic receptor genetic variants and risk of sudden cardiac death.0 aBeta2adrenergic receptor genetic variants and risk of sudden car c2006 Apr 18 a1842-80 v1133 aBACKGROUND: Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the beta2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk.
METHODS AND RESULTS: In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4% and 57.1% among white and 50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23; 95% CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95% CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study.
CONCLUSIONS: Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.
10aAfrican Continental Ancestry Group10aAged10aCase-Control Studies10aDeath, Sudden, Cardiac10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenetic Variation10aGlutamine10aHaplotypes10aHomozygote10aHumans10aMale10aPolymorphism, Single Nucleotide10aReceptors, Adrenergic, beta-210aReproducibility of Results1 aSotoodehnia, Nona1 aSiscovick, David, S1 aVatta, Matteo1 aPsaty, Bruce, M1 aTracy, Russell, P1 aTowbin, Jeffrey, A1 aLemaitre, Rozenn, N1 aRea, Thomas, D1 aDurda, Peter1 aChang, Joel, M1 aLumley, Thomas, S1 aKuller, Lewis, H1 aBurke, Gregory, L1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/89302904nas a2200397 4500008004100000022001400041245009400055210006900149260001300218300001200231490000700243520180100250653000902051653002202060653001902082653001902101653001102120653002202131653001102153653000902164653003602173653002402209653001502233653001102248653001802259100002202277700002502299700002002324700002102344700002302365700002302388700002102411700001902432700002002451856003502471 2006 eng d a0002-861400aBlood pressure level and outcomes in adults aged 65 and older with prior ischemic stroke.0 aBlood pressure level and outcomes in adults aged 65 and older wi c2006 Sep a1309-160 v543 aOBJECTIVES: To examine the association between blood pressure (BP) levels and long-term stroke outcomes in elderly stroke survivors.
DESIGN: Observational study.
SETTING: The Cardiovascular Health Study (CHS) of 5,888 community-dwelling adults.
PARTICIPANTS: Two hundred fifty-four adults aged 65 and older (mean age 78.6) who sustained a nonfatal first ischemic stroke.
MEASUREMENTS: BP levels assessed at prestroke and poststroke CHS visits were examined as predictors of stroke recurrence, coronary heart disease (CHD), combined vascular events (CVEs), and mortality.
RESULTS: Higher poststroke BP level, assessed 261.6 days (mean) after stroke, was associated with higher risk of stroke recurrence over 5.4 years (mean) of follow-up. The multivariate-adjusted hazard ratio for stroke recurrence was 1.42 (95% confidence interval (CI) = 1.03-1.99) per standard deviation (SD) of systolic BP (P = .04) and 1.39 (95% CI = 1.01-1.91) per SD of diastolic BP (P = .04). Mortality was significantly greater in patients with low or high poststroke BP than in those with intermediate BP. Poststroke BP was not associated with risk of CHD or CVE, although further analyses suggested that high systolic BP predicted CHD and CVE in younger but not older subjects. Prestroke BP did not predict poststroke outcomes.
CONCLUSION: In this observational study of adults aged 65 and older assessed approximately 8 months after stroke, low BP was associated with favorable risk of recurrent stroke, although high and low poststroke BP levels were associated with greater mortality. Long-term antihypertensive trials in older stroke survivors would increase knowledge about the benefits of lowering BP in this population.
10aAged10aAged, 80 and over10aBlood Pressure10aBrain Ischemia10aFemale10aFollow-Up Studies10aHumans10aMale10aOutcome Assessment, Health Care10aProspective Studies10aRecurrence10aStroke10aSurvival Rate1 aKaplan, Robert, C1 aTirschwell, David, L1 aLongstreth, W T1 aManolio, Teri, A1 aHeckbert, Susan, R1 aLeValley, Aaron, J1 aLefkowitz, David1 aEl-Saed, Aiman1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/91702489nas a2200361 4500008004100000022001400041245013800055210006900193260001300262300001100275490000700286520145100293653000901744653002201753653001901775653001101794653001801805653001101823653001401834653000901848653002201857653001401879100002601893700002301919700002301942700001901965700001901984700002302003700002402026700002202050700002002072856003502092 2006 eng d a1047-279700aCongestive heart failure incidence and prognosis: case identification using central adjudication versus hospital discharge diagnoses.0 aCongestive heart failure incidence and prognosis case identifica c2006 Feb a115-220 v163 aPURPOSE: We compared hospitalized congestive heart failure (CHF) incidence and prognosis estimates using hospital discharge diagnoses or central adjudication.
METHODS: We used the Cardiovascular Health Study (CHS), a population-based cohort study of 5888 elderly adults. A physician committee adjudicated potential CHF events, confirmed by signs, symptoms, clinical tests, and/or medical therapy. A CHF discharge diagnosis included any of these ICD-9 codes in any position: 428, 425, 398.91, 402.01, 402.11, 402.91, and 997.1. We constructed an inception cohort of 1209 hospitalized, nonfatal, incident CHF cases, identified by discharge diagnosis, adjudication, or both.
RESULTS: Incidence rates for hospitalized CHF were 24.6 per 1000 person-years using discharge diagnoses and 17.1 per 1000 person-years using central adjudication. Compared to the group identified as having CHF by both methods, the group with only a discharge diagnosis (hazard ratio=0.77, 95% confidence interval=0.65-0.91) and the group with central adjudication only (hazard ratio=0.72, 95% confidence interval=0.55-0.94) had lower mortality rates.
CONCLUSIONS: In the elderly, studies using only discharge diagnoses, as compared to central adjudication, may estimate higher rates of incident hospitalized CHF. Mortality following CHF onset may be similar for these methods and higher if both methods are used together.
10aAged10aAged, 80 and over10aCohort Studies10aFemale10aHeart Failure10aHumans10aIncidence10aMale10aPatient Discharge10aPrognosis1 aSchellenbaum, Gina, D1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aRea, Thomas, D1 aLumley, Thomas1 aKitzman, Dalane, W1 aRoger, Veronique, L1 aTaylor, Herman, A1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/84402663nas a2200385 4500008004100000022001400041245010900055210006900164260000900233300000800242490000800250520154800258653003901806653000901845653002501854653004001879653001101919653001501930653001301945653001101958653002001969653000901989653001601998653002302014653002602037653002702063100003102090700001802121700002102139700001502160700002302175700002302198700002102221856003502242 2007 eng d a0049-384800aThe association of alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism in the LITE study.0 aassociation of alphafibrinogen Thr312Ala polymorphism and venous c2007 a1-70 v1213 aINTRODUCTION: The alpha-fibrinogen Thr312Ala variant has been shown to influence clot structure through increased factor XIII cross-linking and formation of thicker fibrin fibers. However, the effect of this common variant on risk of venous thromboembolism (VTE) is unclear. This paper reports the association between the Thr312Ala variant and VTE in the LITE study.
MATERIALS AND METHODS: 506 cases and 1014 controls frequency matched on age, sex, race, and study were drawn from two prospective studies and included in the analysis. Logistic regression was used to examine the association between Thr312Ala and VTE.
RESULTS: In a logistic regression model minimally adjusted for the matching variables, the Thr312Ala TA and AA genotypes were associated with a significantly higher risk of VTE than the TT genotype (TA OR and 95% confidence interval 1.27 [1.01-1.60], AA OR 1.49 [1.00-2.22]). Associations were similar in analyses of PE and DVT considered separately and across racial and study subgroups. The association between alpha-fibrinogen Thr312Ala and VTE was modified by both BMI and the FXIII Val34Leu variant; the combination of elevated BMI or FXIII Val34Leu with alpha-fibrinogen Thr312Ala conveyed lower odds of VTE than would be expected by an additive or multiplicative model of individual risk factors.
CONCLUSIONS: These results suggest that alpha-fibrinogen Thr312Ala is involved in the pathogenesis of VTE and that its action may be modified by other VTE risk factors.
10aAfrican Continental Ancestry Group10aAged10aCase-Control Studies10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenotype10aHumans10aLogistic Models10aMale10aMiddle Aged10aMutation, Missense10aPolymorphism, Genetic10aVenous Thromboembolism1 aRasmussen-Torvik, Laura, J1 aCushman, Mary1 aTsai, Michael, Y1 aZhang, Yan1 aHeckbert, Susan, R1 aRosamond, Wayne, D1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/95802475nas a2200385 4500008004100000022001400041245006400055210006300119260001300182300001000195490000700205520146200212653001601674653000901690653002201699653001101721653002201732653001801754653001101772653000901783653001401792653001901806653002401825653001701849653002001866653001801886653002201904100002101926700002001947700001801967700002301985700002302008700002302031856003502054 2007 eng d a1079-500600aFrailty and risk of venous thromboembolism in older adults.0 aFrailty and risk of venous thromboembolism in older adults c2007 Jan a79-820 v623 aBACKGROUND: Frailty is a common risk factor for morbidity and mortality in elderly persons. Recent evidence links frailty to activation of coagulation and inflammatory pathways. We aimed to determine whether frailty in community-dwelling older adults is a risk factor for venous thromboembolism (VTE).
METHODS: We conducted a prospective cohort study in four U.S. communities involving 4859 participants 65 years old and older. At baseline, in 1989-1993, we assessed frailty based on weight loss, grip strength, feelings of exhaustion, walk time, and physical activity. Incident VTE (deep vein thrombosis or pulmonary embolus) through 2002 was identified by review of hospital records.
RESULTS: Fifty-two percent of the sample was classified as having intermediate or definite frailty. After adjustment for age, race, sex, body mass index, and diabetes, the relative risk of total VTE (n = 150) for people who were frail compared with no frailty was 1.31 (95% confidence interval [CI], 0.93-1.84). The comparably adjusted relative risk for idiopathic VTE (n = 58) was 1.79 (95% CI, 1.02-3.13).
CONCLUSIONS: The incidence rates of idiopathic VTE was higher in community-dwelling older adults with baseline frailty compared with no frailty. Further studies of the clotting process in frailty may allow the development of an improved strategy to determine VTE risk in this vulnerable subset of older adults.
10aAge Factors10aAged10aAged, 80 and over10aFemale10aFollow-Up Studies10aFrail Elderly10aHumans10aMale10aMorbidity10aMotor Activity10aProspective Studies10aRisk Factors10aThromboembolism10aUnited States10aVenous Thrombosis1 aFolsom, Aaron, R1 aBoland, Lori, L1 aCushman, Mary1 aHeckbert, Susan, R1 aRosamond, Wayne, D1 aWalston, Jeremy, D uhttps://chs-nhlbi.org/node/94202459nas a2200385 4500008004100000022001400041245007000055210006900125260001300194300001100207490000700218520139300225653000901618653002201627653002001649653002701669653001601696653001101712653003101723653001101754653001701765653002801782653002501810653000901835653001601844653001701860653002001877653002201897100002701919700001801946700002901964700002301993700002102016856003602037 2008 eng d a1533-345000aChronic kidney disease increases risk for venous thromboembolism.0 aChronic kidney disease increases risk for venous thromboembolism c2008 Jan a135-400 v193 aChronic kidney disease (CKD) is associated with increased risk for cardiovascular disease morbidity and mortality, but its association with incident venous thromboembolism (VTE) in non-dialysis-dependent patients has not been evaluated in a community-based population. With the use of data from the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, 19,073 middle-aged and elderly adults were categorized on the basis of estimated GFR, and cystatin C (available in 4734 participants) was divided into quintiles. During a mean follow-up time of 11.8 yr, 413 participants developed VTE. Compared with participants with normal kidney function, relative risk for VTE was 1.28 (95% confidence interval [CI] 1.02 to 1.59) for those with mildly decreased kidney function and 2.09 (95% CI 1.47 to 2.96) for those with stage 3/4 CKD, when adjusted for age, gender, race, and center. After additional adjustment for cardiovascular disease risk factors, an increased risk for VTE was still observed in participants with stage 3/4 CKD, with a multivariable adjusted relative risk of 1.71 (95% CI 1.18 to 2.49). There was no significant association between cystatin C and VTE. In conclusion, middle-aged and elderly patients with CKD (stages 3 through 4) are at increased risk for incident VTE, suggesting that VTE prophylaxis may be particularly important in this population.
10aAged10aAged, 80 and over10aBody Mass Index10aDiabetic Nephropathies10aFactor VIII10aFemale10aGlomerular Filtration Rate10aHumans10aHypertension10aKidney Failure, Chronic10aLongitudinal Studies10aMale10aMiddle Aged10aRisk Factors10aThromboembolism10aVenous Thrombosis1 aWattanakit, Keattiyoat1 aCushman, Mary1 aStehman-Breen, Catherine1 aHeckbert, Susan, R1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/100102289nas a2200337 4500008004100000022001400041245013800055210006900193260001600262300001200278490000800290520128900298653000901587653002301596653002101619653001101640653001101651653001401662653002501676653000901701653001601710653003201726653001801758653002701776100002701803700002101830700002301851700002301874700001801897856003601915 2008 eng d a1528-002000aHigh-density lipoprotein cholesterol and venous thromboembolism in the Longitudinal Investigation of Thromboembolism Etiology (LITE).0 aHighdensity lipoprotein cholesterol and venous thromboembolism i c2008 Oct 01 a2675-800 v1123 aWe determined prospectively the risk of venous thromboembolism (VTE) in relation to baseline high-density lipoprotein cholesterol (HDL-c) in 19 049 participants of the Longitudinal Investigation of Thromboembolism Etiology (LITE), which was composed of 14 490 participants of the Atherosclerosis Risk in Communities (ARIC) study and 4559 participants of the Cardiovascular Health Study (CHS). In addition, we determined the risk of VTE in relation to baseline subfractions of HDL (HDL(2) and HDL(3)) and apolipoprotein A-I (apoA-I) in 14 488 participants of the ARIC study. Age-adjusted incidence rates of VTE by HDL-c quartile ranged from 1.64 to 1.91 per 1000 person-years in men and 1.40 to 1.94 per 1000 person-years in women; however, there was no apparent trend of VTE incidence across HDL-c quartiles for either sex. The multivariate adjusted hazard ratios of VTE by HDL-c quartiles (with quartile 4 as the reference) were nonsignificant for both sexes and ranged between 0.91 and 0.99 for men and 0.78 and 1.22 for women. Results did not differ in separate evaluations of idiopathic and secondary VTE. In the ARIC study, there was no trend of VTE hazard ratios across quartiles of HDL(2), HDL(3), or apoA-I. Low HDL-c does not appear to be an important VTE risk factor.
10aAged10aApolipoprotein A-I10aCholesterol, HDL10aFemale10aHumans10aIncidence10aLongitudinal Studies10aMale10aMiddle Aged10aProportional Hazards Models10aUnited States10aVenous Thromboembolism1 aChamberlain, Alanna, M1 aFolsom, Aaron, R1 aHeckbert, Susan, R1 aRosamond, Wayne, D1 aCushman, Mary uhttps://chs-nhlbi.org/node/104002896nas a2200385 4500008004100000022001400041245022700055210006900282260001300351300001100364490000700375520165900382653000902041653002302050653002802073653002802101653003602129653001102165653001502176653001502191653001102206653002702217653002302244653001802267653000902285653001702294100002202311700002402333700002302357700002102380700002602401700002302427700002402450856003602474 2008 eng d a1532-541500aHigher levels of inflammation factors and greater insulin resistance are independently associated with higher heart rate and lower heart rate variability in normoglycemic older individuals: the Cardiovascular Health Study.0 aHigher levels of inflammation factors and greater insulin resist c2008 Feb a315-210 v563 aOBJECTIVES: To explore the relationship between (1) insulin resistance and inflammation factors with (2) higher heart rate (HR) and lower heart rate variability (HRV) in normoglycemic older adults.
DESIGN: Cross-sectional population-based study.
PARTICIPANTS: Five hundred forty-five adults aged 65 and older with normoglycemia (fasting glucose <100 mg/dL) who participated in the Cardiovascular Health Study.
MEASUREMENTS: Serum levels of three inflammation proteins (C-reactive protein (CRP), interleukin 6 (IL-6), and fibrinogen); insulin resistance, quantified according to the homeostasis assessment model (HOMA-IR); HR; and four representative measures of HRV (the standard deviation of normal beat to beat intervals (SDNN), the root mean square of successive differences (rMSSD), very low frequency power (VLF), and the low- to high-frequency power ratio (LF/HF)) derived from 24-hour Holter recordings.
RESULTS: High CRP and IL-6 levels were associated with higher HR and lower SDNN and VLF after adjustment for multiple covariates, including HOMA-IR and clinical cardiovascular disease. High IL-6 was also associated with lower LF/HF. Significant univariate inverse relationships between HOMA-IR and HR and HRV were also found, but the strengths of these relationships were attenuated after adjustment for inflammation factors.
CONCLUSION: Increased levels of inflammation markers and HOMA-IR are associated with higher HR and lower HRV. These findings suggest that inflammation may contribute to the pathogenesis of cardiovascular autonomic decline in older adults.
10aAged10aC-Reactive Protein10aCardiovascular Diseases10aCross-Sectional Studies10aElectrocardiography, Ambulatory10aFemale10aFibrinogen10aHeart Rate10aHumans10aInflammation Mediators10aInsulin Resistance10aInterleukin-610aMale10aRisk Factors1 aStein, Phyllis, K1 aBarzilay, Joshua, I1 aChaves, Paulo, H M1 aTraber, Jennifer1 aDomitrovich, Peter, P1 aHeckbert, Susan, R1 aGottdiener, John, S uhttps://chs-nhlbi.org/node/100802223nas a2200325 4500008004100000022001400041245009100055210006900146260001300215300001000228490000700238520130400245653005101549653000901600653001101609653001101620653000901631653001701640653002201657100001601679700002201695700002001717700002101737700002101758700002101779700002301800700002001823700001801843856003601861 2008 eng d a1096-865200aLipoprotein-associated phospholipase A2 and risk of venous thrombosis in older adults.0 aLipoproteinassociated phospholipase A2 and risk of venous thromb c2008 Jul a524-70 v833 aLipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme involved in inflammation and platelet function. Inherited deficiency and elevated levels are associated with atherosclerosis. Given potential common etiologies of atherosclerosis and venous thrombosis (VT), we hypothesized that low and high Lp-PLA2 would be associated with VT risk. Lp-PLA(2) mass and activity were measured in baseline samples of Cardiovascular Health Study participants (5,888 men and women age > or =65), excluding 354 reporting pre-baseline VT. The study endpoint was VT unrelated to cancer after 11.6 years follow-up. Hazard ratios were estimated using Cox proportional hazard models, adjusting for age, race, sex, and body-mass index. With 129 cases of VT, there was no association of Lp-PLA2 activity with risk. Adjusted hazard ratios were 1.19 (CI 0.62, 2.29) and 0.87 (CI 0.43, 1.76) for the lowest and highest decile, respectively, compared to the 10-25th percentile. Corresponding hazard ratios for Lp-PLA2 mass were 1.63 (CI 0.79, 3.34) and 1.33 (CI 0.61, 2.87). Results were robust to several definitions of low or high Lp-PLA2. While the association of Lp-PLA(2) levels with arterial disease events implies a role for this enzyme in atherogenesis, our findings suggest that it is not prothrombotic.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAged10aFemale10aHumans10aMale10aRisk Factors10aVenous Thrombosis1 aOlson, Nels1 aO'Meara, Ellen, S1 aJenny, Nancy, S1 aFolsom, Aaron, R1 aBovill, Edwin, G1 aFurberg, Curt, D1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aCushman, Mary uhttps://chs-nhlbi.org/node/102302767nas a2200397 4500008004100000022001400041245008700055210006900142260001300211300001100224490000700235520168000242653000901922653002201931653002501953653001901978653002201997653001302019653001102032653001102043653000902054653001502063653001702078653001802095653002202113100002802135700002402163700001902187700001802206700002102224700002002245700002102265700002402286700002302310856003602333 2008 eng d a1532-541500aThe relationship between exercise and risk of venous thrombosis in elderly people.0 arelationship between exercise and risk of venous thrombosis in e c2008 Mar a517-220 v563 aOBJECTIVES: To study whether exercise is associated with the risk of venous thrombosis in elderly people.
DESIGN: Observational study with a median follow-up of 11.6 years.
SETTING: The Cardiovascular Health Study in four U.S. communities.
PARTICIPANTS: People aged 65 and older without prior venous thrombosis (deep venous thrombosis or pulmonary embolism).
MEASUREMENTS: Self-reported exercise was measured two or three times during follow-up and was defined as expending more than 500 kcal/wk on exercise, including walking for exercise. Venous thrombosis cases were verified using medical record review.
RESULTS: Of 5,534 participants, 171 developed a first venous thrombosis. Self-reported exercise at baseline was not related to the risk of venous thrombosis after adjustment for sex, age, race, self-reported health, and body mass index (adjusted hazard ratio (HR(adj))=1.16, 95% confidence interval (CI)=0.84-1.61), although with exercise modeled as a time-varying exposure, overall results were in the direction of greater risk of venous thrombosis (HR(adj)=1.38, 95% CI=0.99-1.91). For mild-intensity exercise, such as walking, there was a nonsignificant finding in the direction of benefit (HR(adj)=0.75, 95% CI=0.49-1.16), but strenuous exercise, such as jogging, was associated with greater risk of venous thrombosis (HR(adj)=1.75, 95% CI=1.08-2.83) than no exercise at all.
CONCLUSION: In elderly people, strenuous exercise was associated with a higher risk of venous thrombosis than no exercise at all. Future studies are needed to explain this unexpected higher risk.
10aAged10aAged, 80 and over10aCase-Control Studies10aCohort Studies10aEnergy Metabolism10aExercise10aFemale10aHumans10aMale10aPrevalence10aRisk Factors10aUnited States10aVenous Thrombosis1 avan Stralen, Karlijn, J1 aDoggen, Carine, J M1 aLumley, Thomas1 aCushman, Mary1 aFolsom, Aaron, R1 aPsaty, Bruce, M1 aSiscovick, David1 aRosendaal, Frits, R1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/100703161nas a2200433 4500008004100000022001400041245017600055210006900231260001300300300001100313490000700324520179400331653000902125653002802134653002102162653001402183653001102197653002902208653001102237653002702248653004602275653002202321653001802343653000902361653003602370653003202406653002802438653003202466653001802498100001902516700002202535700002302557700002702580700002002607700001702627700002202644700002502666856003602691 2009 eng d a1880-387300aAssociation of genetic variation in serum amyloid-A with cardiovascular disease and interactions with IL6, IL1RN, IL1beta and TNF genes in the Cardiovascular Health Study.0 aAssociation of genetic variation in serum amyloidA with cardiova c2009 Aug a419-300 v163 aAIM: Since inflammation is an important contributor to atherosclerosis, gene variants mediating inflammation are of interest. We investigated gene variants in acute phase serum amyloid-A (SAA), a sensitive indicator of inflammatory activity, and their associations with cardiovascular disease (CVD) and HDL cholesterol. Interaction of the SAA genes with genetic variants of their regulators, IL-1, IL-6 and TNF-alpha in influencing CVD was also explored.
METHODS: SNPs characterizing common variation in the SAA1 and SAA2 genes were genotyped in European-(EA) and African-American (AA) participants (n=3969 and n=719) of the Cardiovascular Health Study. Using linear and Cox proportional hazards regression, we assessed associations of SNPs with baseline carotid artery intima-media thickness (cIMT) and risk of incident myocardial infarction, ischemic stroke, total CVD events or mortality during 14 years of follow-up.
RESULTS: No associations between SAA SNPs and outcomes were observed in EA, with the exception of total CVD events; each rs4638289 minor allele was associated with an increased risk in obese individuals, HR=1.2 (95%CI: 0.981.4; p=0.086) and decreased risk among non-obese, HR=0.9 (95%CI: 0.80.99; p=0.026). In AA, we observed modest associations between SAA SNPs and cIMT, potentially modified by HDL. SAA SNPs were also associated with lower HDL in EA and AA. Suggestive gene-gene interaction findings for cIMT in AA and CVD mortality in EA were not significant in subsequent model selection tests.
CONCLUSION: Associations of SAA SNPs with cIMT, HDL and total CVD events were identified, unadjusted for multiple testing. These findings should be regarded as hypothesis-generating until confirmed by other studies.
10aAged10aCardiovascular Diseases10aCholesterol, HDL10aCytokines10aFemale10aGene Regulatory Networks10aHumans10aInflammation Mediators10aInterleukin 1 Receptor Antagonist Protein10aInterleukin-1beta10aInterleukin-610aMale10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aSerum Amyloid A Protein10aTumor Necrosis Factor-alpha10aTunica Intima1 aCarty, Cara, L1 aHeagerty, Patrick1 aHeckbert, Susan, R1 aEnquobahrie, Daniel, A1 aJarvik, Gail, P1 aDavis, Scott1 aTracy, Russell, P1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/112602378nas a2200385 4500008004100000022001400041245014200055210006900197260001600266300001200282490000800294520128700302653000901589653002201598653002501620653001401645653001301659653001401672653001501686653001601701653001101717653001101728653002501739653000901764653001601773653001501789653002401804653001701828653002701845100001801872700002201890700002101912700002301933856003601956 2009 eng d a1528-002000aCoagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology.0 aCoagulation factors IX through XIII and the risk of future venou c2009 Oct 01 a2878-830 v1143 aHigher levels of procoagulant factors and factor XII deficiency may be risk factors for first venous thromboembolism (VTE). We studied associations of coagulation factors IX through XIII with risk of future VTE in 2 general population samples. Using a nested case-control study combining the 21 860 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study, we determined antigenic levels of these coagulation factors in primarily pre-event blood samples from 462 participants who subsequently developed VTE and 1047 participants who remained free of VTE. Only elevated levels of factors IX and XI were associated with increased risk of VTE after adjustment for age, sex, race, and study. For factor IX, the odds ratio (OR) was 1.4 (95% confidence interval [CI], 1.0-2.0) comparing the top to bottom quintile. The OR for factor XI was higher: 2.0 (95% CI, 1.4-2.9). With further adjustment for body mass index and diabetes, only elevated factor XI remained associated with VTE risk: OR 1.8 (95% CI, 1.3-2.7). Associations were similar by study and whether the thrombosis was idiopathic or secondary. Factor XII deficiency was not related to VTE risk. Among these procoagulant factors, only elevated factor XI was a risk factor for VTE.
10aAged10aAged, 80 and over10aCase-Control Studies10aFactor IX10aFactor X10aFactor XI10aFactor XII10aFactor XIII10aFemale10aHumans10aLongitudinal Studies10aMale10aMiddle Aged10aOdds Ratio10aProspective Studies10aRisk Factors10aVenous Thromboembolism1 aCushman, Mary1 aO'Meara, Ellen, S1 aFolsom, Aaron, R1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/111503137nas a2200673 4500008004100000022001400041245008300055210006900138260001300207300001200220490000700232520108000239653004101319653001001360653000901370653002501379653002301404653002701427653002701454653002701481653003701508653004001545653003801585653002201623653001801645653001101663653002801674653002701702653002001729653004001749653003601789653003801825653001701863653002001880100002901900700002201929700002101951700002501972700001701997700001902014700001902033700002302052700002602075700002502101700002202126700002302148700002202171700001702193700003002210700001902240700002302259700003002282700002802312700002002340700001902360700002202379700002602401856003602427 2009 eng d a1546-171800aCommon variants at ten loci influence QT interval duration in the QTGEN Study.0 aCommon variants at ten loci influence QT interval duration in th c2009 Apr a399-4060 v413 aQT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.
10aAdaptor Proteins, Signal Transducing10aAdult10aAged10aArrhythmias, Cardiac10aChromosome Mapping10aDeath, Sudden, Cardiac10aElectroencephalography10aERG1 Potassium Channel10aEther-A-Go-Go Potassium Channels10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenetic Variation10aGenome, Human10aHumans10aKCNQ1 Potassium Channel10aMeta-Analysis as Topic10aMuscle Proteins10aNAV1.5 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aPotassium Channels, Voltage-Gated10aRisk Factors10aSodium Channels1 aNewton-Cheh, Christopher1 aEijgelsheim, Mark1 aRice, Kenneth, M1 ade Bakker, Paul, I W1 aYin, Xiaoyan1 aEstrada, Karol1 aBis, Joshua, C1 aMarciante, Kristin1 aRivadeneira, Fernando1 aNoseworthy, Peter, A1 aSotoodehnia, Nona1 aSmith, Nicholas, L1 aRotter, Jerome, I1 aKors, Jan, A1 aWitteman, Jacqueline, C M1 aHofman, Albert1 aHeckbert, Susan, R1 aO'Donnell, Christopher, J1 aUitterlinden, André, G1 aPsaty, Bruce, M1 aLumley, Thomas1 aLarson, Martin, G1 aStricker, Bruno, H Ch uhttps://chs-nhlbi.org/node/108705728nas a2201213 4500008004100000022001400041245013400055210006900189260001600258300001100274490000800285520227000293653001002563653000902573653002202582653001002604653002802614653002102642653004002663653001102703653003402714653001302748653001602761653002102777653001102798653000902809653001602818653001502834653001402849653003602863653001702899653003402916653003102950100002702981700002203008700002103030700001903051700002103070700002203091700002303113700002203136700002303158700001903181700002303200700002003223700002203243700002203265700002203287700001903309700002403328700002003352700001803372700001803390700002303408700002103431700001903452700002603471700002203497700002403519700001803543700002003561700001503581700002703596700002703623700001703650700002303667700002103690700001803711700002103729700001703750700002003767700002003787700002303807700003003830700002303860700002303883700002103906700002503927700002603952700001703978700002203995700001804017700002104035700001904056700002404075700002804099700002204127700002004149700002004169700002004189700002004209700002304229700002204252700002204274700002104296700002404317700002204341700002804363700002404391700002004415700001904435700002404454856003604478 2009 eng d a1538-359800aGenetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.0 aGenetic variants associated with cardiac structure and function c2009 Jul 08 a168-780 v3023 aCONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.
OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.
DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.
MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.
RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).
CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
10aAdult10aAged10aAged, 80 and over10aAorta10aCardiovascular Diseases10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart Atria10aHeart Ventricles10aHumans10aMale10aMiddle Aged10aOrgan Size10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aVentricular Dysfunction, Left10aVentricular Function, Left1 aVasan, Ramachandran, S1 aGlazer, Nicole, L1 aFelix, Janine, F1 aLieb, Wolfgang1 aWild, Philipp, S1 aFelix, Stephan, B1 aWatzinger, Norbert1 aLarson, Martin, G1 aSmith, Nicholas, L1 aDehghan, Abbas1 aGrosshennig, Anika1 aSchillert, Arne1 aTeumer, Alexander1 aSchmidt, Reinhold1 aKathiresan, Sekar1 aLumley, Thomas1 aAulchenko, Yurii, S1 aKönig, Inke, R1 aZeller, Tanja1 aHomuth, Georg1 aStruchalin, Maksim1 aAragam, Jayashri1 aBis, Joshua, C1 aRivadeneira, Fernando1 aErdmann, Jeanette1 aSchnabel, Renate, B1 aDörr, Marcus1 aZweiker, Robert1 aLind, Lars1 aRodeheffer, Richard, J1 aGreiser, Karin, Halina1 aLevy, Daniel1 aHaritunians, Talin1 aDeckers, Jaap, W1 aStritzke, Jan1 aLackner, Karl, J1 aVölker, Uwe1 aIngelsson, Erik1 aKullo, Iftikhar1 aHaerting, Johannes1 aO'Donnell, Christopher, J1 aHeckbert, Susan, R1 aStricker, Bruno, H1 aZiegler, Andreas1 aReffelmann, Thorsten1 aRedfield, Margaret, M1 aWerdan, Karl1 aMitchell, Gary, F1 aRice, Kenneth1 aArnett, Donna, K1 aHofman, Albert1 aGottdiener, John, S1 aUitterlinden, André, G1 aMeitinger, Thomas1 aBlettner, Maria1 aFriedrich, Nele1 aWang, Thomas, J1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aWichmann, H-Erich1 aMunzel, Thomas, F1 aKroemer, Heyo, K1 aBenjamin, Emelia, J1 aRotter, Jerome, I1 aWitteman, Jacqueline, C1 aSchunkert, Heribert1 aSchmidt, Helena1 aVölzke, Henry1 aBlankenberg, Stefan uhttps://chs-nhlbi.org/node/110804313nas a2200889 4500008004100000022001400041245004600055210004500101260001600146300001200162490000800174520183800182653003902020653000902059653003202068653001902100653004002119653001102159653002002170653003802190653003402228653001302262653001102275653000902286653001602295653003602311653003202347653001702379653001102396100002002407700002002427700001902447700002002466700002402486700002402510700002302534700001902557700002102576700002802597700002002625700001802645700001802663700002202681700001702703700002302720700001702743700002202760700002302782700002602805700002602831700002002857700001802877700001902895700002102914700002302935700002402958700001602982700002302998700002003021700001803041700002303059700001703082700002303099700002003122700002303142700001903165700002803184700002203212700002103234700002003255700002203275700002303297700002703320700002003347700002003367856003603387 2009 eng d a1533-440600aGenomewide association studies of stroke.0 aGenomewide association studies of stroke c2009 Apr 23 a1718-280 v3603 aBACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.
METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.
RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.
CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.
10aAfrican Continental Ancestry Group10aAged10aChromosomes, Human, Pair 1210aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aRisk Factors10aStroke1 aIkram, Arfan, M1 aSeshadri, Sudha1 aBis, Joshua, C1 aFornage, Myriam1 aDeStefano, Anita, L1 aAulchenko, Yurii, S1 aDebette, Stephanie1 aLumley, Thomas1 aFolsom, Aaron, R1 avan den Herik, Evita, G1 aBos, Michiel, J1 aBeiser, Alexa1 aCushman, Mary1 aLauner, Lenore, J1 aShahar, Eyal1 aStruchalin, Maksim1 aDu, Yangchun1 aGlazer, Nicole, L1 aRosamond, Wayne, D1 aRivadeneira, Fernando1 aKelly-Hayes, Margaret1 aLopez, Oscar, L1 aCoresh, Josef1 aHofman, Albert1 aDeCarli, Charles1 aHeckbert, Susan, R1 aKoudstaal, Peter, J1 aYang, Qiong1 aSmith, Nicholas, L1 aKase, Carlos, S1 aRice, Kenneth1 aHaritunians, Talin1 aRoks, Gerwin1 ade Kort, Paul, L M1 aTaylor, Kent, D1 ade Lau, Lonneke, M1 aOostra, Ben, A1 aUitterlinden, André, G1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aMosley, Thomas, H1 aDuijn, Cornelia, M1 aBreteler, Monique, M B1 aLongstreth, W T1 aWolf, Philip, A uhttps://chs-nhlbi.org/node/109202372nas a2200373 4500008004100000022001400041245016100055210006900216260001300285300001000298490000800308520125300316653001701569653002501586653003501611653001101646653001301657653001101670653002001681653000901701653001601710653001501726653002601741653002401767653002801791653000901819653002701828100002401855700001801879700002301897700002101920700002101941856003601962 2009 eng d a1365-214100aLack of association of soluble endothelial protein C receptor and PROCR 6936A/G polymorphism with the risk of venous thromboembolism in a prospective study.0 aLack of association of soluble endothelial protein C receptor an c2009 Apr a221-60 v1453 aPrior case-control studies reported that levels of the soluble form of the endothelial protein C receptor (sEPCR) were strongly controlled by the PROCR 6963A/G polymorphism and higher levels were a risk factor for venous thromboembolism (VTE). We sought to prospectively examine the association of sEPCR and the 6963A/G polymorphism with the incidence of VTE. The Longitudinal Investigation of Thromboembolism Etiology (LITE) pooled data from the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) Study on men and women aged > or =45 years. A nested case-control study of 458 incident VTE and 1038 controls was performed. sEPCR levels were distributed trimodally according to 6963A/G polymorphism. Adjusting for age, sex and race, there was no overall association between sEPCR level and VTE: odds ratio (OR) [95% confidence interval] for highest versus lowest quartile = 1.17[0.86-1.59]. However, higher sEPCR was associated with VTE in non-whites (OR = 1.84[1.05-3.22]) and women (OR = 1.51[1.01-2.26]). The 6963A/G polymorphism was not associated with VTE risk (OR = 0.93[0.70-1.25]). In conclusion, sEPCR levels and the PROCR 6963A/G polymorphism were not associated overall with increased risk of VTE.
10aAntigens, CD10aCase-Control Studies10aEndothelial Protein C Receptor10aFemale10aGenotype10aHumans10aLogistic Models10aMale10aMiddle Aged10aOdds Ratio10aPolymorphism, Genetic10aProspective Studies10aReceptors, Cell Surface10aRisk10aVenous Thromboembolism1 aYamagishi, Kazumasa1 aCushman, Mary1 aHeckbert, Susan, R1 aTsai, Michael, Y1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/108002964nas a2200385 4500008004100000022001400041245014300055210006900198260001600267300001200283490000800295520179300303653000902096653002202105653002402127653001102151653001102162653001602173653002502189653000902214653003102223653002202254653003002276653001502306653003202321653001702353100002302370700002402393700002302417700002702440700002702467700002402494700002402518856003602542 2009 eng d a1524-453900aN-terminal pro-B-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the Cardiovascular Health Study.0 aNterminal proBtype natriuretic peptide is a major predictor of t c2009 Nov 03 a1768-740 v1203 aBACKGROUND: Atrial fibrillation (AF), the most common cardiac rhythm abnormality, is associated with significant morbidity, mortality, and healthcare expenditures. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure, AF, and mortality.
METHODS AND RESULTS: The relation between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and AF was studied in 5445 Cardiovascular Health Study participants with the use of relative risk regression for predicting prevalent AF and Cox proportional hazards for predicting incident AF. NT-proBNP levels were strongly associated with prevalent AF, with an unadjusted prevalence ratio of 128 for the highest quintile (95% confidence interval, 17.9 to 913.3; P<0.001) and adjusted prevalence ratio of 147 for the highest quintile (95% confidence interval, 20.4 to 1064.3; P<0.001) compared with the lowest. After a median follow-up of 10 years (maximum of 16 years), there were 1126 cases of incident AF (a rate of 2.2 per 100 person-years). NT-proBNP was highly predictive of incident AF, with an unadjusted hazard ratio of 5.2 (95% confidence interval, 4.3 to 6.4; P<0.001) for the development of AF for the highest quintile compared with the lowest; for the same contrast, NT-proBNP remained the strongest predictor of incident AF after adjustment for an extensive number of covariates, including age, sex, medication use, blood pressure, echocardiographic parameters, diabetes mellitus, and heart failure, with an adjusted hazard ratio of 4.0 (95% confidence interval, 3.2 to 5.0; P<0.001).
CONCLUSIONS: In a community-based population of older adults, NT-proBNP was a remarkable predictor of incident AF, independent of any other previously described risk factor.
10aAged10aAged, 80 and over10aAtrial Fibrillation10aFemale10aHumans10aImmunoassay10aLongitudinal Studies10aMale10aNatriuretic Peptide, Brain10aPeptide Fragments10aPredictive Value of Tests10aPrevalence10aProportional Hazards Models10aRisk Factors1 aPatton, Kristen, K1 aEllinor, Patrick, T1 aHeckbert, Susan, R1 aChristenson, Robert, H1 aDeFilippi, Christopher1 aGottdiener, John, S1 aKronmal, Richard, A uhttps://chs-nhlbi.org/node/113803278nas a2200937 4500008004100000022001400041245009900055210006900154260001300223300001100236490000700247520051100254653002400765653003200789653004000821653003800861653003400899653002500933653001100958653002700969653001300996653003601009653003101045100002401076700002101100700001901121700001801140700002501158700002101183700002401204700001901228700002101247700002201268700001901290700002201309700002501331700001901356700002001375700001801395700001901413700002901432700002201461700002601483700002401509700002601533700002001559700002401579700001701603700002001620700001201640700002701652700001901679700002701698700002201725700002201747700002001769700002201789700002601811700001301837700002201850700002301872700002601895700002801921700002001949700002201969700001901991700002302010700002202033700002102055700002002076700002302096700002202119700002402141700002302165700002402188700001902212700001902231700002402250700003002274856003602304 2009 eng d a1546-171800aVariants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.0 aVariants in ZFHX3 are associated with atrial fibrillation in ind c2009 Aug a879-810 v413 aWe conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).
10aAtrial Fibrillation10aChromosomes, Human, Pair 1610aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHomeodomain Proteins10aHumans10aMeta-Analysis as Topic10aMutation10aPolymorphism, Single Nucleotide10aReproducibility of Results1 aBenjamin, Emelia, J1 aRice, Kenneth, M1 aArking, Dan, E1 aPfeufer, Arne1 avan Noord, Charlotte1 aSmith, Albert, V1 aSchnabel, Renate, B1 aBis, Joshua, C1 aBoerwinkle, Eric1 aSinner, Moritz, F1 aDehghan, Abbas1 aLubitz, Steven, A1 aD'Agostino, Ralph, B1 aLumley, Thomas1 aEhret, Georg, B1 aHeeringa, Jan1 aAspelund, Thor1 aNewton-Cheh, Christopher1 aLarson, Martin, G1 aMarciante, Kristin, D1 aSoliman, Elsayed, Z1 aRivadeneira, Fernando1 aWang, Thomas, J1 aEiriksdottir, Gudny1 aLevy, Daniel1 aPsaty, Bruce, M1 aLi, Man1 aChamberlain, Alanna, M1 aHofman, Albert1 aVasan, Ramachandran, S1 aHarris, Tamara, B1 aRotter, Jerome, I1 aKao, Linda, W H1 aAgarwal, Sunil, K1 aStricker, Bruno, H Ch1 aWang, Ke1 aLauner, Lenore, J1 aSmith, Nicholas, L1 aChakravarti, Aravinda1 aUitterlinden, André, G1 aWolf, Philip, A1 aSotoodehnia, Nona1 aKöttgen, Anna1 aDuijn, Cornelia, M1 aMeitinger, Thomas1 aMueller, Martina1 aPerz, Siegfried1 aSteinbeck, Gerhard1 aWichmann, H-Erich1 aLunetta, Kathryn, L1 aHeckbert, Susan, R1 aGudnason, Vilmundur1 aAlonso, Alvaro1 aKääb, Stefan1 aEllinor, Patrick, T1 aWitteman, Jacqueline, C M uhttps://chs-nhlbi.org/node/111404239nas a2200781 4500008004100000022001400041245024400055210006900299260001300368300001100381490000600392520185900398653002202257653000902279653002202288653001902310653001902329653004002348653001102388653003402399653001802433653001102451653001402462653000902476653001602485653003602501653000902537653003302546100002302579700002102602700002402623700002302647700002202670700002002692700002502712700001902737700001902756700002302775700001902798700002602817700001902843700002102862700002102883700002402904700002302928700001802951700002102969700001802990700002303008700002403031700002303055700002003078700002103098700001903119700002303138700001803161700003003179700002803209700002203237700002403259700001703283700002303300700002003323700003003343700002103373700002703394856003603421 2010 eng d a1942-326800aAssociation of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.0 aAssociation of genomewide variation with the risk of incident he c2010 Jun a256-660 v33 aBACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.
METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.
CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.
10aAfrican Americans10aAged10aAged, 80 and over10aCohort Studies10aEndopeptidases10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHeart Failure10aHumans10aIncidence10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk10aUbiquitin-Specific Proteases1 aSmith, Nicholas, L1 aFelix, Janine, F1 aMorrison, Alanna, C1 aDemissie, Serkalem1 aGlazer, Nicole, L1 aLoehr, Laura, R1 aCupples, Adrienne, L1 aDehghan, Abbas1 aLumley, Thomas1 aRosamond, Wayne, D1 aLieb, Wolfgang1 aRivadeneira, Fernando1 aBis, Joshua, C1 aFolsom, Aaron, R1 aBenjamin, Emelia1 aAulchenko, Yurii, S1 aHaritunians, Talin1 aCouper, David1 aMurabito, Joanne1 aWang, Ying, A1 aStricker, Bruno, H1 aGottdiener, John, S1 aChang, Patricia, P1 aWang, Thomas, J1 aRice, Kenneth, M1 aHofman, Albert1 aHeckbert, Susan, R1 aFox, Ervin, R1 aO'Donnell, Christopher, J1 aUitterlinden, André, G1 aRotter, Jerome, I1 aWillerson, James, T1 aLevy, Daniel1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aWitteman, Jacqueline, C M1 aBoerwinkle, Eric1 aVasan, Ramachandran, S uhttps://chs-nhlbi.org/node/119704142nas a2200757 4500008004100000022001400041245008700055210006900142260001300211300001100224490000600235520194100241653002202182653002102204653002102225653001902246653002302265653004002288653003202328653001302360653001102373653001402384653001902398653003602417653002002453653001802473100002002491700002202511700001802533700002302551700002602574700002202600700002402622700001602646700002002662700001802682700002102700700001902721700002202740700002402762700002502786700002002811700001802831700002302849700002402872700002902896700002302925700002002948700002802968700002102996700002003017700002103037700001903058700002103077700002203098700002203120700002203142700002703164700002103191700002203212700002403234700002103258700002303279710004603302856003603348 2010 eng d a1942-326800aCandidate gene association resource (CARe): design, methods, and proof of concept.0 aCandidate gene association resource CARe design methods and proo c2010 Jun a267-750 v33 aBACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.
METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.
CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.
10aAfrican Americans10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aDatabases, Genetic10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenotype10aHumans10aPhenotype10aPilot Projects10aPolymorphism, Single Nucleotide10aResearch Design10aTriglycerides1 aMusunuru, Kiran1 aLettre, Guillaume1 aYoung, Taylor1 aFarlow, Deborah, N1 aPirruccello, James, P1 aEjebe, Kenechi, G1 aKeating, Brendan, J1 aYang, Qiong1 aChen, Ming-Huei1 aLapchyk, Nina1 aCrenshaw, Andrew1 aZiaugra, Liuda1 aRachupka, Anthony1 aBenjamin, Emelia, J1 aCupples, Adrienne, L1 aFornage, Myriam1 aFox, Ervin, R1 aHeckbert, Susan, R1 aHirschhorn, Joel, N1 aNewton-Cheh, Christopher1 aNizzari, Marcia, M1 aPaltoo, Dina, N1 aPapanicolaou, George, J1 aPatel, Sanjay, R1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRedline, Susan1 aRich, Stephen, S1 aRotter, Jerome, I1 aTaylor, Herman, A1 aTracy, Russell, P1 aVasan, Ramachandran, S1 aWilson, James, G1 aKathiresan, Sekar1 aFabsitz, Richard, R1 aBoerwinkle, Eric1 aGabriel, Stacey, B1 aNHLBI Candidate Gene Association Resource uhttps://chs-nhlbi.org/node/118805521nas a2201561 4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520109100256653001201347653002101359653002301380653002601403653002401429653001701453653003401470653002801504653001101532653000901543653002101552653001901573653002201592653004001614653003601654653002001690100002201710700001801732700002501750700001801775700002901793700001901822700001501841700002101856700002201877700001901899700002101918700002501939700002201964700002601986700001902012700002302031700001702054700002202071700002602093700001802119700002002137700002202157700001202179700001902191700002602210700001902236700001902255700001802274700001802292700001902310700001802329700001802347700002702365700001902392700002402411700001902435700001702454700002002471700002702491700001702518700002602535700002202561700001702583700002302600700002202623700002402645700002402669700002002693700001902713700002502732700002002757700002302777700002802800700001902828700002402847700001702871700002102888700002402909700002202933700002002955700001702975700002202992700001903014700003003033700002103063700002003084700002303104700002203127700001903149700002003168700002103188700002803209700002903237700003003266700002603296700002303322700002103345700001903366700001603385700001703401700002603418700002403444700002203468700002203490700002903512700002003541700002003561700001803581700001603599700002003615700002103635700002603656700002403682700002003706700002403726700002303750700002203773700002203795700002003817700002603837700002203863700001903885700001903904856003603923 2010 eng d a1546-171800aCommon variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.0 aCommon variants in 22 loci are associated with QRS duration and c2010 Dec a1068-760 v423 aThe QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
10aAnimals10aAnimals, Newborn10aChromosomes, Human10aComputational Biology10aElectrocardiography10aGenetic Loci10aGenome-Wide Association Study10aHeart Conduction System10aHumans10aMice10aMice, Transgenic10aModels, Animal10aMyocytes, Cardiac10aNAV1.8 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aSodium Channels1 aSotoodehnia, Nona1 aIsaacs, Aaron1 ade Bakker, Paul, I W1 aDörr, Marcus1 aNewton-Cheh, Christopher1 aNolte, Ilja, M1 aHarst, Pim1 aMüller, Martina1 aEijgelsheim, Mark1 aAlonso, Alvaro1 aHicks, Andrew, A1 aPadmanabhan, Sandosh1 aHayward, Caroline1 aSmith, Albert, Vernon1 aPolasek, Ozren1 aGiovannone, Steven1 aFu, Jingyuan1 aMagnani, Jared, W1 aMarciante, Kristin, D1 aPfeufer, Arne1 aGharib, Sina, A1 aTeumer, Alexander1 aLi, Man1 aBis, Joshua, C1 aRivadeneira, Fernando1 aAspelund, Thor1 aKöttgen, Anna1 aJohnson, Toby1 aRice, Kenneth1 aSie, Mark, P S1 aWang, Ying, A1 aKlopp, Norman1 aFuchsberger, Christian1 aWild, Sarah, H1 aLeach, Irene, Mateo1 aEstrada, Karol1 aVölker, Uwe1 aWright, Alan, F1 aAsselbergs, Folkert, W1 aQu, Jiaxiang1 aChakravarti, Aravinda1 aSinner, Moritz, F1 aKors, Jan, A1 aPetersmann, Astrid1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aOostra, Ben, A1 aCupples, Adrienne, L1 aPerz, Siegfried1 ade Boer, Rudolf, A1 aUitterlinden, André, G1 aVölzke, Henry1 aSpector, Timothy, D1 aLiu, Fang-Yu1 aBoerwinkle, Eric1 aDominiczak, Anna, F1 aRotter, Jerome, I1 avan Herpen, Gé1 aLevy, Daniel1 aWichmann, H-Erich1 aGilst, Wiek, H1 aWitteman, Jacqueline, C M1 aKroemer, Heyo, K1 aKao, Linda, W H1 aHeckbert, Susan, R1 aMeitinger, Thomas1 aHofman, Albert1 aCampbell, Harry1 aFolsom, Aaron, R1 avan Veldhuisen, Dirk, J1 aSchwienbacher, Christine1 aO'Donnell, Christopher, J1 aVolpato, Claudia, Beu1 aCaulfield, Mark, J1 aConnell, John, M1 aLauner, Lenore1 aLu, Xiaowen1 aFranke, Lude1 aFehrmann, Rudolf, S N1 aMeerman, Gerard, te1 aGroen, Harry, J M1 aWeersma, Rinse, K1 avan den Berg, Leonard, H1 aWijmenga, Cisca1 aOphoff, Roel, A1 aNavis, Gerjan1 aRudan, Igor1 aSnieder, Harold1 aWilson, James, F1 aPramstaller, Peter, P1 aSiscovick, David, S1 aWang, Thomas, J1 aGudnason, Vilmundur1 aDuijn, Cornelia, M1 aFelix, Stephan, B1 aFishman, Glenn, I1 aJamshidi, Yalda1 aStricker, Bruno, H Ch1 aSamani, Nilesh, J1 aKääb, Stefan1 aArking, Dan, E uhttps://chs-nhlbi.org/node/124404063nas a2201069 4500008004100000022001400041245007500055210006900130260001300199300001000212490000700222520107100229653001501300653001001315653000901325653002401334653002501358653001901383653001101402653003401413653001101447653001201458653000901470653002701479653001601506653003601522653005901558653001601617100002401633700002401657700002201681700001801703700001901721700001901740700002201759700002501781700002101806700002201827700001501849700001901864700002301883700002301906700002401929700002401953700002101977700002601998700002202024700002502046700001302071700002002084700002202104700002202126700002302148700002102171700002202192700002202214700001802236700001602254700002002270700002002290700001602310700001902326700002002345700002902365700001202394700002402406700002002430700002002450700002702470700002302497700002102520700002602541700001902567700002802586700001702614700002102631700002102652700001902673700002602692700002402718700002002742700001802762700002202780700002202802700003002824700001802854700001902872700002402891700002302915700001902938856003602957 2010 eng d a1546-171800aCommon variants in KCNN3 are associated with lone atrial fibrillation.0 aCommon variants in KCNN3 are associated with lone atrial fibrill c2010 Mar a240-40 v423 aAtrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.
10aAdolescent10aAdult10aAged10aAtrial Fibrillation10aCase-Control Studies10aCohort Studies10aFemale10aGenome-Wide Association Study10aHumans10aIntrons10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aSmall-Conductance Calcium-Activated Potassium Channels10aYoung Adult1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aGlazer, Nicole, L1 aPfeufer, Arne1 aAlonso, Alvaro1 aChung, Mina, K1 aSinner, Moritz, F1 ade Bakker, Paul, I W1 aMueller, Martina1 aLubitz, Steven, A1 aFox, Ervin1 aDarbar, Dawood1 aSmith, Nicholas, L1 aSmith, Jonathan, D1 aSchnabel, Renate, B1 aSoliman, Elsayed, Z1 aRice, Kenneth, M1 aVan Wagoner, David, R1 aBeckmann, Britt-M1 avan Noord, Charlotte1 aWang, Ke1 aEhret, Georg, B1 aRotter, Jerome, I1 aHazen, Stanley, L1 aSteinbeck, Gerhard1 aSmith, Albert, V1 aLauner, Lenore, J1 aHarris, Tamara, B1 aMakino, Seiko1 aNelis, Mari1 aMilan, David, J1 aPerz, Siegfried1 aEsko, Tõnu1 aKöttgen, Anna1 aMoebus, Susanne1 aNewton-Cheh, Christopher1 aLi, Man1 aMöhlenkamp, Stefan1 aWang, Thomas, J1 aKao, Linda, W H1 aVasan, Ramachandran, S1 aNöthen, Markus, M1 aMacRae, Calum, A1 aStricker, Bruno, H Ch1 aHofman, Albert1 aUitterlinden, André, G1 aLevy, Daniel1 aBoerwinkle, Eric1 aMetspalu, Andres1 aTopol, Eric, J1 aChakravarti, Aravinda1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aRoden, Dan, M1 aMeitinger, Thomas1 aWichmann, H-Erich1 aWitteman, Jacqueline, C M1 aBarnard, John1 aArking, Dan, E1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aKääb, Stefan uhttps://chs-nhlbi.org/node/117003170nas a2200481 4500008004100000022001400041245008500055210006900140260001600209300001200225490000800237520177400245653002202019653000902041653002402050653004002074653001102114653003402125653001102159653000902170653001602179653001702195100002302212700001902235700002302254700002202277700002202299700002202321700001802343700002402361700001702385700002202402700001502424700002202439700002302461700002402484700002002508700002402528700002402552700002302576710005302599856003602652 2010 eng d a1524-453900aEuropean ancestry as a risk factor for atrial fibrillation in African Americans.0 aEuropean ancestry as a risk factor for atrial fibrillation in Af c2010 Nov 16 a2009-150 v1223 aBACKGROUND: Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown whether the higher risk is due to genetic or environmental factors. Because African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF.
METHODS AND RESULTS: We studied whites (n=4543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10 902) and African Americans (n=3517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3517). Percent European ancestry in African Americans was estimated with 1747 ancestry informative markers from the Illumina custom ITMAT-Broad-CARe array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3517 ARIC participants developed incident AF. A meta-analysis from the 2 studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (hazard ratio, 1.13; 95% confidence interval, 1.03 to 1.23; P=0.007). After adjustment for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% confidence interval, 1.07 to 1.29; P=0.001). A second analysis using 3192 ancestry informative markers from a genome-wide Affymetrix 6.0 array in ARIC African Americans yielded similar results.
CONCLUSIONS: European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative.
10aAfrican Americans10aAged10aAtrial Fibrillation10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aRisk Factors1 aMarcus, Gregory, M1 aAlonso, Alvaro1 aPeralta, Carmen, A1 aLettre, Guillaume1 aVittinghoff, Eric1 aLubitz, Steven, A1 aFox, Ervin, R1 aLevitzky, Yamini, S1 aMehra, Reena1 aKerr, Kathleen, F1 aDeo, Rajat1 aSotoodehnia, Nona1 aAkylbekova, Meggie1 aEllinor, Patrick, T1 aPaltoo, Dina, N1 aSoliman, Elsayed, Z1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aCandidate-Gene Association Resource (CARe) Study uhttps://chs-nhlbi.org/node/124805209nas a2201129 4500008004100000022001400041245009100055210006900146260001600215300001300231490000600244520200900250653001502259653001002274653000902284653002202293653002802315653001002343653002102353653003202374653003202406653003102438653003102469653001902500653004002519653001102559653001702570653003402587653001102621653000902632653002702641653002102668653001602689653003602705653002002741653001602761100001802777700001702795700001702812700002302829700002502852700002002877700002002897700001902917700001802936700002402954700002702978700001703005700001703022700001903039700002803058700002603086700001903112700002703131700002303158700001503181700002003196700002603216700002203242700001903264700002203283700002003305700002303325700002403348700001903372700002203391700002203413700002003435700001603455700002203471700001803493700002603511700002103537700002203558700002403580700002003604700001703624700002203641700002303663700002803686700001703714700001903731700001603750700002703766700002103793700002303814700002203837700002203859700002103881700001903902700002403921700002403945700002803969700001803997710002804015856003604043 2010 eng d a1553-740400aFour novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.0 aFour novel Loci 19q13 6q24 12q24 and 5q14 influence the microcir c2010 Oct 28 ae10011840 v63 aThere is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aCardiovascular Diseases10aChild10aChild, Preschool10aChromosomes, Human, Pair 1210aChromosomes, Human, Pair 1910aChromosomes, Human, Pair 510aChromosomes, Human, Pair 610aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMicrocirculation10aMiddle Aged10aPolymorphism, Single Nucleotide10aRetinal Vessels10aYoung Adult1 aIkram, Kamran1 aSim, Xueling1 aXueling, Sim1 aJensen, Richard, A1 aCotch, Mary, Frances1 aHewitt, Alex, W1 aIkram, Arfan, M1 aWang, Jie, Jin1 aKlein, Ronald1 aKlein, Barbara, E K1 aBreteler, Monique, M B1 aCheung, Ning1 aLiew, Gerald1 aMitchell, Paul1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aHofman, Albert1 ade Jong, Paulus, T V M1 aDuijn, Cornelia, M1 aKao, Linda1 aCheng, Ching-Yu1 aSmith, Albert, Vernon1 aGlazer, Nicole, L1 aLumley, Thomas1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aJonasson, Fridbert1 aEiriksdottir, Gudny1 aAspelund, Thor1 aHarris, Tamara, B1 aLauner, Lenore, J1 aTaylor, Kent, D1 aLi, Xiaohui1 aIyengar, Sudha, K1 aXi, Quansheng1 aSivakumaran, Theru, A1 aMackey, David, A1 aMacgregor, Stuart1 aMartin, Nicholas, G1 aYoung, Terri, L1 aBis, Josh, C1 aWiggins, Kerri, L1 aHeckbert, Susan, R1 aHammond, Christopher, J1 aAndrew, Toby1 aFahy, Samantha1 aAttia, John1 aHolliday, Elizabeth, G1 aScott, Rodney, J1 aIslam, F, M Amirul1 aRotter, Jerome, I1 aMcAuley, Annie, K1 aBoerwinkle, Eric1 aTai, Shyong, E1 aGudnason, Vilmundur1 aSiscovick, David, S1 aVingerling, Johannes, R1 aWong, Tien, Y1 aGlobal BPgen Consortium uhttps://chs-nhlbi.org/node/124305113nas a2201189 4500008004100000022001400041245009300055210006900148260001600217300001200233490000700245520181400252653001002066653000902076653001702085653001902102653001102121653001702132653001802149653003402167653001502201653001102216653000902227653001602236653003602252653000902288100002202297700002902319700002202348700002502370700002102395700002402416700002102440700001802461700001802479700001802497700001702515700002702532700001902559700001902578700001902597700002002616700001902636700002402655700001902679700002202698700002402720700002602744700002502770700002102795700002002816700001902836700002002855700001702875700002402892700002302916700001802939700001902957700001902976700002202995700002303017700002303040700001903063700002203082700002103104700001903125700002103144700002003165700002003185700001803205700001903223700002103242700001803263700001903281700002003300700002203320700001703342700003003359700002003389700002203409700002203431700001903453700002403472700002003496700002803516700002103544700002203565700002103587700002303608700002003631700002603651700002303677700002303700700002203723700002403745700001803769700002303787700002603810700002103836700003003857856003603887 2010 eng d a1460-208300aGenome-wide association analysis identifies multiple loci related to resting heart rate.0 aGenomewide association analysis identifies multiple loci related c2010 Oct 01 a3885-940 v193 aHigher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.
10aAdult10aAged10aBase Pairing10aCohort Studies10aFemale10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHeart Rate10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRest1 aEijgelsheim, Mark1 aNewton-Cheh, Christopher1 aSotoodehnia, Nona1 ade Bakker, Paul, I W1 aMüller, Martina1 aMorrison, Alanna, C1 aSmith, Albert, V1 aIsaacs, Aaron1 aSanna, Serena1 aDörr, Marcus1 aNavarro, Pau1 aFuchsberger, Christian1 aNolte, Ilja, M1 aGeus, Eco, J C1 aEstrada, Karol1 aHwang, Shih-Jen1 aBis, Joshua, C1 aRückert, Ina-Maria1 aAlonso, Alvaro1 aLauner, Lenore, J1 aHottenga, Jouke Jan1 aRivadeneira, Fernando1 aNoseworthy, Peter, A1 aRice, Kenneth, M1 aPerz, Siegfried1 aArking, Dan, E1 aSpector, Tim, D1 aKors, Jan, A1 aAulchenko, Yurii, S1 aTarasov, Kirill, V1 aHomuth, Georg1 aWild, Sarah, H1 aMarroni, Fabio1 aGieger, Christian1 aLicht, Carmilla, M1 aPrineas, Ronald, J1 aHofman, Albert1 aRotter, Jerome, I1 aHicks, Andrew, A1 aErnst, Florian1 aNajjar, Samer, S1 aWright, Alan, F1 aPeters, Annette1 aFox, Ervin, R1 aOostra, Ben, A1 aKroemer, Heyo, K1 aCouper, David1 aVölzke, Henry1 aCampbell, Harry1 aMeitinger, Thomas1 aUda, Manuela1 aWitteman, Jacqueline, C M1 aPsaty, Bruce, M1 aWichmann, H-Erich1 aHarris, Tamara, B1 aKääb, Stefan1 aSiscovick, David, S1 aJamshidi, Yalda1 aUitterlinden, André, G1 aFolsom, Aaron, R1 aLarson, Martin, G1 aWilson, James, F1 aPenninx, Brenda, W1 aSnieder, Harold1 aPramstaller, Peter, P1 aDuijn, Cornelia, M1 aLakatta, Edward, G1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aPfeufer, Arne1 aHeckbert, Susan, R1 aStricker, Bruno, H Ch1 aBoerwinkle, Eric1 aO'Donnell, Christopher, J uhttps://chs-nhlbi.org/node/121704951nas a2201009 4500008004100000022001400041245010900055210006900164260001300233300001000246490000700256520207300263653002202336653000902358653001002367653002102377653001902398653002802417653001102445653001902456653002002475653003802495653002002533653002202553653003402575653001102609653002702620653003102647653000902678653001602687653003602703653002402739100002302763700001902786700002002805700002002825700002002845700002502865700001902890700002302909700002102932700002202953700002102975700001902996700002203015700002403037700002403061700002403085700002403109700002003133700002003153700002403173700001903197700001903216700002403235700001803259700002203277700002403299700002103323700002103344700002203365700002603387700002103413700001803434700002603452700002403478700002803502700002603530700001803556700001703574700002103591700002403612700001903636700002003655700001703675700002303692700001403715700002303729700002003752700002203772700002003794700002703814700002203841700002203863700002003885856003603905 2010 eng d a1524-462800aGenome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.0 aGenomewide association studies of MRIdefined brain infarcts meta c2010 Feb a210-70 v413 aBACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).
RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.
CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.
10aAfrican Americans10aAged10aBrain10aBrain Infarction10aCohort Studies10aDNA Mutational Analysis10aFemale10aGene Frequency10aGenetic Markers10aGenetic Predisposition to Disease10aGenetic Testing10aGenetic Variation10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProspective Studies1 aDebette, Stephanie1 aBis, Joshua, C1 aFornage, Myriam1 aSchmidt, Helena1 aIkram, Arfan, M1 aSigurdsson, Sigurdur1 aHeiss, Gerardo1 aStruchalin, Maksim1 aSmith, Albert, V1 avan der Lugt, Aad1 aDeCarli, Charles1 aLumley, Thomas1 aKnopman, David, S1 aEnzinger, Christian1 aEiriksdottir, Gudny1 aKoudstaal, Peter, J1 aDeStefano, Anita, L1 aPsaty, Bruce, M1 aDufouil, Carole1 aCatellier, Diane, J1 aFazekas, Franz1 aAspelund, Thor1 aAulchenko, Yurii, S1 aBeiser, Alexa1 aRotter, Jerome, I1 aTzourio, Christophe1 aShibata, Dean, K1 aTscherner, Maria1 aHarris, Tamara, B1 aRivadeneira, Fernando1 aAtwood, Larry, D1 aRice, Kenneth1 aGottesman, Rebecca, F1 avan Buchem, Mark, A1 aUitterlinden, André, G1 aKelly-Hayes, Margaret1 aCushman, Mary1 aZhu, Yicheng1 aBoerwinkle, Eric1 aGudnason, Vilmundur1 aHofman, Albert1 aRomero, Jose, R1 aLopez, Oscar1 aDuijn, Cornelia, M1 aAu, Rhoda1 aHeckbert, Susan, R1 aWolf, Philip, A1 aMosley, Thomas, H1 aSeshadri, Sudha1 aBreteler, Monique, M B1 aSchmidt, Reinhold1 aLauner, Lenore, J1 aLongstreth, W T uhttps://chs-nhlbi.org/node/115604048nas a2201057 4500008004100000022001400041245005000055210004800105260001300153300001000166490000700176520109100183653000901274653002401283653001901307653002401326653001101350653001701361653003801378653003401416653002801450653001101478653000901489653002701498100001801525700002501543700002601568700001901594700002201613700002601635700002301661700002101684700002201705700002201727700002601749700001201775700002001787700001901807700001801826700001901844700002001863700001801883700002201901700002601923700001901949700001701968700002501985700002802010700002302038700002302061700001902084700002202103700002202125700002902147700002002176700002202196700002402218700001902242700001802261700002302279700002602302700002702328700001902355700002402374700002202398700002202420700002102442700002002463700002402483700001702507700002502524700002802549700002002577700002102597700002602618700002402644700002402668700002002692700002202712700002202734700001702756700002402773700002402797700001802821700001902839700003002858700001902888700002402907700002302931856003602954 2010 eng d a1546-171800aGenome-wide association study of PR interval.0 aGenomewide association study of PR interval c2010 Feb a153-90 v423 aThe electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.
10aAged10aAtrial Fibrillation10aCohort Studies10aElectrocardiography10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHeart Conduction System10aHumans10aMale10aMeta-Analysis as Topic1 aPfeufer, Arne1 avan Noord, Charlotte1 aMarciante, Kristin, D1 aArking, Dan, E1 aLarson, Martin, G1 aSmith, Albert, Vernon1 aTarasov, Kirill, V1 aMüller, Martina1 aSotoodehnia, Nona1 aSinner, Moritz, F1 aVerwoert, Germaine, C1 aLi, Man1 aKao, Linda, W H1 aKöttgen, Anna1 aCoresh, Josef1 aBis, Joshua, C1 aPsaty, Bruce, M1 aRice, Kenneth1 aRotter, Jerome, I1 aRivadeneira, Fernando1 aHofman, Albert1 aKors, Jan, A1 aStricker, Bruno, H C1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aBeckmann, Britt, M1 aSauter, Wiebke1 aGieger, Christian1 aLubitz, Steven, A1 aNewton-Cheh, Christopher1 aWang, Thomas, J1 aMagnani, Jared, W1 aSchnabel, Renate, B1 aChung, Mina, K1 aBarnard, John1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aVasan, Ramachandran, S1 aAspelund, Thor1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aLauner, Lenore, J1 aNajjar, Samer, S1 aLakatta, Edward1 aSchlessinger, David1 aUda, Manuela1 aAbecasis, Goncalo, R1 aMüller-Myhsok, Bertram1 aEhret, Georg, B1 aBoerwinkle, Eric1 aChakravarti, Aravinda1 aSoliman, Elsayed, Z1 aLunetta, Kathryn, L1 aPerz, Siegfried1 aWichmann, H-Erich1 aMeitinger, Thomas1 aLevy, Daniel1 aGudnason, Vilmundur1 aEllinor, Patrick, T1 aSanna, Serena1 aKääb, Stefan1 aWitteman, Jacqueline, C M1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/115903706nas a2200685 4500008004100000022001400041245008300055210006900138260001600207300001100223490000800234520175600242653000901998653002202007653002402029653002302053653003102076653004002107653001102147653002002158653003802178653001502216653001102231653000902242653001602251653003602267653001702303100002202320700002202342700002402364700001802388700001802406700002002424700002502444700001802469700001902487700002202506700001902528700002002547700002402567700002002591700002102611700002002632700002502652700002002677700002502697700002102722700002502743700002502768700002302793700001902816700002302835700002402858700002102882700001902903700001902922700001902941700002402960856003602984 2010 eng d a1524-453900aIndependent susceptibility markers for atrial fibrillation on chromosome 4q25.0 aIndependent susceptibility markers for atrial fibrillation on ch c2010 Sep 07 a976-840 v1223 aBACKGROUND: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus.
METHODS AND RESULTS: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals.
CONCLUSIONS: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.
10aAged10aAged, 80 and over10aAtrial Fibrillation10aChromosome Mapping10aChromosomes, Human, Pair 410aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aLubitz, Steven, A1 aSinner, Moritz, F1 aLunetta, Kathryn, L1 aMakino, Seiko1 aPfeufer, Arne1 aRahman, Rosanna1 aVeltman, Caroline, E1 aBarnard, John1 aBis, Joshua, C1 aDanik, Stephan, P1 aSonni, Akshata1 aShea, Marisa, A1 aDel Monte, Federica1 aPerz, Siegfried1 aMüller, Martina1 aPeters, Annette1 aGreenberg, Steven, M1 aFurie, Karen, L1 avan Noord, Charlotte1 aBoerwinkle, Eric1 aStricker, Bruno, H C1 aWitteman, Jacqueline1 aSmith, Jonathan, D1 aChung, Mina, K1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aRosand, Jonathan1 aArking, Dan, E1 aAlonso, Alvaro1 aKääb, Stefan1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/122602729nas a2200409 4500008004100000022001400041245014700055210006900202260001300271300000900284490000700293520152600300653000901826653002801835653002101863653001101884653001501895653003801910653002201948653001101970653001801981653000901999653002302008653002602031653003602057653000902093653001102102100001902113700002202132700002302154700002002177700002102197700001802218700002202236700002502258856003602283 2010 eng d a1469-180900aInteraction between fibrinogen and IL-6 genetic variants and associations with cardiovascular disease risk in the Cardiovascular Health Study.0 aInteraction between fibrinogen and IL6 genetic variants and asso c2010 Jan a1-100 v743 aThe inflammatory cytokine interleukin-6 (IL-6) is a main regulator of fibrinogen synthesis, though its interaction with fibrinogen genes (FGA, FGB, FGG) and subsequent impact on cardiovascular disease (CVD) risk is not well-studied. We investigated joint associations of fibrinogen and IL6 tagSNPs with fibrinogen concentrations, carotid intima-media thickness, and myocardial infarction or ischemic stroke in 3900 European-American Cardiovascular Health Study participants. To identify combinations of genetic main effects and interactions associated with outcomes, we used logic regression. We also evaluated whether the relationship between fibrinogen SNPs and fibrinogen level varied by IL-6 level using linear regression models with multiplicative interaction terms. Combinations of fibrinogen and IL6 SNPs were significantly associated with fibrinogen level (p < 0.005), but not with other outcomes. Fibrinogen levels were higher in individuals having FGB1437 (rs1800790) and lacking FGA6534 (rs6050) minor alleles; these SNPs interacted with IL6 rs1800796 to influence fibrinogen level. Marginally significant (p= 0.03) interactions between IL-6 level and FGA and FGG promoter SNPs associated with fibrinogen levels were detected. We identified potential gene-gene interactions influencing fibrinogen levels. Although IL-6 responsive binding sites are present in fibrinogen gene promoter regions, we did not find strong evidence of interaction between fibrinogen SNPs and IL6 SNPs or levels influencing CVD.
10aAged10aCardiovascular Diseases10aCarotid Arteries10aFemale10aFibrinogen10aGenetic Predisposition to Disease10aGenetic Variation10aHumans10aInterleukin-610aMale10aModels, Biological10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aRisk10aStroke1 aCarty, Cara, L1 aHeagerty, Patrick1 aHeckbert, Susan, R1 aJarvik, Gail, P1 aLange, Leslie, A1 aCushman, Mary1 aTracy, Russell, P1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/115802822nas a2200637 4500008004100000022001400041245011200055210006900167260001300236300001000249490000700259520095900266653002301225653001101248653002901259653003801288653001801326653003401344653001101378653000901389653001801398653000901416653002701425653003601452653001501488653001901503100002101522700002201543700001901565700002001584700002001604700002601624700002301650700003001673700001901703700001701722700002501739700002101764700002201785700002001807700002301827700002201850700002801872700001901900700002301919700002601942700002401968700002101992700001902013700002302032700001902055700002502074700002402099700002502123856003602148 2010 eng d a1546-171800aMeta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.0 aMetaanalyses of genomewide association studies identify multiple c2010 Jan a45-520 v423 aSpirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.
10aDatabases, Genetic10aFemale10aForced Expiratory Volume10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLung10aLung Diseases10aMale10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aSpirometry10aVital Capacity1 aHancock, Dana, B1 aEijgelsheim, Mark1 aWilk, Jemma, B1 aGharib, Sina, A1 aLoehr, Laura, R1 aMarciante, Kristin, D1 aFranceschini, Nora1 avan Durme, Yannick, M T A1 aChen, Ting-Hsu1 aBarr, Graham1 aSchabath, Matthew, B1 aCouper, David, J1 aBrusselle, Guy, G1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aRotter, Jerome, I1 aUitterlinden, André, G1 aHofman, Albert1 aPunjabi, Naresh, M1 aRivadeneira, Fernando1 aMorrison, Alanna, C1 aEnright, Paul, L1 aNorth, Kari, E1 aHeckbert, Susan, R1 aLumley, Thomas1 aStricker, Bruno, H C1 aO'Connor, George, T1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/115002515nas a2200373 4500008004100000022001400041245014800055210006900203260001300272300001100285490000800296520142800304653001601732653000901748653002601757653003301783653001101816653001101827653000901838653001601847653001101863653001401874653002501888653001801913653002701931100001901958700002101977700001801998700002202016700002102038700002302059700002302082856003602105 2010 eng d a1365-214100aReproductive history, hormone replacement, and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology.0 aReproductive history hormone replacement and incidence of venous c2010 May a606-120 v1493 aNumerous studies have established that hormone replacement therapy increases the risk of venous thromboembolism (VTE), but an association of endogenous oestrogen exposure with the incidence of VTE is not fully established. Using a prospective design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, we studied the 12-year risk of VTE in relation to hormone replacement therapy use, age at menopause, parity number, and type of menopause in 8236 post-menopausal women. There were no significant associations of age at menopause, parity number, or type of menopause with incidence of VTE. Women currently using hormone replacement had a 1.6-times higher multivariate-adjusted rate ratio (RR) of VTE compared with those without hormone use in the time-dependent model (RR=1.60, 95% confidence interval [CI], 1.06-2.36; Population attributable fraction=6.7%, 95%CI, 1.0-10.3). When we excluded women with 1-year or more duration of hormone therapy at baseline, the association was stronger (RR=2.02, 95%CI, 1.31-3.12). The multivariate-adjusted RRs of VTE for current users tended to be higher in those with idiopathic VTE (RR=2.40, 95%CI, 1.40-4.12) than those with secondary VTE (RR=1.08, 95%CI, 0.63-1.85). Hormone replacement therapy is associated with increased risk of VTE, but reproductive history markers of endogenous oestrogen exposure were not associated with VTE.
10aAge Factors10aAged10aEpidemiologic Methods10aEstrogen Replacement Therapy10aFemale10aHumans10aMale10aMiddle Aged10aParity10aPregnancy10aReproductive History10aUnited States10aVenous Thromboembolism1 aOhira, Tetsuya1 aFolsom, Aaron, R1 aCushman, Mary1 aWhite, Richard, H1 aHannan, Peter, J1 aRosamond, Wayne, D1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/117502220nas a2200325 4500008004100000022001400041245005400055210005300109260001300162300001000175490000800185520139400193653000901587653001501596653001101611653002201622653001101644653001401655653000901669653001601678653001701694653001801711653001801729653002701747100002101774700002201795700002301817700001801840856003601858 2010 eng d a2567-689X00aSerum albumin and risk of venous thromboembolism.0 aSerum albumin and risk of venous thromboembolism c2010 Jul a100-40 v1043 aThe incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n = 462 in ARIC and n = 174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated glomerular filtration rate, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95% confidence interval [CI] = 1.08, 1.31) in ARIC and 1.10 (95% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (vs. above) the fifth percentile was 1.28 (95% CI = 0.90, 1.84) in ARIC and 1.80 (95% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.
10aAged10aBiomarkers10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aMiddle Aged10aRisk Factors10aSerum Albumin10aUnited States10aVenous Thromboembolism1 aFolsom, Aaron, R1 aLutsey, Pamela, L1 aHeckbert, Susan, R1 aCushman, Mary uhttps://chs-nhlbi.org/node/118403858nas a2200685 4500008004100000022001400041245008900055210006900144260001600213300001200229490000800241520195200249653003902201653001602240653000902256653002202265653001502287653002402302653001902326653002002345653001902365653002402384653001102408653004002419653001102459653002202470653001802492653001102510653001702521653001402538653002602552653000902578653001602587653003202603653001702635653001602652653001202668653001802680100002402698700001902722700001202741700002202753700002402775700002202799700002402821700002502845700001702870700002302887700002002910700002402930700002002954700002202974700002202996700002703018700002003045700002403065700002403089700002303113856003603136 2010 eng d a1538-367900aValidation of an atrial fibrillation risk algorithm in whites and African Americans.0 aValidation of an atrial fibrillation risk algorithm in whites an c2010 Nov 22 a1909-170 v1703 aBACKGROUND: We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups.
METHODS: We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure.
RESULTS: We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk.
CONCLUSIONS: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.
10aAfrican Continental Ancestry Group10aAge Factors10aAged10aAged, 80 and over10aAlgorithms10aAtrial Fibrillation10aBlood Pressure10aBody Mass Index10aCohort Studies10aElectrocardiography10aEurope10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aHeart Failure10aHumans10aHypertension10aIncidence10aKaplan-Meier Estimate10aMale10aMiddle Aged10aProportional Hazards Models10aRisk Factors10aSex Factors10aSystole10aUnited States1 aSchnabel, Renate, B1 aAspelund, Thor1 aLi, Guo1 aSullivan, Lisa, M1 aSuchy-Dicey, Astrid1 aHarris, Tamara, B1 aPencina, Michael, J1 aD'Agostino, Ralph, B1 aLevy, Daniel1 aKannel, William, B1 aWang, Thomas, J1 aKronmal, Richard, A1 aWolf, Philip, A1 aBurke, Gregory, L1 aLauner, Lenore, J1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aBenjamin, Emelia, J1 aGudnason, Vilmundur1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/124703692nas a2200637 4500008004100000022001400041245006800055210006500123260001300188300001000201490000700211520184500218653001002063653000902073653002202082653003402104653002502138653002802163653001102191653002202202653003402224653002802258653001102286653005102297653000902348653001602357653003102373653003602404653001402440653001902454653000902473653004702482653006302529100002602592700001802618700002302636700001902659700001402678700002202692700002002714700001702734700002202751700002202773700002202795700001902817700002202836700001202858700002202870700002002892700002202912700002402934700001802958700002202976700002002998856003603018 2011 eng d a1744-688000aCerivastatin, genetic variants, and the risk of rhabdomyolysis.0 aCerivastatin genetic variants and the risk of rhabdomyolysis c2011 May a280-80 v213 aOBJECTIVE: The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.
METHODS: This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.
RESULTS: Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63).
CONCLUSION: We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.
10aAdult10aAged10aAged, 80 and over10aAryl Hydrocarbon Hydroxylases10aCase-Control Studies10aCytochrome P-450 CYP2C810aFemale10aGenetic Variation10aGenome-Wide Association Study10aGlucuronosyltransferase10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aMale10aMiddle Aged10aOrganic Anion Transporters10aPolymorphism, Single Nucleotide10aPyridines10aRhabdomyolysis10aRisk10aRyanodine Receptor Calcium Release Channel10aSolute Carrier Organic Anion Transporter Family Member 1b11 aMarciante, Kristin, D1 aDurda, Jon, P1 aHeckbert, Susan, R1 aLumley, Thomas1 aRice, Ken1 aMcKnight, Barbara1 aTotah, Rheem, A1 aTamraz, Bani1 aKroetz, Deanna, L1 aFukushima, Hisayo1 aKaspera, Rüdiger1 aBis, Joshua, C1 aGlazer, Nicole, L1 aLi, Guo1 aAustin, Thomas, R1 aTaylor, Kent, D1 aRotter, Jerome, I1 aJaquish, Cashell, E1 aKwok, Pui-Yan1 aTracy, Russell, P1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/127502783nas a2200457 4500008004100000022001400041245011000055210006900165260001300234300001200247490000700259520152800266653000901794653002201803653001801825653002001843653001901863653001201882653001101894653001101905653001401916653002301930653000901953653000901962653001101971100002101982700002002003700002202023700002302045700002002068700002402088700002002112700002002132700002102152700002702173700002002200700002202220700002302242700002402265856003602289 2011 eng d a1524-462800aFasting and post-glucose load measures of insulin resistance and risk of ischemic stroke in older adults.0 aFasting and postglucose load measures of insulin resistance and c2011 Dec a3347-510 v423 aBACKGROUND AND PURPOSE: Few studies have assessed post-glucose load measures of insulin resistance and ischemic stroke risk, and data are sparse for older adults. We investigated whether fasting and post-glucose load measures of insulin resistance were related to incident ischemic stroke in nondiabetic, older adults.
METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without prevalent diabetes or stroke at baseline, followed for 17 years for incident ischemic stroke. The Gutt insulin sensitivity index was calculated from baseline body weight and from fasting and 2-hour postload insulin and glucose; a lower Gutt index indicates higher insulin resistance.
RESULTS: Analyses included 3442 participants (42% men) with a mean age of 73 years. Incidence of ischemic stroke was 9.8 strokes per 1000 person-years. The relative risk (RR) for lowest quartile versus highest quartile of Gutt index was 1.64 (95% CI, 1.24-2.16), adjusted for demographics and prevalent cardiovascular and kidney disease. Similarly, the adjusted RR for highest quartile versus lowest quartile of 2-hour glucose was 1.84 (95% CI, 1.39-2.42). In contrast, the adjusted RR for highest quartile versus lowest quartile of fasting insulin was 1.10 (95% CI, 0.84-1.46).
CONCLUSIONS: In nondiabetic, older adults, insulin resistance measured by Gutt index or 2-hour glucose, but not by fasting insulin, was associated with risk of incident ischemic stroke.
10aAged10aAged, 80 and over10aBlood Glucose10aBody Mass Index10aBrain Ischemia10aFasting10aFemale10aHumans10aIncidence10aInsulin Resistance10aMale10aRisk10aStroke1 aThacker, Evan, L1 aPsaty, Bruce, M1 aMcKnight, Barbara1 aHeckbert, Susan, R1 aLongstreth, W T1 aMukamal, Kenneth, J1 aMeigs, James, B1 ade Boer, Ian, H1 aBoyko, Edward, J1 aCarnethon, Mercedes, R1 aKizer, Jorge, R1 aTracy, Russell, P1 aSmith, Nicholas, L1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/133913785nas a2204513 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2011 eng d a1476-468700aGenetic variants in novel pathways influence blood pressure and cardiovascular disease risk.0 aGenetic variants in novel pathways influence blood pressure and c2011 Sep 11 a103-90 v4783 aBlood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
10aAfrica10aAsia10aBlood Pressure10aCardiovascular Diseases10aCoronary Artery Disease10aEurope10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHypertension10aKidney Diseases10aPolymorphism, Single Nucleotide10aStroke1 aInternational Consortium for Blood Pressure Genome-Wide Association Studies1 aEhret, Georg, B1 aMunroe, Patricia, B1 aRice, Kenneth, M1 aBochud, Murielle1 aJohnson, Andrew, D1 aChasman, Daniel, I1 aSmith, Albert, V1 aTobin, Martin, D1 aVerwoert, Germaine, C1 aHwang, Shih-Jen1 aPihur, Vasyl1 aVollenweider, Peter1 aO'Reilly, Paul, F1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aTeumer, Alexander1 aGlazer, Nicole, L1 aLauner, Lenore1 aZhao, Jing Hua1 aAulchenko, Yurii1 aHeath, Simon1 aSõber, Siim1 aParsa, Afshin1 aLuan, Jian'an1 aArora, Pankaj1 aDehghan, Abbas1 aZhang, Feng1 aLucas, Gavin1 aHicks, Andrew, A1 aJackson, Anne, U1 aPeden, John, F1 aTanaka, Toshiko1 aWild, Sarah, H1 aRudan, Igor1 aIgl, Wilmar1 aMilaneschi, Yuri1 aParker, Alex, N1 aFava, Cristiano1 aChambers, John, C1 aFox, Ervin, R1 aKumari, Meena1 aGo, Min Jin1 aHarst, Pim1 aKao, Wen Hong Linda1 aSjögren, Marketa1 aVinay, D G1 aAlexander, Myriam1 aTabara, Yasuharu1 aShaw-Hawkins, Sue1 aWhincup, Peter, H1 aLiu, Yongmei1 aShi, Gang1 aKuusisto, Johanna1 aTayo, Bamidele1 aSeielstad, Mark1 aSim, Xueling1 aNguyen, Khanh-Dung Hoang1 aLehtimäki, Terho1 aMatullo, Giuseppe1 aWu, Ying1 aGaunt, Tom, R1 aOnland-Moret, Charlotte, N1 aCooper, Matthew, N1 aPlatou, Carl, G P1 aOrg, Elin1 aHardy, Rebecca1 aDahgam, Santosh1 aPalmen, Jutta1 aVitart, Veronique1 aBraund, Peter, S1 aKuznetsova, Tatiana1 aUiterwaal, Cuno, S P M1 aAdeyemo, Adebowale1 aPalmas, Walter1 aCampbell, Harry1 aLudwig, Barbara1 aTomaszewski, Maciej1 aTzoulaki, Ioanna1 aPalmer, Nicholette, D1 aAspelund, Thor1 aGarcia, Melissa1 aChang, Yen-Pei, C1 aO'Connell, Jeffrey, R1 aSteinle, Nanette, I1 aGrobbee, Diederick, E1 aArking, Dan, E1 aKardia, Sharon, L1 aMorrison, Alanna, C1 aHernandez, Dena1 aNajjar, Samer1 aMcArdle, Wendy, L1 aHadley, David1 aBrown, Morris, J1 aConnell, John, M1 aHingorani, Aroon, D1 aDay, Ian, N M1 aLawlor, Debbie, A1 aBeilby, John, P1 aLawrence, Robert, W1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aDreisbach, Albert, W1 aLi, Yali1 aYoung, Hunter, J1 aBis, Joshua, C1 aKähönen, Mika1 aViikari, Jorma1 aAdair, Linda, S1 aLee, Nanette, R1 aChen, Ming-Huei1 aOlden, Matthias1 aPattaro, Cristian1 aBolton, Judith Hoffman, A1 aKöttgen, Anna1 aBergmann, Sven1 aMooser, Vincent1 aChaturvedi, Nish1 aFrayling, Timothy, M1 aIslam, Muhammad1 aJafar, Tazeen, H1 aErdmann, Jeanette1 aKulkarni, Smita, R1 aBornstein, Stefan, R1 aGrässler, Jürgen1 aGroop, Leif1 aVoight, Benjamin, F1 aKettunen, Johannes1 aHoward, Philip1 aTaylor, Andrew1 aGuarrera, Simonetta1 aRicceri, Fulvio1 aEmilsson, Valur1 aPlump, Andrew1 aBarroso, Inês1 aKhaw, Kay-Tee1 aWeder, Alan, B1 aHunt, Steven, C1 aSun, Yan, V1 aBergman, Richard, N1 aCollins, Francis, S1 aBonnycastle, Lori, L1 aScott, Laura, J1 aStringham, Heather, M1 aPeltonen, Leena1 aPerola, Markus1 aVartiainen, Erkki1 aBrand, Stefan-Martin1 aStaessen, Jan, A1 aWang, Thomas, J1 aBurton, Paul, R1 aArtigas, Maria, Soler1 aDong, Yanbin1 aSnieder, Harold1 aWang, Xiaoling1 aZhu, Haidong1 aLohman, Kurt, K1 aRudock, Megan, E1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aDoumatey, Ayo1 aShriner, Daniel1 aVeldre, Gudrun1 aViigimaa, Margus1 aKinra, Sanjay1 aPrabhakaran, Dorairaj1 aTripathy, Vikal1 aLangefeld, Carl, D1 aRosengren, Annika1 aThelle, Dag, S1 aCorsi, Anna Maria1 aSingleton, Andrew1 aForrester, Terrence1 aHilton, Gina1 aMcKenzie, Colin, A1 aSalako, Tunde1 aIwai, Naoharu1 aKita, Yoshikuni1 aOgihara, Toshio1 aOhkubo, Takayoshi1 aOkamura, Tomonori1 aUeshima, Hirotsugu1 aUmemura, Satoshi1 aEyheramendy, Susana1 aMeitinger, Thomas1 aWichmann, H-Erich1 aCho, Yoon Shin1 aKim, Hyung-Lae1 aLee, Jong-Young1 aScott, James1 aSehmi, Joban, S1 aZhang, Weihua1 aHedblad, Bo1 aNilsson, Peter1 aSmith, George Davey1 aWong, Andrew1 aNarisu, Narisu1 aStančáková, Alena1 aRaffel, Leslie, J1 aYao, Jie1 aKathiresan, Sekar1 aO'Donnell, Christopher, J1 aSchwartz, Stephen, M1 aIkram, Arfan, M1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aShrine, Nick, R G1 aWain, Louise, V1 aMorken, Mario, A1 aSwift, Amy, J1 aLaitinen, Jaana1 aProkopenko, Inga1 aZitting, Paavo1 aCooper, Jackie, A1 aHumphries, Steve, E1 aDanesh, John1 aRasheed, Asif1 aGoel, Anuj1 aHamsten, Anders1 aWatkins, Hugh1 aBakker, Stephan, J L1 aGilst, Wiek, H1 aJanipalli, Charles, S1 aMani, Radha, K1 aYajnik, Chittaranjan, S1 aHofman, Albert1 aMattace-Raso, Francesco, U S1 aOostra, Ben, A1 aDemirkan, Ayse1 aIsaacs, Aaron1 aRivadeneira, Fernando1 aLakatta, Edward, G1 aOrrù, Marco1 aScuteri, Angelo1 aAla-Korpela, Mika1 aKangas, Antti, J1 aLyytikäinen, Leo-Pekka1 aSoininen, Pasi1 aTukiainen, Taru1 aWürtz, Peter1 aOng, Rick Twee-Hee1 aDörr, Marcus1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aZelenika, Diana1 aDeloukas, Panos1 aMangino, Massimo1 aSpector, Tim, D1 aZhai, Guangju1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aTerzic, Janos1 aKumar, Kranthi, M V1 aDenniff, Matthew1 aZukowska-Szczechowska, Ewa1 aWagenknecht, Lynne, E1 aFowkes, Gerald, F R1 aCharchar, Fadi, J1 aSchwarz, Peter, E H1 aHayward, Caroline1 aGuo, Xiuqing1 aRotimi, Charles1 aBots, Michiel, L1 aBrand, Eva1 aSamani, Nilesh, J1 aPolasek, Ozren1 aTalmud, Philippa, J1 aNyberg, Fredrik1 aKuh, Diana1 aLaan, Maris1 aHveem, Kristian1 aPalmer, Lyle, J1 aSchouw, Yvonne, T1 aCasas, Juan, P1 aMohlke, Karen, L1 aVineis, Paolo1 aRaitakari, Olli1 aGanesh, Santhi, K1 aWong, Tien, Y1 aTai, Shyong, E1 aCooper, Richard, S1 aLaakso, Markku1 aRao, Dabeeru, C1 aHarris, Tamara, B1 aMorris, Richard, W1 aDominiczak, Anna, F1 aKivimaki, Mika1 aMarmot, Michael, G1 aMiki, Tetsuro1 aSaleheen, Danish1 aChandak, Giriraj, R1 aCoresh, Josef1 aNavis, Gerjan1 aSalomaa, Veikko1 aHan, Bok-Ghee1 aZhu, Xiaofeng1 aKooner, Jaspal, S1 aMelander, Olle1 aRidker, Paul, M1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWright, Alan, F1 aWilson, James, F1 aFerrucci, Luigi1 aFarrall, Martin1 aTuomilehto, Jaakko1 aPramstaller, Peter, P1 aElosua, Roberto1 aSoranzo, Nicole1 aSijbrands, Eric, J G1 aAltshuler, David1 aLoos, Ruth, J F1 aShuldiner, Alan, R1 aGieger, Christian1 aMeneton, Pierre1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aRettig, Rainer1 aUda, Manuela1 aStrachan, David, P1 aWitteman, Jacqueline, C M1 aHartikainen, Anna-Liisa1 aBeckmann, Jacques, S1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aBoehnke, Michael1 aLarson, Martin, G1 aJarvelin, Marjo-Riitta1 aPsaty, Bruce, M1 aAbecasis, Goncalo, R1 aChakravarti, Aravinda1 aElliott, Paul1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aCaulfield, Mark, J1 aJohnson, Toby1 aCARDIoGRAM consortium1 aCKDGen Consortium1 aKidneyGen Consortium1 aEchoGen consortium1 aCHARGE-HF consortium 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2011 eng d a1546-171800aGenome-wide association and large-scale follow up identifies 16 new loci influencing lung function.0 aGenomewide association and largescale follow up identifies 16 ne c2011 Sep 25 a1082-900 v433 aPulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
10aChild10aEuropean Continental Ancestry Group10aGenome-Wide Association Study10aHumans10aPulmonary Disease, Chronic Obstructive10aRespiratory Function Tests1 aArtigas, Maria, Soler1 aLoth, Daan, W1 aWain, Louise, V1 aGharib, Sina, A1 aObeidat, Ma'en1 aTang, Wenbo1 aZhai, Guangju1 aZhao, Jing Hua1 aSmith, Albert, Vernon1 aHuffman, Jennifer, E1 aAlbrecht, Eva1 aJackson, Catherine, M1 aEvans, David, M1 aCadby, Gemma1 aFornage, Myriam1 aManichaikul, Ani1 aLopez, Lorna, M1 aJohnson, Toby1 aAldrich, Melinda, C1 aAspelund, Thor1 aBarroso, Inês1 aCampbell, Harry1 aCassano, Patricia, A1 aCouper, David, J1 aEiriksdottir, Gudny1 aFranceschini, Nora1 aGarcia, Melissa1 aGieger, Christian1 aGislason, Gauti, Kjartan1 aGrkovic, Ivica1 aHammond, Christopher, J1 aHancock, Dana, B1 aHarris, Tamara, B1 aRamasamy, Adaikalavan1 aHeckbert, Susan, R1 aHeliövaara, Markku1 aHomuth, Georg1 aHysi, Pirro, G1 aJames, Alan, L1 aJankovic, Stipan1 aJoubert, Bonnie, R1 aKarrasch, Stefan1 aKlopp, Norman1 aKoch, Beate1 aKritchevsky, Stephen, B1 aLauner, Lenore, J1 aLiu, Yongmei1 aLoehr, Laura, R1 aLohman, Kurt1 aLoos, Ruth, J F1 aLumley, Thomas1 aBalushi, Khalid, A Al1 aAng, Wei, Q1 aBarr, Graham1 aBeilby, John1 aBlakey, John, D1 aBoban, Mladen1 aBoraska, Vesna1 aBrisman, Jonas1 aBritton, John, R1 aBrusselle, Guy, G1 aCooper, Cyrus1 aCurjuric, Ivan1 aDahgam, Santosh1 aDeary, Ian, J1 aEbrahim, Shah1 aEijgelsheim, Mark1 aFrancks, Clyde1 aGaysina, Darya1 aGranell, Raquel1 aGu, Xiangjun1 aHankinson, John, L1 aHardy, Rebecca1 aHarris, Sarah, E1 aHenderson, John1 aHenry, Amanda1 aHingorani, Aroon, D1 aHofman, Albert1 aHolt, Patrick, G1 aHui, Jennie1 aHunter, Michael, L1 aImboden, Medea1 aJameson, Karen, A1 aKerr, Shona, M1 aKolcic, Ivana1 aKronenberg, Florian1 aLiu, Jason, Z1 aMarchini, Jonathan1 aMcKeever, Tricia1 aMorris, Andrew, D1 aOlin, Anna-Carin1 aPorteous, David, J1 aPostma, Dirkje, S1 aRich, Stephen, S1 aRing, Susan, M1 aRivadeneira, Fernando1 aRochat, Thierry1 aSayer, Avan Aihie1 aSayers, Ian1 aSly, Peter, D1 aSmith, George Davey1 aSood, Akshay1 aStarr, John, M1 aUitterlinden, André, G1 aVonk, Judith, M1 aWannamethee, Goya1 aWhincup, Peter, H1 aWijmenga, Cisca1 aWilliams, Dale1 aWong, Andrew1 aMangino, Massimo1 aMarciante, Kristin, D1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorrison, Alanna, C1 aNorth, Kari, E1 aOmenaas, Ernst1 aPalmer, Lyle, J1 aPietiläinen, Kirsi, H1 aPin, Isabelle1 aEk, Ozren, Pola Sbrev1 aPouta, Anneli1 aPsaty, Bruce, M1 aHartikainen, Anna-Liisa1 aRantanen, Taina1 aRipatti, Samuli1 aRotter, Jerome, I1 aRudan, Igor1 aRudnicka, Alicja, R1 aSchulz, Holger1 aShin, So-Youn1 aSpector, Tim, D1 aSurakka, Ida1 aVitart, Veronique1 aVölzke, Henry1 aWareham, Nicholas, J1 aWarrington, Nicole, M1 aWichmann, H-Erich1 aWild, Sarah, H1 aWilk, Jemma, B1 aWjst, Matthias1 aWright, Alan, F1 aZgaga, Lina1 aZemunik, Tatijana1 aPennell, Craig, E1 aNyberg, Fredrik1 aKuh, Diana1 aHolloway, John, W1 aBoezen, Marike1 aLawlor, Debbie, A1 aMorris, Richard, W1 aProbst-Hensch, Nicole1 aKaprio, Jaakko1 aWilson, James, F1 aHayward, Caroline1 aKähönen, Mika1 aHeinrich, Joachim1 aMusk, Arthur, W1 aJarvis, Deborah, L1 aGläser, Sven1 aJarvelin, Marjo-Riitta1 aStricker, Bruno, H Ch1 aElliott, Paul1 aO'Connor, George, T1 aStrachan, David, P1 aLondon, Stephanie, J1 aHall, Ian, P1 aGudnason, Vilmundur1 aTobin, Martin, D1 aInternational Lung Cancer Consortium1 aGIANT Consortium uhttps://chs-nhlbi.org/node/609605055nas a2201153 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2011 eng d a1531-824900aGenome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.0 aGenomewide association studies of cerebral white matter lesion b c2011 Jun a928-390 v693 aOBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).
INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
10aAged10aAged, 80 and over10aCerebral Cortex10aChromosomes, Human, Pair 1710aCognition Disorders10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLeukoencephalopathies10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aMovement Disorders10aNerve Fibers, Myelinated10aPolymorphism, Single Nucleotide10aResidence Characteristics10aRNA, Messenger1 aFornage, Myriam1 aDebette, Stephanie1 aBis, Joshua, C1 aSchmidt, Helena1 aIkram, Arfan, M1 aDufouil, Carole1 aSigurdsson, Sigurdur1 aLumley, Thomas1 aDeStefano, Anita, L1 aFazekas, Franz1 aVrooman, Henri, A1 aShibata, Dean, K1 aMaillard, Pauline1 aZijdenbos, Alex1 aSmith, Albert, V1 aGudnason, Haukur1 ade Boer, Renske1 aCushman, Mary1 aMazoyer, Bernard1 aHeiss, Gerardo1 aVernooij, Meike, W1 aEnzinger, Christian1 aGlazer, Nicole, L1 aBeiser, Alexa1 aKnopman, David, S1 aCavalieri, Margherita1 aNiessen, Wiro, J1 aHarris, Tamara, B1 aPetrovic, Katja1 aLopez, Oscar, L1 aAu, Rhoda1 aLambert, Jean-Charles1 aHofman, Albert1 aGottesman, Rebecca, F1 aGarcia, Melissa1 aHeckbert, Susan, R1 aAtwood, Larry, D1 aCatellier, Diane, J1 aUitterlinden, André, G1 aYang, Qiong1 aSmith, Nicholas, L1 aAspelund, Thor1 aRomero, Jose, R1 aRice, Kenneth1 aTaylor, Kent, D1 aNalls, Michael, A1 aRotter, Jerome, I1 aSharrett, Richey1 aDuijn, Cornelia, M1 aAmouyel, Philippe1 aWolf, Philip, A1 aGudnason, Vilmundur1 avan der Lugt, Aad1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aSeshadri, Sudha1 aTzourio, Christophe1 aBreteler, Monique, M B1 aMosley, Thomas, H1 aSchmidt, Reinhold1 aLongstreth, W T1 aDeCarli, Charles1 aLauner, Lenore, J uhttps://chs-nhlbi.org/node/129804127nas a2200745 4500008004100000022001400041245023700055210006900292260001300361300001100374490000600385520175300391653002202144653000902166653001202175653002402187653003102211653001902242653004002261653001102301653001102312653000902323653001602332653005302348653003602401653002902437653001702466653001102483653001802494100002402512700002202536700002202558700002602580700002302606700002202629700002202651700002002673700001502693700002702708700002402735700001702759700001702776700001802793700001902811700002202830700003002852700002102882700002202903700002002925700002302945700002202968700002402990700002203014700002103036700002703057700002203084700002903106700001903135700002403154700001903178700002403197700002303221710010103244856003603345 2011 eng d a1942-326800aLarge-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) project.0 aLargescale candidate gene analysis in whites and African America c2011 Oct a557-640 v43 aBACKGROUND: The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.
METHODS AND RESULTS: We examined a panel of approximately 50,000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18,524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95% confidence interval [CI], 0.85-0.95; P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72-1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57-0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95% CI, 1.16-1.69; P=0.0005).
CONCLUSIONS: In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.
10aAfrican Americans10aAged10aAlleles10aAtrial Fibrillation10aChromosomes, Human, Pair 410aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aHumans10aMale10aMiddle Aged10aNational Heart, Lung, and Blood Institute (U.S.)10aPolymorphism, Single Nucleotide10aReceptors, Interleukin-610aRisk Factors10aStroke10aUnited States1 aSchnabel, Renate, B1 aKerr, Kathleen, F1 aLubitz, Steven, A1 aAlkylbekova, Ermeg, L1 aMarcus, Gregory, M1 aSinner, Moritz, F1 aMagnani, Jared, W1 aWolf, Philip, A1 aDeo, Rajat1 aLloyd-Jones, Donald, M1 aLunetta, Kathryn, L1 aMehra, Reena1 aLevy, Daniel1 aFox, Ervin, R1 aArking, Dan, E1 aMosley, Thomas, H1 aMüller-Nurasyid, Martina1 aYoung, Taylor, R1 aWichmann, H-Erich1 aSeshadri, Sudha1 aFarlow, Deborah, N1 aRotter, Jerome, I1 aSoliman, Elsayed, Z1 aGlazer, Nicole, L1 aWilson, James, G1 aBreteler, Monique, M B1 aSotoodehnia, Nona1 aNewton-Cheh, Christopher1 aKääb, Stefan1 aEllinor, Patrick, T1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aCandidate Gene Association Resource (CARe) Atrial Fibrillation/Electrocardiography Working Group uhttps://chs-nhlbi.org/node/131602654nas a2200373 4500008004100000022001400041245017700055210006900232260001300301300001100314490000800325520157100333653001001904653000901914653001801923653001601941653001101957653002201968653001101990653000802001653000902009653001602018653002202034653002402056653001702080653001802097653002702115100002202142700001802164700002302182700001802205700002102223856003602244 2011 eng d a2567-689X00aLonger legs are associated with greater risk of incident venous thromboembolism independent of total body height. The Longitudinal Study of Thromboembolism Etiology (LITE).0 aLonger legs are associated with greater risk of incident venous c2011 Jul a113-200 v1063 aSeveral studies have reported that taller individuals are at greater risk of venous thromboembolism (VTE). We hypothesised that longer leg length would be positively associated with incident VTE, and would explain the height association. LITE ascertained VTE in a prospective population-based sample of 21,860 individuals aged 45 and older. Leg length was measured as standing height minus torso length. Cox regression models were adjusted for age, race, sex, waist circumference, diabetes, and factor VIII. To evaluate whether leg length was associated with VTE risk independent of height, we standardised leg length and height per 1 standard deviation (SD), and then included them simultaneously in Cox regression models. A total of 641 incident VTE cases accrued over a median follow-up of 16 years. Participants in the highest quintile of leg length were at 59% (95% CI: 22%-108%) greater risk of VTE, relative to the lowest quintile. For height, risk was 45% (12%-88%) greater for those in the highest quintile, compared to the lowest. When leg length and height were modelled simultaneously leg length remained associated with VTE risk (HR per 1 SD: 1.21 (1.04-1.40) while height was unrelated (HR per 1 SD: 1.00 (0.86-1.16). To conclude, participants with longer legs were at greater risk of incident VTE, and leg length explained the relation of height to VTE. It remains to be established whether this finding is due to greater venous surface area, a larger number of venous valves, or greater hydrostatic pressure among individuals with longer legs.
10aAdult10aAged10aAnthropometry10aBody Height10aFemale10aFollow-Up Studies10aHumans10aLeg10aMale10aMiddle Aged10aPopulation Groups10aProspective Studies10aRisk Factors10aUnited States10aVenous Thromboembolism1 aLutsey, Pamela, L1 aCushman, Mary1 aHeckbert, Susan, R1 aTang, Weihong1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/129505459nas a2201501 4500008004100000022001400041245016600055210006900221260001600290300001000306490000700316520120500323653001001528653000901538653001001547653002001557653003501577653001901612653002801631653004001659653001701699653003801716653001801754653003401772653001301806653001001819653001101829653001601840653001401856653002801870653003601898653001701934100001901951700002001970700002301990700001802013700002502031700001802056700001902074700002102093700002502114700002002139700002202159700002502181700002202206700001802228700002002246700002302266700001902289700001602308700001602324700001702340700002502357700002202382700002002404700002302424700002002447700001802467700001902485700002002504700002002524700002102544700001802565700002602583700001702609700001902626700002302645700002002668700002302688700002402711700001802735700001802753700001902771700002302790700002202813700002402835700001702859700002402876700002102900700002102921700002002942700001802962700002102980700001703001700001903018700002303037700002403060700002203084700002203106700001903128700002103147700001803168700002003186700001903206700002203225700002503247700002303272700002503295700002003320700002103340700002303361700002703384700002203411700002003433700002003453700002103473700001203494700002303506700001703529700002103546700001803567700002003585700002103605700001903626700002103645700002403666700002003690700002503710700001903735700002403754700002003778700001803798700002503816700002403841700003003865710002603895856003603921 2011 eng d a1546-171800aMeta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.0 aMetaanalysis of genomewide association studies from the CHARGE c c2011 Sep 11 a940-70 v433 aCarotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.
10aAdult10aAged10aAging10aAtherosclerosis10aCarotid Intima-Media Thickness10aCohort Studies10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHeart10aHumans10aMiddle Aged10aPhenotype10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aRisk Factors1 aBis, Joshua, C1 aKavousi, Maryam1 aFranceschini, Nora1 aIsaacs, Aaron1 aAbecasis, Goncalo, R1 aSchminke, Ulf1 aPost, Wendy, S1 aSmith, Albert, V1 aCupples, Adrienne, L1 aMarkus, Hugh, S1 aSchmidt, Reinhold1 aHuffman, Jennifer, E1 aLehtimäki, Terho1 aBaumert, Jens1 aMünzel, Thomas1 aHeckbert, Susan, R1 aDehghan, Abbas1 aNorth, Kari1 aOostra, Ben1 aBevan, Steve1 aStoegerer, Eva-Maria1 aHayward, Caroline1 aRaitakari, Olli1 aMeisinger, Christa1 aSchillert, Arne1 aSanna, Serena1 aVölzke, Henry1 aCheng, Yu-Ching1 aThorsson, Bolli1 aFox, Caroline, S1 aRice, Kenneth1 aRivadeneira, Fernando1 aNambi, Vijay1 aHalperin, Eran1 aPetrovic, Katja, E1 aPeltonen, Leena1 aWichmann, Erich, H1 aSchnabel, Renate, B1 aDörr, Marcus1 aParsa, Afshin1 aAspelund, Thor1 aDemissie, Serkalem1 aKathiresan, Sekar1 aReilly, Muredach, P1 aTaylor, Kent1 aUitterlinden, Andre1 aCouper, David, J1 aSitzer, Matthias1 aKähönen, Mika1 aIllig, Thomas1 aWild, Philipp, S1 aOrrù, Marco1 aLüdemann, Jan1 aShuldiner, Alan, R1 aEiriksdottir, Gudny1 aWhite, Charles, C1 aRotter, Jerome, I1 aHofman, Albert1 aSeissler, Jochen1 aZeller, Tanja1 aUsala, Gianluca1 aErnst, Florian1 aLauner, Lenore, J1 aD'Agostino, Ralph, B1 aO'Leary, Daniel, H1 aBallantyne, Christie1 aThiery, Joachim1 aZiegler, Andreas1 aLakatta, Edward, G1 aChilukoti, Ravi, Kumar1 aHarris, Tamara, B1 aWolf, Philip, A1 aPsaty, Bruce, M1 aPolak, Joseph, F1 aLi, Xia1 aRathmann, Wolfgang1 aUda, Manuela1 aBoerwinkle, Eric1 aKlopp, Norman1 aSchmidt, Helena1 aWilson, James, F1 aViikari, Jorma1 aKoenig, Wolfgang1 aBlankenberg, Stefan1 aNewman, Anne, B1 aWitteman, Jacqueline1 aHeiss, Gerardo1 avan Duijn, Cornelia1 aScuteri, Angelo1 aHomuth, Georg1 aMitchell, Braxton, D1 aGudnason, Vilmundur1 aO'Donnell, Christopher, J1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/132307496nas a2202305 4500008004100000022001400041245006700055210006600122260001600188300001000204490000800214520114000222653001201362653002001374653001401394653002801408653002401436653001101460653003001471653001901501653001801520653003401538653001801572653001101590653001901601653001901620653002901639653002701668653001401695653002301709100002201732700002601754700001601780700001801796700002001814700002001834700002901854700001901883700002301902700001801925700002001943700001801963700002001981700002002001700002002021700002102041700002202062700001702084700001802101700002602119700001902145700002202164700002002186700002402206700002402230700001802254700002202272700001802294700001602312700002002328700002202348700002102370700001802391700002302409700001502432700002602447700002002473700002002493700002102513700002502534700001702559700002902576700001902605700001902624700002302643700002202666700002202688700002102710700001702731700001702748700002302765700001902788700002002807700001802827700002202845700002002867700001802887700001402905700002102919700001902940700002202959700002202981700001903003700002803022700002303050700002803073700001803101700001803119700002003137700002103157700001903178700002103197700003103218700002003249700002503269700001903294700002103313700002003334700002403354700002203378700001803400700002503418700002503443700002103468700002003489700001803509700002003527700001903547700002303566700001803589700002603607700001803633700001903651700002203670700002203692700001903714700001703733700002203750700002303772700002403795700002203819700002403841700001703865700002303882700002003905700001903925700002203944700002303966700002203989700001704011700001904028700002104047700001804068700001704086700001804103700002804121700002304149700001704172700002204189700002204211700002304233700001804256700002004274700001904294700002104313700002504334700002104359700002204380700002104402700001904423700002304442700002004465700002304485700002304508700001804531700001804549700002204567700002204589700002704611700002404638700002304662700002004685700002404705700002504729700002804754700001904782700002004801700002404821700001604845700002204861700001904883700002204902700002104924700002104945700001904966700002104985700002105006700001805027700002105045700002005066700002405086700002405110700002005134856003605154 2011 eng d a1476-468700aNew gene functions in megakaryopoiesis and platelet formation.0 aNew gene functions in megakaryopoiesis and platelet formation c2011 Nov 30 a201-80 v4803 aPlatelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
10aAnimals10aBlood Platelets10aCell Size10aDrosophila melanogaster10aDrosophila Proteins10aEurope10aGene Expression Profiling10aGene Silencing10aGenome, Human10aGenome-Wide Association Study10aHematopoiesis10aHumans10aMegakaryocytes10aPlatelet Count10aProtein Interaction Maps10aTranscription, Genetic10aZebrafish10aZebrafish Proteins1 aGieger, Christian1 aRadhakrishnan, Aparna1 aCvejic, Ana1 aTang, Weihong1 aPorcu, Eleonora1 aPistis, Giorgio1 aSerbanovic-Canic, Jovana1 aElling, Ulrich1 aGoodall, Alison, H1 aLabrune, Yann1 aLopez, Lorna, M1 aMägi, Reedik1 aMeacham, Stuart1 aOkada, Yukinori1 aPirastu, Nicola1 aSorice, Rossella1 aTeumer, Alexander1 aVoss, Katrin1 aZhang, Weihua1 aRamirez-Solis, Ramiro1 aBis, Joshua, C1 aEllinghaus, David1 aGögele, Martin1 aHottenga, Jouke-Jan1 aLangenberg, Claudia1 aKovacs, Peter1 aO'Reilly, Paul, F1 aShin, So-Youn1 aEsko, Tõnu1 aHartiala, Jaana1 aKanoni, Stavroula1 aMurgia, Federico1 aParsa, Afshin1 aStephens, Jonathan1 aHarst, Pim1 avan der Schoot, Ellen1 aAllayee, Hooman1 aAttwood, Antony1 aBalkau, Beverley1 aBastardot, François1 aBasu, Saonli1 aBaumeister, Sebastian, E1 aBiino, Ginevra1 aBomba, Lorenzo1 aBonnefond, Amélie1 aCambien, Francois1 aChambers, John, C1 aCucca, Francesco1 aD'Adamo, Pio1 aDavies, Gail1 ade Boer, Rudolf, A1 aGeus, Eco, J C1 aDöring, Angela1 aElliott, Paul1 aErdmann, Jeanette1 aEvans, David, M1 aFalchi, Mario1 aFeng, Wei1 aFolsom, Aaron, R1 aFrazer, Ian, H1 aGibson, Quince, D1 aGlazer, Nicole, L1 aHammond, Chris1 aHartikainen, Anna-Liisa1 aHeckbert, Susan, R1 aHengstenberg, Christian1 aHersch, Micha1 aIllig, Thomas1 aLoos, Ruth, J F1 aJolley, Jennifer1 aKhaw, Kay, Tee1 aKuhnel, Brigitte1 aKyrtsonis, Marie-Christine1 aLagou, Vasiliki1 aLloyd-Jones, Heather1 aLumley, Thomas1 aMangino, Massimo1 aMaschio, Andrea1 aLeach, Irene, Mateo1 aMcKnight, Barbara1 aMemari, Yasin1 aMitchell, Braxton, D1 aMontgomery, Grant, W1 aNakamura, Yusuke1 aNauck, Matthias1 aNavis, Gerjan1 aNöthlings, Ute1 aNolte, Ilja, M1 aPorteous, David, J1 aPouta, Anneli1 aPramstaller, Peter, P1 aPullat, Janne1 aRing, Susan, M1 aRotter, Jerome, I1 aRuggiero, Daniela1 aRuokonen, Aimo1 aSala, Cinzia1 aSamani, Nilesh, J1 aSambrook, Jennifer1 aSchlessinger, David1 aSchreiber, Stefan1 aSchunkert, Heribert1 aScott, James1 aSmith, Nicholas, L1 aSnieder, Harold1 aStarr, John, M1 aStumvoll, Michael1 aTakahashi, Atsushi1 aTang, W, H Wilson1 aTaylor, Kent1 aTenesa, Albert1 aThein, Swee, Lay1 aTönjes, Anke1 aUda, Manuela1 aUlivi, Sheila1 avan Veldhuisen, Dirk, J1 aVisscher, Peter, M1 aVölker, Uwe1 aWichmann, H-Erich1 aWiggins, Kerri, L1 aWillemsen, Gonneke1 aYang, Tsun-Po1 aZhao, Jing, Hua1 aZitting, Paavo1 aBradley, John, R1 aDedoussis, George, V1 aGasparini, Paolo1 aHazen, Stanley, L1 aMetspalu, Andres1 aPirastu, Mario1 aShuldiner, Alan, R1 avan Pelt, Joost1 aZwaginga, Jaap-Jan1 aBoomsma, Dorret, I1 aDeary, Ian, J1 aFranke, Andre1 aFroguel, Philippe1 aGanesh, Santhi, K1 aJarvelin, Marjo-Riitta1 aMartin, Nicholas, G1 aMeisinger, Christa1 aPsaty, Bruce, M1 aSpector, Timothy, D1 aWareham, Nicholas, J1 aAkkerman, Jan-Willem, N1 aCiullo, Marina1 aDeloukas, Panos1 aGreinacher, Andreas1 aJupe, Steve1 aKamatani, Naoyuki1 aKhadake, Jyoti1 aKooner, Jaspal, S1 aPenninger, Josef1 aProkopenko, Inga1 aStemple, Derek1 aToniolo, Daniela1 aWernisch, Lorenz1 aSanna, Serena1 aHicks, Andrew, A1 aRendon, Augusto1 aFerreira, Manuel, A1 aOuwehand, Willem, H1 aSoranzo, Nicole uhttps://chs-nhlbi.org/node/135503098nas a2200421 4500008004100000022001400041245015100055210007000206260001600276300001200292490000800304520186800312653000902180653002402189653001502213653001702228653002602245653002602271653002502297653001102322653002202333653001102355653001402366653000902380653003202389653001702421653001202438100001802450700002402468700001902492700001902511700002002530700001802550700002302568700002402591700002502615856003602640 2012 eng d a1524-453900aAssociation of plasma phospholipid long-chain ω-3 fatty acids with incident atrial fibrillation in older adults: the cardiovascular health study.0 aAssociation of plasma phospholipid longchain ω3 fatty acids with c2012 Mar 06 a1084-930 v1253 aBACKGROUND: Experimental studies suggest that long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) may reduce the risk of atrial fibrillation (AF). Prior studies evaluating fish or n-3 PUFA consumption from dietary questionnaires and incident AF have been conflicting. Circulating levels of n-3 PUFAs provide an objective measurement of exposure.
METHODS AND RESULTS: Among 3326 US men and women ≥65 years of age and free of AF or heart failure at baseline, plasma phospholipid levels of eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid were measured at baseline by use of standardized methods. Incident AF (789 cases) was identified prospectively from hospital discharge records and study visit ECGs during 31 169 person-years of follow-up (1992-2006). In multivariable Cox models adjusted for other risk factors, the relative risk in the top versus lowest quartile of total n-3 PUFAs (eicosapentaenoic acid+docosapentaenoic acid+docosahexaenoic acid) levels was 0.71 (95% confidence interval, 0.57-0.89; P for trend=0.004) and of DHA levels was 0.77 (95% confidence interval, 0.62-0.96; P for trend=0.01). Eicosapentaenoic acid and docosapentaenoic acid levels were not significantly associated with incident AF. Evaluated nonparametrically, both total n-3 PUFAs and docosahexaenoic acid showed graded and linear inverse associations with incidence of AF. Adjustment for intervening events such as heart failure or myocardial infarction during follow-up did not appreciably alter results.
CONCLUSIONS: In older adults, higher circulating total long-chain n-3 PUFA and docosahexaenoic acid levels were associated with lower risk of incident AF. These results highlight the need to evaluate whether increased dietary intake of these fatty acids could be effective for the primary prevention of AF.
10aAged10aAtrial Fibrillation10aBiomarkers10aDietary Fats10aDocosahexaenoic Acids10aEicosapentaenoic Acid10aFatty Acids, Omega-310aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aProportional Hazards Models10aRisk Factors10aSeafood1 aH Y Wu, Jason1 aLemaitre, Rozenn, N1 aKing, Irena, B1 aSong, Xiaoling1 aSacks, Frank, M1 aRimm, Eric, B1 aHeckbert, Susan, R1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/136202911nas a2200361 4500008004100000022001400041245010900055210006900164260001300233300001100246490000700257520184800264653000902112653002402121653002402145653001302169653003002182653001102212653001102223653002602234653002502260653000902285653003102294653002202325653001702347653001802364653003402382100002602416700002402442700002302466700002402489856003602513 2012 eng d a1522-964500aEchocardiographic diastolic parameters and risk of atrial fibrillation: the Cardiovascular Health Study.0 aEchocardiographic diastolic parameters and risk of atrial fibril c2012 Apr a904-120 v333 aAIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia in the elderly, and shares several risk factors with diastolic dysfunction, including hypertension and advanced age. The purpose of this study is to examine diastolic dysfunction as a risk for incident AF.
METHODS AND RESULTS: We examined the association of echocardiographic parameters of diastolic function with the incidence of AF in 4480 participants enrolled in the Cardiovascular Health Study, an ongoing cohort of community-dwelling older adults from four US communities. Participants underwent baseline echocardiography in 1989-1990 and were followed for incident AF on routine follow-up and hospitalizations. After 50 941 person-years of follow-up (median follow-up time 12.1 years), 1219 participants developed AF. In multivariable-adjusted age-stratified Cox models, diastolic echocardiographic parameters were significantly associated with the risk of incident AF. The most significant parameters were the Doppler peak E-wave velocity and left atrial diameter, which demonstrated a positive nonlinear association [HR 1.5 (CI 1.3-1.9) and HR 1.7 (CI 1.4-2.1) for highest vs. lowest quintile, respectively], and Doppler A-wave velocity time integral, which displayed a U-shaped relationship with the risk of AF [HR 0.7 (CI 0.6-0.9) for middle vs. lowest quintile]. Each diastolic parameter displayed a significant association with adjusted NT-proBNP levels, although the nature of the association did not entirely parallel the risk of AF. Further cluster analysis revealed unique patterns of diastolic function that may identify patients at risk for AF.
CONCLUSION: In a community-based population of older adults, echocardiographic measures of diastolic function are significantly associated with an increased risk of AF.
10aAged10aAtrial Fibrillation10aBlood Flow Velocity10aDiastole10aEchocardiography, Doppler10aFemale10aHumans10aKaplan-Meier Estimate10aLongitudinal Studies10aMale10aNatriuretic Peptide, Brain10aPeptide Fragments10aRisk Factors10aUnited States10aVentricular Dysfunction, Left1 aRosenberg, Michael, A1 aGottdiener, John, S1 aHeckbert, Susan, R1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/133705378nas a2201249 4500008004100000022001400041245010600055210006900161260001600230300001100246490000800257520186000265653000902125653001102134653002902145653003402174653001102208653000902219653001602228653002602244653003602270653004302306653002502349653003202374653001202406653001902418100001902437700002202456700002002478700001902498700002102517700002002538700002602558700002302584700002202607700001602629700001802645700001902663700001602682700002002698700002602718700002102744700002102765700001502786700002002801700002002821700002302841700002202864700002402886700001902910700001802929700002002947700001702967700001902984700002303003700001903026700002103045700002203066700001903088700001903107700001903126700001803145700001903163700002203182700002203204700001703226700002003243700002003263700001903283700002603302700002203328700001903350700002403369700002003393700002203413700001903435700002203454700002003476700002103496700002603517700002003543700002203563700002603585700001903611700002803630700002503658700002003683700001803703700002503721700002403746700001803770700002003788700002503808700002403833700001703857700002003874700002303894700002503917700001903942700002603961700002003987700001704007700002404024700002104048700002304069856003604092 2012 eng d a1535-497000aGenome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.0 aGenomewide association studies identify CHRNA53 and HTR4 in the c2012 Oct 01 a622-320 v1863 aRATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.
METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.
MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.
CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
10aAged10aFemale10aForced Expiratory Volume10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPulmonary Disease, Chronic Obstructive10aReceptors, Nicotinic10aReceptors, Serotonin, 5-HT410aSmoking10aVital Capacity1 aWilk, Jemma, B1 aShrine, Nick, R G1 aLoehr, Laura, R1 aZhao, Jing Hua1 aManichaikul, Ani1 aLopez, Lorna, M1 aSmith, Albert, Vernon1 aHeckbert, Susan, R1 aSmolonska, Joanna1 aTang, Wenbo1 aLoth, Daan, W1 aCurjuric, Ivan1 aHui, Jennie1 aCho, Michael, H1 aLatourelle, Jeanne, C1 aHenry, Amanda, P1 aAldrich, Melinda1 aBakke, Per1 aBeaty, Terri, H1 aBentley, Amy, R1 aBorecki, Ingrid, B1 aBrusselle, Guy, G1 aBurkart, Kristin, M1 aChen, Ting-Hsu1 aCouper, David1 aCrapo, James, D1 aDavies, Gail1 aDupuis, Josée1 aFranceschini, Nora1 aGulsvik, Amund1 aHancock, Dana, B1 aHarris, Tamara, B1 aHofman, Albert1 aImboden, Medea1 aJames, Alan, L1 aKhaw, Kay-Tee1 aLahousse, Lies1 aLauner, Lenore, J1 aLitonjua, Augusto1 aLiu, Yongmei1 aLohman, Kurt, K1 aLomas, David, A1 aLumley, Thomas1 aMarciante, Kristin, D1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorrison, Alanna, C1 aMusk, Arthur, W1 aMyers, Richard, H1 aNorth, Kari, E1 aPostma, Dirkje, S1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRivadeneira, Fernando1 aRochat, Thierry1 aRotter, Jerome, I1 aArtigas, Maria, Soler1 aStarr, John, M1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aWijmenga, Cisca1 aZanen, Pieter1 aProvince, Michael, A1 aSilverman, Edwin, K1 aDeary, Ian, J1 aPalmer, Lyle, J1 aCassano, Patricia, A1 aGudnason, Vilmundur1 aBarr, Graham1 aLoos, Ruth, J F1 aStrachan, David, P1 aLondon, Stephanie, J1 aBoezen, Marike1 aProbst-Hensch, Nicole1 aGharib, Sina, A1 aHall, Ian, P1 aO'Connor, George, T1 aTobin, Martin, D1 aStricker, Bruno, H uhttps://chs-nhlbi.org/node/609205536nas a2201405 4500008004100000022001400041245012000055210006900175260000900244300001300253490000600266520151700272653002901789653002001818653001801838653003401856653002001890653002301910653001101933653000901944653002601953653003601979653004402015653004302059653002802102653001202130653003002142653001902172100002102191700002602212700002002238700001802258700002102276700002602297700001802323700001902341700001602360700002202376700002102398700002202419700001702441700001602458700001902474700001802493700001902511700002002530700002402550700001902574700002202593700001802615700001702633700002202650700002102672700001802693700001902711700001802730700002002748700001702768700002002785700002202805700002602827700001902853700002202872700002402894700002202918700001902940700002402959700002302983700002203006700002203028700002003050700001903070700002003089700001903109700002103128700001903149700002403168700002303192700002603215700002103241700002803262700001703290700001903307700002003326700002003346700002803366700002003394700002103414700002003435700002403455700001903479700002103498700001903519700002203538700001803560700002803578700002803606700001803634700002303652700001703675700002503692700001903717700002503736700002403761700002903785700002003814700002703834700002303861700002403884700001903908700001703927700002503944700002303969700002003992700001704012700001904029700002104048700002504069856003604094 2012 eng d a1553-740400aGenome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.0 aGenomewide joint metaanalysis of SNP and SNPbysmoking interactio c2012 ae10030980 v83 aGenome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
10aForced Expiratory Volume10aGene Expression10aGenome, Human10aGenome-Wide Association Study10aHLA-DQ Antigens10aHLA-DQ beta-Chains10aHumans10aLung10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPotassium Channels, Inwardly Rectifying10aPulmonary Disease, Chronic Obstructive10aReceptors, Cell Surface10aSmoking10aSOX9 Transcription Factor10aVital Capacity1 aHancock, Dana, B1 aArtigas, Maria, Soler1 aGharib, Sina, A1 aHenry, Amanda1 aManichaikul, Ani1 aRamasamy, Adaikalavan1 aLoth, Daan, W1 aImboden, Medea1 aKoch, Beate1 aMcArdle, Wendy, L1 aSmith, Albert, V1 aSmolonska, Joanna1 aSood, Akshay1 aTang, Wenbo1 aWilk, Jemma, B1 aZhai, Guangju1 aZhao, Jing Hua1 aAschard, Hugues1 aBurkart, Kristin, M1 aCurjuric, Ivan1 aEijgelsheim, Mark1 aElliott, Paul1 aGu, Xiangjun1 aHarris, Tamara, B1 aJanson, Christer1 aHomuth, Georg1 aHysi, Pirro, G1 aLiu, Jason, Z1 aLoehr, Laura, R1 aLohman, Kurt1 aLoos, Ruth, J F1 aManning, Alisa, K1 aMarciante, Kristin, D1 aObeidat, Ma'en1 aPostma, Dirkje, S1 aAldrich, Melinda, C1 aBrusselle, Guy, G1 aChen, Ting-Hsu1 aEiriksdottir, Gudny1 aFranceschini, Nora1 aHeinrich, Joachim1 aRotter, Jerome, I1 aWijmenga, Cisca1 aWilliams, Dale1 aBentley, Amy, R1 aHofman, Albert1 aLaurie, Cathy, C1 aLumley, Thomas1 aMorrison, Alanna, C1 aJoubert, Bonnie, R1 aRivadeneira, Fernando1 aCouper, David, J1 aKritchevsky, Stephen, B1 aLiu, Yongmei1 aWjst, Matthias1 aWain, Louise, V1 aVonk, Judith, M1 aUitterlinden, André, G1 aRochat, Thierry1 aRich, Stephen, S1 aPsaty, Bruce, M1 aO'Connor, George, T1 aNorth, Kari, E1 aMirel, Daniel, B1 aMeibohm, Bernd1 aLauner, Lenore, J1 aKhaw, Kay-Tee1 aHartikainen, Anna-Liisa1 aHammond, Christopher, J1 aGläser, Sven1 aMarchini, Jonathan1 aKraft, Peter1 aWareham, Nicholas, J1 aVölzke, Henry1 aStricker, Bruno, H C1 aSpector, Timothy, D1 aProbst-Hensch, Nicole, M1 aJarvis, Deborah1 aJarvelin, Marjo-Riitta1 aHeckbert, Susan, R1 aGudnason, Vilmundur1 aBoezen, Marike1 aBarr, Graham1 aCassano, Patricia, A1 aStrachan, David, P1 aFornage, Myriam1 aHall, Ian, P1 aDupuis, Josée1 aTobin, Martin, D1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/608801866nas a2200205 4500008004100000022001400041245016000055210006900215260000900284300001000293490000600303520117400309100002701483700002701510700002301537700002201560700002001582700002201602856003601624 2012 eng d a1948-175600aHemodynamic fluid shear stress response genes and carotid intima-media thickness: a candidate gene association analysis in the cardiovascular health study.0 aHemodynamic fluid shear stress response genes and carotid intima c2012 a174-80 v33 aOBJECTIVE: This study examined whether carotid artery intimal-medial thickness (cIMT) is associated with genetic variations (SNPs) in a hemodynamics-responsive gene pathway.
METHODS: Subjects were Cardiovascular Health Study participants free of cardiovascular events at baseline (N=3388). Genotype was measured using Illumina 370CNV HumanHap chip. Carotid IMT was measured using ultrasound. Estimated mean differences in cIMT per additional minor allele for 366 SNPs in MAP2K5, MAPK7, MEF2A/C, and KLF2 were adjusted for sex, age, clinic, and medication use. SNP-SNP interactions were examined using logic regression for 71 tagSNPs.
RESULTS: None of the associations was significant after correction for multiple comparisons; smallest P-value=0.065 for MAP2K5 and common cIMT. The best-performing logic regression tree combined two SNPs in MAP2K5-rs745212 and rs12905175- and common cIMT; this association was not significant, corrected P-value=0.062.
CONCLUSION: There was not strong evidence of association between genetic variants in a hemodynamics-responsive gene pathway and atherosclerosis among older adults.
1 aSuchy-Dicey, Astrid, M1 aEnquobahrie, Daniel, A1 aHeckbert, Susan, R1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aMcKnight, Barbara uhttps://chs-nhlbi.org/node/139404494nas a2200925 4500008004100000022001400041245008800055210006900143260001300212300001100225490000600236520191100242653001002153653002202163653000902185653002402194653004002218653001102258653002702269653002202296653001802318653003402336653001102370653000902381653001602390653003602406100001802442700002202460700002102482700002202503700001702525700001902542700002002561700002002581700001702601700002002618700001802638700002202656700002202678700002402700700002402724700001202748700002402760700002202784700001402806700001902820700001602839700001902855700002202874700001702896700002002913700002402933700001902957700002502976700002103001700002403022700002503046700002003071700002403091700002203115700002803137700001903165700002003184700001903204700002003223700001903243700002303262700002203285700002103307700002003328700001903348700002203367700001803389700002203407700002303429700002103452700002903473710003003502856003603532 2012 eng d a1942-326800aImpact of ancestry and common genetic variants on QT interval in African Americans.0 aImpact of ancestry and common genetic variants on QT interval in c2012 Dec a647-550 v53 aBACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.
METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.
CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.
10aAdult10aAfrican Americans10aAged10aElectrocardiography10aEuropean Continental Ancestry Group10aFemale10aGenealogy and Heraldry10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aSmith, Gustav1 aAvery, Christy, L1 aEvans, Daniel, S1 aNalls, Michael, A1 aMeng, Yan, A1 aSmith, Erin, N1 aPalmer, Cameron1 aTanaka, Toshiko1 aMehra, Reena1 aButler, Anne, M1 aYoung, Taylor1 aBuxbaum, Sarah, G1 aKerr, Kathleen, F1 aBerenson, Gerald, S1 aSchnabel, Renate, B1 aLi, Guo1 aEllinor, Patrick, T1 aMagnani, Jared, W1 aChen, Wei1 aBis, Joshua, C1 aCurb, David1 aHsueh, Wen-Chi1 aRotter, Jerome, I1 aLiu, Yongmei1 aNewman, Anne, B1 aLimacher, Marian, C1 aNorth, Kari, E1 aReiner, Alexander, P1 aQuibrera, Miguel1 aSchork, Nicholas, J1 aSingleton, Andrew, B1 aPsaty, Bruce, M1 aSoliman, Elsayed, Z1 aSolomon, Allen, J1 aSrinivasan, Sathanur, R1 aAlonso, Alvaro1 aWallace, Robert1 aRedline, Susan1 aZhang, Zhu-Ming1 aPost, Wendy, S1 aZonderman, Alan, B1 aTaylor, Herman, A1 aMurray, Sarah, S1 aFerrucci, Luigi1 aArking, Dan, E1 aEvans, Michele, K1 aFox, Ervin, R1 aSotoodehnia, Nona1 aHeckbert, Susan, R1 aWhitsel, Eric, A1 aNewton-Cheh, Christopher1 aCARe and COGENT consortia uhttps://chs-nhlbi.org/node/617902754nas a2200385 4500008004100000022001400041245009400055210006900149260001300218300001200231490000700243520167100250653000901921653002401930653001601954653002601970653001101996653001102007653000902018653001602027653001802043100002602061700002302087700002202110700002002132700002002152700002402172700002002196700002102216700002402237700002402261700002302285700002402308856003602332 2012 eng d a1522-964500aThe impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study.0 aimpact of height on the risk of atrial fibrillation the Cardiova c2012 Nov a2709-170 v333 aAIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia. Increased body size has been associated with AF, but the relationship is not well understood. In this study, we examined the effect of increased height on the risk of AF and explore potential mediators and implications for clinical practice.
METHODS AND RESULTS: We examined data from 5860 individuals taking part in the Cardiovascular Health Study, a cohort study of older US adults followed for a median of 13.6 (women) and 10.3 years (men). Multivariate linear models and age-stratified Cox proportional hazards and risk models were used, with focus on the effect of height on both prevalent and incident AF. Among 684 (22.6%) and 568 (27.1%) incident cases in women and men, respectively, greater height was significantly associated with AF risk [hazard ratio (HR)(women) per 10 cm 1.32, confidence interval (CI) 1.16-1.50, P < 0.0001; HR(men) per 10 cm 1.26, CI 1.11-1.44, P < 0.0001]. The association was such that the incremental risk from sex was completely attenuated by the inclusion of height (for men, HR 1.48, CI 1.32-1.65, without height, and HR 0.94, CI 0.85-1.20, with height included). Inclusion of height in the Framingham model for incident AF improved discrimination. In sequential models, however, we found minimal attenuation of the risk estimates for AF with adjustment for left ventricular (LV) mass and left atrial (LA) dimension. The associations of LA and LV size measurements with AF risk were weakened when indexed to height.
CONCLUSION: Independent from sex, increased height is significantly associated with the risk of AF.
10aAged10aAtrial Fibrillation10aBody Height10aEpidemiologic Methods10aFemale10aHumans10aMale10aSex Factors10aUnited States1 aRosenberg, Michael, A1 aPatton, Kristen, K1 aSotoodehnia, Nona1 aKaras, Maria, G1 aKizer, Jorge, R1 aZimetbaum, Peter, J1 aChang, James, D1 aSiscovick, David1 aGottdiener, John, S1 aKronmal, Richard, A1 aHeckbert, Susan, R1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/140704917nas a2201453 4500008004100000022001400041245008200055210006900137260001600206300001000222490000700232520088500239653001501124653001001139653000901149653002201158653003701180653002401217653001001241653002101251653004001272653001101312653001701323653003801340653003401378653001101412653001101423653002001434653000901454653001601463653003601479653001701515653001601532100002401548700002401572700002501596700002201621700002401643700002101667700001901688700003001707700002201737700002201759700001901781700001901800700001801819700001901837700002201856700001801878700001801896700002201914700001701936700002001953700002301973700002301996700002202019700002102041700002602062700002202088700001702110700002202127700002202149700002302171700002202194700002202216700002302238700002202261700001902283700001702302700001902319700002002338700001902358700002102377700001702398700002402415700002402439700001202463700002602475700001902501700002002520700001902540700002002559700001702579700002302596700002302619700002202642700001402664700002202678700001702700700002102717700001802738700001902756700002002775700002102795700002102816700002002837700002202857700002002879700002202899700003002921700002002951700002202971700001802993700002803011700002603039700002203065700002203087700002003109700001703129700002303146700001903169700002203188700002603210700002203236700001903258700001903277700001803296700002303314700002303337700002403360700002403384700001903408856003603427 2012 eng d a1546-171800aMeta-analysis identifies six new susceptibility loci for atrial fibrillation.0 aMetaanalysis identifies six new susceptibility loci for atrial f c2012 Apr 29 a670-50 v443 aAtrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChild10aChild, Preschool10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aInfant10aInfant, Newborn10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors10aYoung Adult1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aAlbert, Christine, M1 aGlazer, Nicole, L1 aRitchie, Marylyn, D1 aSmith, Albert, V1 aArking, Dan, E1 aMüller-Nurasyid, Martina1 aKrijthe, Bouwe, P1 aLubitz, Steven, A1 aBis, Joshua, C1 aChung, Mina, K1 aDörr, Marcus1 aOzaki, Kouichi1 aRoberts, Jason, D1 aSmith, Gustav1 aPfeufer, Arne1 aSinner, Moritz, F1 aLohman, Kurt1 aDing, Jingzhong1 aSmith, Nicholas, L1 aSmith, Jonathan, D1 aRienstra, Michiel1 aRice, Kenneth, M1 aVan Wagoner, David, R1 aMagnani, Jared, W1 aWakili, Reza1 aClauss, Sebastian1 aRotter, Jerome, I1 aSteinbeck, Gerhard1 aLauner, Lenore, J1 aDavies, Robert, W1 aBorkovich, Matthew1 aHarris, Tamara, B1 aLin, Honghuang1 aVölker, Uwe1 aVölzke, Henry1 aMilan, David, J1 aHofman, Albert1 aBoerwinkle, Eric1 aChen, Lin, Y1 aSoliman, Elsayed, Z1 aVoight, Benjamin, F1 aLi, Guo1 aChakravarti, Aravinda1 aKubo, Michiaki1 aTedrow, Usha, B1 aRose, Lynda, M1 aRidker, Paul, M1 aConen, David1 aTsunoda, Tatsuhiko1 aFurukawa, Tetsushi1 aSotoodehnia, Nona1 aXu, Siyan1 aKamatani, Naoyuki1 aLevy, Daniel1 aNakamura, Yusuke1 aParvez, Babar1 aMahida, Saagar1 aFurie, Karen, L1 aRosand, Jonathan1 aMuhammad, Raafia1 aPsaty, Bruce, M1 aMeitinger, Thomas1 aPerz, Siegfried1 aWichmann, H-Erich1 aWitteman, Jacqueline, C M1 aKao, Linda, W H1 aKathiresan, Sekar1 aRoden, Dan, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aMcKnight, Barbara1 aSjögren, Marketa1 aNewman, Anne, B1 aLiu, Yongmei1 aGollob, Michael, H1 aMelander, Olle1 aTanaka, Toshihiro1 aStricker, Bruno, H Ch1 aFelix, Stephan, B1 aAlonso, Alvaro1 aDarbar, Dawood1 aBarnard, John1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aGudnason, Vilmundur1 aKääb, Stefan uhttps://chs-nhlbi.org/node/138304310nas a2200901 4500008004100000022001400041245011000055210006900165260001300234300001100247490000600258520179200264653001002056653002202066653001902088653002402107653001102131653001702142653003402159653001102193653000902204653002702213653001602240653003602256100002002292700001702312700002102329700002202350700001902372700002002391700001202411700002202423700002102445700001902466700001902485700002402504700002402528700001702552700001402569700001502583700002402598700002302622700001902645700001902664700002402683700002202707700001202729700002402741700001702765700002202782700002602804700001702830700001702847700002002864700002902884700001902913700002302932700002002955700002102975700001902996700002003015700002203035700002403057700002403081700002503105700001803130700002403148700002803172700002003200700002303220700002003243700002103263700002203284700002203306700002203328700002203350856003603372 2012 eng d a1942-326800aNovel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.0 aNovel loci associated with PR interval in a genomewide associati c2012 Dec a639-460 v53 aBACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.
METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).
CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.
10aAdult10aAfrican Americans10aCohort Studies10aElectrocardiography10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide1 aButler, Anne, M1 aYin, Xiaoyan1 aEvans, Daniel, S1 aNalls, Michael, A1 aSmith, Erin, N1 aTanaka, Toshiko1 aLi, Guo1 aBuxbaum, Sarah, G1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBenjamin, Emelia, J1 aBerenson, Gerald, S1 aBis, Josh, C1 aChen, Wei1 aDeo, Rajat1 aEllinor, Patrick, T1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHsueh, Wen-Chi1 aKeating, Brendan, J1 aKerr, Kathleen, F1 aLi, Yun1 aLimacher, Marian, C1 aLiu, Yongmei1 aLubitz, Steven, A1 aMarciante, Kristin, D1 aMehra, Reena1 aMeng, Yan, A1 aNewman, Anne, B1 aNewton-Cheh, Christopher1 aNorth, Kari, E1 aPalmer, Cameron, D1 aPsaty, Bruce, M1 aQuibrera, Miguel1 aRedline, Susan1 aReiner, Alex, P1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aSchork, Nicholas, J1 aSingleton, Andrew, B1 aSmith, Gustav1 aSoliman, Elsayed, Z1 aSrinivasan, Sathanur, R1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aFerrucci, Luigi1 aMurray, Sarah, S1 aEvans, Michele, K1 aSotoodehnia, Nona1 aMagnani, Jared, W1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/608402910nas a2200493 4500008004100000022001400041245010000055210006900155260001600224300001000240490000800250520152600258653000901784653002401793653002301817653003001840653003101870653001101901653002201912653001101934653001701945653001401962653002201976653002201998653000902020653003102029653001202060653002202072653002402094653001602118653001802134653001802152100001902170700002002189700001902209700002302228700002002251700002102271700002402292700002202316700002402338700001802362856003602380 2012 eng d a1879-191300aPlasma free fatty acids and risk of atrial fibrillation (from the Cardiovascular Health Study).0 aPlasma free fatty acids and risk of atrial fibrillation from the c2012 Jul 15 a212-60 v1103 aAtrial fibrillation (AF) is a highly prevalent cardiac arrhythmia in clinical practice, affecting approximately 2.3 million residents of the United States and 4.5 million residents of the European Union. It is unclear whether plasma free fatty acids (FFAs) influence the risk of AF in older adults. The aim of this study was to prospectively examine the association between plasma FFAs and incident AF in a prospective cohort of 4,175 men and women ≥65 years old from the Cardiovascular Health Study. Plasma concentrations of FFAs were measured 2 times during the 1992 to 1993 examination. Incident AF was ascertained based on study electrocardiographic and hospitalization records during follow-up. We used Cox regression to estimate relative risks of AF. Average age at baseline was 74.6 ± 5.1 years. During a mean follow-up of 10.0 years, 1,041 new cases of AF occurred. Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years across consecutive quartiles of plasma FFAs. There was a positive association between plasma FFAs and risk of AF. Multivariable adjusted hazard ratios (95% confidence intervals) for incident AF were 1.00 (referent), 1.02 (0.85 to 1.21), 1.05 (0.88 to 1.26), and 1.29 (1.08 to 1.55) from the lowest to highest quartiles of FFAs, respectively. In a secondary analysis restricted to the first 5 years of follow-up, this association persisted. In conclusion, our data show an increased risk of AF with higher plasma FFAs in community-dwelling older adults.
10aAged10aAtrial Fibrillation10aC-Reactive Protein10aDiabetes Mellitus, Type 210aFatty Acids, Nonesterified10aFemale10aFollow-Up Studies10aHumans10aHypertension10aIncidence10aLipoproteins, HDL10aLipoproteins, LDL10aMale10aNatriuretic Peptide, Brain10aObesity10aPeptide Fragments10aProspective Studies10aSex Factors10aTriglycerides10aUnited States1 aKhawaja, Owais1 aBartz, Traci, M1 aIx, Joachim, H1 aHeckbert, Susan, R1 aKizer, Jorge, R1 aZieman, Susan, J1 aMukamal, Kenneth, J1 aTracy, Russell, P1 aSiscovick, David, S1 aDjoussé, Luc uhttps://chs-nhlbi.org/node/137903504nas a2200505 4500008004100000022001400041245021500055210006900270260001300339300000900352490000600361520189100367653003902258653002002297653004002317653001102357653003402368653001102402653000902413653001602422653003502438653003602473653002402509653003002533653001702563653001502580100001302595700001902608700002002627700001702647700002202664700001802686700002202704700002202726700003002748700003002778700002202808700001402830700002302844700002802867700002002895700002102915710002602936856003602962 2013 eng d a1942-326800aAssociation of genome-wide variation with highly sensitive cardiac troponin-T levels in European Americans and Blacks: a meta-analysis from atherosclerosis risk in communities and cardiovascular health studies.0 aAssociation of genomewide variation with highly sensitive cardia c2013 Feb a82-80 v63 aBACKGROUND: High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels.
METHODS AND RESULTS: We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004).
CONCLUSIONS: We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.
10aAfrican Continental Ancestry Group10aAtherosclerosis10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNuclear Receptor Coactivator 210aPolymorphism, Single Nucleotide10aProspective Studies10aResidence Characteristics10aRisk Factors10aTroponin T1 aYu, Bing1 aBarbalic, Maja1 aBrautbar, Ariel1 aNambi, Vijay1 aHoogeveen, Ron, C1 aTang, Weihong1 aMosley, Thomas, H1 aRotter, Jerome, I1 adeFilippi, Christopher, R1 aO'Donnell, Christopher, J1 aKathiresan, Sekar1 aRice, Ken1 aHeckbert, Susan, R1 aBallantyne, Christie, M1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/585702959nas a2200529 4500008004100000022001400041245015700055210006900212260001600281300001200297490000600309520144300315653001601758653000901774653002201783653002501805653002401830653001501854653000901869653001101878653001101889653001401900653001801914653002501932653000901957653002301966653001801989653003202007653002402039653002002063653001702083653001702100653001802117100002202135700002502157700002402182700002302206700002202229700001902251700001802270700002002288700002002308700001902328700002202347700002402369856003602393 2013 eng d a2047-998000aAssociations of plasma phospholipid and dietary alpha linolenic acid with incident atrial fibrillation in older adults: the Cardiovascular Health Study.0 aAssociations of plasma phospholipid and dietary alpha linolenic c2013 Jan 31 ae0038140 v23 aBACKGROUND: Few studies have examined the relationship of α-linolenic acid (ALA 18:3n-3), an intermediate-chain essential n-3 polyunsaturated fatty acid derived from plants and vegetable oils, with incident atrial fibrillation (AF).
METHODS AND RESULTS: The study population included participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 or older, free of prevalent coronary heart disease and atrial fibrillation. We assessed the associations of plasma phospholipid and dietary ALA with incident AF using Cox regression. The biomarker analysis comprised a total of 2899 participants, and the dietary analysis comprised 4337 participants. We found no association of plasma phospholipid ALA and incident AF. Comparing each of the second, third, and fourth quartiles to the lowest quartile, the hazard ratios for AF were 1.11 (95% CI, 0.90 to 1.37), 1.09 (95% CI, 0.88 to 1.35), and 0.92 (95% CI, 0.74 to 1.15), after adjustment for age, sex, race, clinic, education, smoking, alcohol, body mass index, waist circumference, diabetes, heart failure, stroke, treated hypertension, and physical activity (P trend=0.48). When dietary ALA was considered the exposure of interest, results were similar.
CONCLUSIONS: Results from this prospective cohort study of older adults indicate no association of plasma phospholipid or dietary ALA and incident AF.
10aAge Factors10aAged10aAged, 80 and over10aalpha-Linolenic Acid10aAtrial Fibrillation10aBiomarkers10aDiet10aFemale10aHumans10aIncidence10aLinear Models10aLongitudinal Studies10aMale10aNutritional Status10aPhospholipids10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aTime Factors10aUnited States1 aFretts, Amanda, M1 aMozaffarian, Dariush1 aSiscovick, David, S1 aHeckbert, Susan, R1 aMcKnight, Barbara1 aKing, Irena, B1 aRimm, Eric, B1 aPsaty, Bruce, M1 aSacks, Frank, M1 aSong, Xiaoling1 aSpiegelman, Donna1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/584603298nas a2200397 4500008004100000022001400041245008200055210006900137260001600206300001000222490000800232520217800240653000902418653002402427653002002451653001902471653002402490653001102514653001102525653000902536653002402545653002702569653002402596653002002620100002302640700002202663700002102685700002302706700002402729700002202753700002002775700002202795700002402817700002302841856003602864 2013 eng d a1539-370400aAtrial ectopy as a predictor of incident atrial fibrillation: a cohort study.0 aAtrial ectopy as a predictor of incident atrial fibrillation a c c2013 Dec 03 a721-80 v1593 aBACKGROUND: Atrial fibrillation (AF) prediction models have unclear clinical utility given the absence of AF prevention therapies and the immutability of many risk factors. Premature atrial contractions (PACs) play a critical role in AF pathogenesis and may be modifiable.
OBJECTIVE: To investigate whether PAC count improves model performance for AF risk.
DESIGN: Prospective cohort study.
SETTING: 4 U.S. communities.
PATIENTS: A random subset of 1260 adults without prevalent AF enrolled in the Cardiovascular Health Study between 1989 and 1990.
MEASUREMENTS: The PAC count was quantified by 24-hour electrocardiography. Participants were followed for the diagnosis of incident AF or death. The Framingham AF risk algorithm was used as the comparator prediction model.
RESULTS: In adjusted analyses, doubling the hourly PAC count was associated with a significant increase in AF risk (hazard ratio, 1.17 [95% CI, 1.13 to 1.22]; P < 0.001) and overall mortality (hazard ratio, 1.06 [CI, 1.03 to 1.09]; P < 0.001). Compared with the Framingham model, PAC count alone resulted in similar AF risk discrimination at 5 and 10 years of follow-up and superior risk discrimination at 15 years. The addition of PAC count to the Framingham model resulted in significant 10-year AF risk discrimination improvement (c-statistic, 0.65 vs. 0.72; P < 0.001), net reclassification improvement (23.2% [CI, 12.8% to 33.6%]; P < 0.001), and integrated discrimination improvement (5.6% [CI, 4.2% to 7.0%]; P < 0.001). The specificity for predicting AF at 15 years exceeded 90% for PAC counts more than 32 beats/h.
LIMITATION: This study does not establish a causal link between PACs and AF.
CONCLUSION: The addition of PAC count to a validated AF risk algorithm provides superior AF risk discrimination and significantly improves risk reclassification. Further study is needed to determine whether PAC modification can prospectively reduce AF risk.
PRIMARY FUNDING SOURCE: American Heart Association, Joseph Drown Foundation, and National Institutes of Health.
10aAged10aAtrial Fibrillation10aAtrial Function10aCause of Death10aElectrocardiography10aFemale10aHumans10aMale10aModels, Statistical10aMyocardial Contraction10aProspective Studies10aRisk Assessment1 aDewland, Thomas, A1 aVittinghoff, Eric1 aMandyam, Mala, C1 aHeckbert, Susan, R1 aSiscovick, David, S1 aStein, Phyllis, K1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aGottdiener, John, S1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/616602861nas a2200409 4500008004100000022001400041245007600055210006900131260001600200300001100216490000700227520170000234653001601934653000901950653002201959653002401981653002402005653001602029653001102045653001102056653001402067653002502081653004602106653000902152653003002161100002102191700002202212700002002234700002002254700002402274700001902298700002102317700002802338700002602366700002302392856003602415 2013 eng d a1526-632X00aAtrial fibrillation and cognitive decline: a longitudinal cohort study.0 aAtrial fibrillation and cognitive decline a longitudinal cohort c2013 Jul 09 a119-250 v813 aOBJECTIVE: We sought to determine whether in the absence of clinical stroke, people with atrial fibrillation experience faster cognitive decline than people without atrial fibrillation.
METHODS: We conducted a longitudinal analysis in the Cardiovascular Health Study, a community-based study of 5,888 men and women aged 65 years and older, enrolled in 1989/1990 or 1992/1993. Participants did not have atrial fibrillation or a history of stroke at baseline. Participants were censored when they experienced incident clinical stroke. Incident atrial fibrillation was identified by hospital discharge diagnosis codes and annual study ECGs. The main outcome was rate of decline in mean scores on the 100-point Modified Mini-Mental State Examination (3MSE), administered annually up to 9 times.
RESULTS: Analyses included 5,150 participants, of whom 552 (10.7%) developed incident atrial fibrillation during a mean of 7 years of follow-up. Mean 3MSE scores declined faster after incident atrial fibrillation compared with no prior atrial fibrillation. For example, the predicted 5-year decline in mean 3MSE score from age 80 to age 85 was -6.4 points (95% confidence interval [CI]: -7.0, -5.9) for participants without a history of atrial fibrillation, but was -10.3 points (95% CI: -11.8, -8.9) for participants experiencing incident atrial fibrillation at age 80, a 5-year difference of -3.9 points (95% CI: -5.3, -2.5).
CONCLUSIONS: In the absence of clinical stroke, people with incident atrial fibrillation are likely to reach thresholds of cognitive impairment or dementia at earlier ages than people with no history of atrial fibrillation.
10aAge Factors10aAged10aAged, 80 and over10aAtrial Fibrillation10aCognition Disorders10aComorbidity10aFemale10aHumans10aIncidence10aLongitudinal Studies10aLuria-Nebraska Neuropsychological Battery10aMale10aPredictive Value of Tests1 aThacker, Evan, L1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aLongstreth, W T1 aSitlani, Colleen, M1 aDublin, Sascha1 aArnold, Alice, M1 aFitzpatrick, Annette, L1 aGottesman, Rebecca, F1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/600203502nas a2200481 4500008004100000022001400041245014100055210006900196260001600265300001000281490000800291520213900299653000902438653002402447653002802471653002702499653001502526653001802541653001102559653001102570653001402581653000902595653001602604653003202620653002002652653001702672653001602689653001802705100001702723700002202740700002102762700001902783700001802802700002302820700002002843700002402863700001902887700001702906700002102923700002102944700001902965856003602984 2013 eng d a2168-611400aAtrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study.0 aAtrial fibrillation and the risk of sudden cardiac death the ath c2013 Jan 14 a29-350 v1733 aBACKGROUND: It is unknown whether atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. This association was examined in 2 population-based cohorts.
METHODS: In the Atherosclerosis Risk in Communities (ARIC) Study, we analyzed data from 15 439 participants (baseline age, 45-64 years; 55.2% women; and 26.6% black) from baseline (1987-1989) through December 31, 2001. In the Cardiovascular Health Study (CHS), we analyzed data from 5479 participants (baseline age, ≥65 years; 58.2% women; and 15.4% black) from baseline (first cohort, 1989-1990; second cohort, 1992-1993) through December 31, 2006. The main outcome was physician-adjudicated SCD, defined as death from a sudden, pulseless condition presumed to be due to a ventricular tachyarrhythmia. The secondary outcome was non-SCD (NSCD), defined as coronary heart disease death not meeting SCD criteria. We used Cox proportional hazards models to assess the association between AF and SCD/NSCD, adjusting for baseline demographic and cardiovascular risk factors.
RESULTS: In the ARIC Study, 894 AF, 269 SCD, and 233 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 2.89 per 1000 person-years (with AF) and 1.30 per 1000 person-years (without AF). The multivariable hazard ratios (HRs) (95% CIs) of AF for SCD and NSCD were 3.26 (2.17-4.91) and 2.43 (1.60-3.71), respectively. In the CHS, 1458 AF, 292 SCD, and 581 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 12.00 per 1000 person-years (with AF) and 3.82 per 1000 person-years (without AF). The multivariable HRs (95% CIs) of AF for SCD and NSCD were 2.14 (1.60-2.87) and 3.10 (2.58-3.72), respectively. The meta-analyzed HRs (95% CIs) of AF for SCD and NSCD were 2.47 (1.95-3.13) and 2.98 (2.52-3.53), respectively.
CONCLUSIONS: Incident AF is associated with an increased risk of SCD and NSCD in the general population. Additional research to identify predictors of SCD in patients with AF is warranted.
10aAged10aAtrial Fibrillation10aCardiovascular Diseases10aDeath, Sudden, Cardiac10aDemography10aEthnic Groups10aFemale10aHumans10aIncidence10aMale10aMiddle Aged10aProportional Hazards Models10aRisk Assessment10aRisk Factors10aSex Factors10aUnited States1 aChen, Lin, Y1 aSotoodehnia, Nona1 aBůzková, Petra1 aLopez, Faye, L1 aYee, Laura, M1 aHeckbert, Susan, R1 aPrineas, Ronald1 aSoliman, Elsayed, Z1 aAdabag, Selcuk1 aKonety, Suma1 aFolsom, Aaron, R1 aSiscovick, David1 aAlonso, Alvaro uhttps://chs-nhlbi.org/node/585003436nas a2200529 4500008004100000022001400041245014600055210006900201260001300270300001100283490000700294520191500301653003102216653000902247653002402256653001902280653001602299653001502315653002202330653002402352653001202376653001102388653001802399653001102417653001802428653002502446653000902471653002002480653002402500653001702524653004302541653003002584653001502614100001702629700002102646700001702667700002402684700001702708700001802725700002202743700002002765700001802785700002302803700002402826700002002850856003602870 2013 eng d a1541-256300aEffects of respiratory and non-respiratory factors on disability among older adults with airway obstruction: the Cardiovascular Health Study.0 aEffects of respiratory and nonrespiratory factors on disability c2013 Oct a588-960 v103 aBACKGROUND: High rates of disability associated with chronic airway obstruction may be caused by impaired pulmonary function, pulmonary symptoms, other chronic diseases, or systemic inflammation.
METHODS: We analyzed data from the Cardiovascular Health Study, a longitudinal cohort of 5888 older adults. Categories of lung function (normal; restricted; borderline, mild-moderate, and severe obstruction) were delineated by baseline spirometry (without bronchodilator). Disability-free years were calculated as total years alive and without self-report of difficulty performing &γτ;1 Instrumental Activities of Daily Living over 6 years of follow-up. Using linear regression, we compared disability-free years by lung disease category, adjusting for demographic factors, body mass index, smoking, cognition, and other chronic co-morbidities. Among participants with airflow obstruction, we examined the association of respiratory factors (FEV1 and dyspnea) and non-respiratory factors (ischemic heart disease, congestive heart failure, diabetes, muscle weakness, osteoporosis, depression and cognitive impairment) on disability-free years.
RESULTS: The average disability free years were 4.0 out of a possible 6 years. Severe obstruction was associated with 1 fewer disability-free year compared to normal spirometry in the adjusted model. For the 1,048 participants with airway obstruction, both respiratory factors (FEV1 and dyspnea) and non-respiratory factors (heart disease, coronary artery disease, diabetes, depression, osteoporosis, cognitive function, and weakness) were associated with decreased disability-free years.
CONCLUSIONS: Severe obstruction is associated with greater disability compared to patients with normal spirometery. Both respiratory and non-respiratory factors contribute to disability in older adults with abnormal spirometry.
10aActivities of Daily Living10aAged10aCognition Disorders10aCohort Studies10aComorbidity10aDepression10aDiabetes Mellitus10aDisease Progression10aDyspnea10aFemale10aHeart Failure10aHumans10aLinear Models10aLongitudinal Studies10aMale10aMuscle Weakness10aMyocardial Ischemia10aOsteoporosis10aPulmonary Disease, Chronic Obstructive10aSeverity of Illness Index10aSpirometry1 aLocke, Emily1 aThielke, Stephen1 aDiehr, Paula1 aWilsdon, Anthony, G1 aBarr, Graham1 aHansel, Nadia1 aKapur, Vishesh, K1 aKrishnan, Jerry1 aEnright, Paul1 aHeckbert, Susan, R1 aKronmal, Richard, A1 aFan, Vincent, S uhttps://chs-nhlbi.org/node/599704061nas a2200781 4500008004100000022001400041245015900055210006900214260001300283300001200296490000700308520179500315653000902110653001002119653002502129653001902154653001102173653003402184653001102218653000902229653002702238653001602265653003602281653002402317653001702341653002702358100001802385700002202403700002302425700001802448700002902466700001202495700002102507700002202528700002102550700002302571700002402594700002002618700001702638700001802655700001602673700002502689700001902714700002302733700002802756700001802784700002102802700001802823700001902841700002602860700002202886700002102908700002802929700002202957700001902979700002102998700001903019700002203038700002103060700002203081700003203103700001803135700002603153700002003179700002103199700002303220856003603243 2013 eng d a1098-227200aA genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.0 agenomewide association study for venous thromboembolism the exte c2013 Jul a512-5210 v373 aVenous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
10aAged10aAging10aCase-Control Studies10aCohort Studies10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aRegression Analysis10aRisk Factors10aVenous Thromboembolism1 aTang, Weihong1 aTeichert, Martina1 aChasman, Daniel, I1 aHeit, John, A1 aMorange, Pierre-Emmanuel1 aLi, Guo1 aPankratz, Nathan1 aLeebeek, Frank, W1 aParé, Guillaume1 ade Andrade, Mariza1 aTzourio, Christophe1 aPsaty, Bruce, M1 aBasu, Saonli1 aRuiter, Rikje1 aRose, Lynda1 aArmasu, Sebastian, M1 aLumley, Thomas1 aHeckbert, Susan, R1 aUitterlinden, André, G1 aLathrop, Mark1 aRice, Kenneth, M1 aCushman, Mary1 aHofman, Albert1 aLambert, Jean-Charles1 aGlazer, Nicole, L1 aPankow, James, S1 aWitteman, Jacqueline, C1 aAmouyel, Philippe1 aBis, Joshua, C1 aBovill, Edwin, G1 aKong, Xiaoxiao1 aTracy, Russell, P1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aTrégouët, David-Alexandre1 aLoth, Daan, W1 aStricker, Bruno, H Ch1 aRidker, Paul, M1 aFolsom, Aaron, R1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/602904246nas a2200769 4500008004100000022001400041245015300055210006900208260001300277300001000290490000600300520206100306653002202367653000902389653001902398653001302417653002102430653004002451653001102491653003402502653001302536653001002549653001102559653000902570653001602579653001402595653003602609653001202645100001802657700002302675700001902698700001902717700001302736700002402749700002302773700002102796700002202817700001902839700002002858700002102878700002302899700002502922700002202947700002302969700001602992700002103008700001903029700001303048700001803061700002503079700002003104700002903124700002103153700002403174700002203198700002403220700001903244700001803263700002203281700002203303700002203325700002003347700002303367700002303390700002703413856003603440 2013 eng d a1942-326800aGenome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study.0 aGenomewide association study of cardiac structure and systolic f c2013 Feb a37-460 v63 aBACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.
METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.
CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
10aAfrican Americans10aAged10aCohort Studies10aDiastole10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aSystole1 aFox, Ervin, R1 aMusani, Solomon, K1 aBarbalic, Maja1 aLin, Honghuang1 aYu, Bing1 aOgunyankin, Kofo, O1 aSmith, Nicholas, L1 aKutlar, Abdullah1 aGlazer, Nicole, L1 aPost, Wendy, S1 aPaltoo, Dina, N1 aDries, Daniel, L1 aFarlow, Deborah, N1 aDuarte, Christine, W1 aKardia, Sharon, L1 aMeyers, Kristin, J1 aSun, Yan, V1 aArnett, Donna, K1 aPatki, Amit, A1 aSha, Jin1 aCui, Xiangqui1 aSamdarshi, Tandaw, E1 aPenman, Alan, D1 aBibbins-Domingo, Kirsten1 aBůzková, Petra1 aBenjamin, Emelia, J1 aBluemke, David, A1 aMorrison, Alanna, C1 aHeiss, Gerardo1 aCarr, Jeffrey1 aTracy, Russell, P1 aMosley, Thomas, H1 aTaylor, Herman, A1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aCappola, Thomas, P1 aVasan, Ramachandran, S uhttps://chs-nhlbi.org/node/663204041nas a2200805 4500008004100000022001400041245010600055210006900161260001300230300001000243490000800253520176400261653001002025653001302035653003202048653003202080653001902112653001102131653003402142653003802176653001102214653002702225653000902252653000902261653002202270653001602292653003602308653004302344100002102387700002002408700002202428700001602450700001802466700001902484700001602503700002102519700001802540700001702558700002402575700002302599700002002622700001202642700001802654700002302672700001902695700002402714700002102738700001902759700001902778700002202797700002202819700001802841700003202859700002402891700002302915700002002938700002002958700002102978700001502999700001903014700002003033700001803053700002003071700002103091700002303112700002003135700002003155700002403175856003603199 2013 eng d a1432-120300aGenome-wide study identifies two loci associated with lung function decline in mild to moderate COPD.0 aGenomewide study identifies two loci associated with lung functi c2013 Jan a79-900 v1323 aAccelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.
10aAdult10aAnkyrins10aChromosomes, Human, Pair 1010aChromosomes, Human, Pair 1410aCohort Studies10aFemale10aGenome-Wide Association Study10aHepatocyte Nuclear Factor 3-alpha10aHumans10aLinkage Disequilibrium10aLung10aMale10aMembrane Proteins10aMiddle Aged10aPolymorphism, Single Nucleotide10aPulmonary Disease, Chronic Obstructive1 aHansel, Nadia, N1 aRuczinski, Ingo1 aRafaels, Nicholas1 aSin, Don, D1 aDaley, Denise1 aMalinina, Alla1 aHuang, Lili1 aSandford, Andrew1 aMurray, Tanda1 aKim, Yoonhee1 aVergara, Candelaria1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aLi, Guo1 aElliott, Mark1 aAminuddin, Farzian1 aDupuis, Josée1 aO'Connor, George, T1 aDoheny, Kimberly1 aScott, Alan, F1 aBoezen, Marike1 aPostma, Dirkje, S1 aSmolonska, Joanna1 aZanen, Pieter1 aHoesein, Firdaus, A Mohamed1 ade Koning, Harry, J1 aCrystal, Ronald, G1 aTanaka, Toshiko1 aFerrucci, Luigi1 aSilverman, Edwin1 aWan, Emily1 aVestbo, Jorgen1 aLomas, David, A1 aConnett, John1 aWise, Robert, A1 aNeptune, Enid, R1 aMathias, Rasika, A1 aParé, Peter, D1 aBeaty, Terri, H1 aBarnes, Kathleen, C uhttps://chs-nhlbi.org/node/606811009nas a2203553 4500008004100000022001400041245011100055210006900166260001300235300001100248490000700259520106100266653001201327653002501339653001901364653001701383653003401400653002801434653001501462653001101477653003601488653003601524653002801560100002201588700002201610700001601632700002701648700001901675700002001694700001901714700002301733700001601756700002501772700002101797700001801818700001801836700001501854700001901869700001901888700002001907700001601927700001901943700002101962700002301983700002502006700002502031700001802056700001502074700002202089700002402111700001602135700002102151700002102172700001802193700001802211700002302229700002102252700002302273700002202296700002002318700002202338700002502360700002302385700002002408700001702428700002002445700002502465700002202490700001902512700002102531700001802552700002502570700002102595700002202616700002202638700002102660700003102681700001302712700002302725700001602748700001602764700001802780700002502798700001902823700001902842700002502861700002102886700002502907700002002932700001902952700002502971700001802996700002403014700002103038700001603059700001903075700002003094700001803114700001803132700002203150700002003172700002703192700001903219700002203238700002403260700002203284700002803306700002203334700002303356700002103379700001903400700002203419700002803441700002403469700002203493700001903515700002103534700001903555700001603574700002003590700001803610700002303628700002203651700001703673700001803690700001703708700001803725700002303743700002403766700002103790700001703811700002103828700002403849700002103873700002603894700002503920700002403945700002203969700002503991700002204016700002304038700002504061700002404086700003004110700001704140700001604157700002604173700003004199700001604229700002004245700002004265700001904285700001804304700002604322700002004348700002004368700001904388700002504407700001704432700001804449700002104467700002004488700001904508700002004527700002504547700002104572700002004593700002004613700001804633700002604651700002304677700002804700700002404728700002004752700002304772700002004795700001904815700002304834700002104857700003004878700001704908700001704925700002004942700001904962700002304981700002305004700002305027700002305050700001705073700002105090700002205111700002105133700002005154700001905174700002405193700001505217700001505232700002405247700001905271700002305290700002405313700002205337700002205359700002905381700001705410700002305427700002005450700002905470700002505499700002105524700002305545700002105568700002505589700002205614700001705636700001805653700002005671700002005691700001905711700002105730700002505751700001605776700002005792700001905812700001705831700002305848700002105871700002205892700001505914700002705929700001605956700002005972700002705992700003006019700002206049700001706071700002206088700002206110700002606132700002506158700001806183700002406201700001906225700002106244700001106265700002306276700001806299700001906317700002006336700001606356700002006372700002006392700002206412700002306434700001906457700002206476700002106498700002306519700002406542700002806566700002206594700002806616700001906644700001906663700002406682700002006706700002106726700001906747700002106766700002306787700002006810700001706830700002206847700002206869700001806891700002206909700002906931700002406960700002606984700002107010700001907031700002507050700002407075700002107099700002507120700002407145700002007169700002007189700002007209700002207229700002007251710002807271710002607299710002307325710002407348710002207372710002507394856003607419 2013 eng d a1546-171800aIdentification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.0 aIdentification of heart rateassociated loci and their effects on c2013 Jun a621-310 v453 aElevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
10aAnimals10aArrhythmias, Cardiac10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aHeart Conduction System10aHeart Rate10aHumans10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aHoed, Marcel, den1 aEijgelsheim, Mark1 aEsko, Tõnu1 aBrundel, Bianca, J J M1 aPeal, David, S1 aEvans, David, M1 aNolte, Ilja, M1 aSegrè, Ayellet, V1 aHolm, Hilma1 aHandsaker, Robert, E1 aWestra, Harm-Jan1 aJohnson, Toby1 aIsaacs, Aaron1 aYang, Jian1 aLundby, Alicia1 aZhao, Jing Hua1 aKim, Young, Jin1 aGo, Min Jin1 aAlmgren, Peter1 aBochud, Murielle1 aBoucher, Gabrielle1 aCornelis, Marilyn, C1 aGudbjartsson, Daniel1 aHadley, David1 aHarst, Pim1 aHayward, Caroline1 aHeijer, Martin, den1 aIgl, Wilmar1 aJackson, Anne, U1 aKutalik, Zoltán1 aLuan, Jian'an1 aKemp, John, P1 aKristiansson, Kati1 aLadenvall, Claes1 aLorentzon, Mattias1 aMontasser, May, E1 aNjajou, Omer, T1 aO'Reilly, Paul, F1 aPadmanabhan, Sandosh1 aSt Pourcain, Beate1 aRankinen, Tuomo1 aSalo, Perttu1 aTanaka, Toshiko1 aTimpson, Nicholas, J1 aVitart, Veronique1 aWaite, Lindsay1 aWheeler, William1 aZhang, Weihua1 aDraisma, Harmen, H M1 aFeitosa, Mary, F1 aKerr, Kathleen, F1 aLind, Penelope, A1 aMihailov, Evelin1 aOnland-Moret, Charlotte, N1 aSong, Ci1 aWeedon, Michael, N1 aXie, Weijia1 aYengo, Loic1 aAbsher, Devin1 aAlbert, Christine, M1 aAlonso, Alvaro1 aArking, Dan, E1 ade Bakker, Paul, I W1 aBalkau, Beverley1 aBarlassina, Cristina1 aBenaglio, Paola1 aBis, Joshua, C1 aBouatia-Naji, Nabila1 aBrage, Søren1 aChanock, Stephen, J1 aChines, Peter, S1 aChung, Mina1 aDarbar, Dawood1 aDina, Christian1 aDörr, Marcus1 aElliott, Paul1 aFelix, Stephan, B1 aFischer, Krista1 aFuchsberger, Christian1 aGeus, Eco, J C1 aGoyette, Philippe1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHartikainen, Anna-Liisa1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHicks, Andrew, A1 aHofman, Albert1 aHolewijn, Suzanne1 aHoogstra-Berends, Femke1 aHottenga, Jouke-Jan1 aJensen, Majken, K1 aJohansson, Asa1 aJunttila, Juhani1 aKääb, Stefan1 aKanon, Bart1 aKetkar, Shamika1 aKhaw, Kay-Tee1 aKnowles, Joshua, W1 aKooner, Angrad, S1 aKors, Jan, A1 aKumari, Meena1 aMilani, Lili1 aLaiho, Päivi1 aLakatta, Edward, G1 aLangenberg, Claudia1 aLeusink, Maarten1 aLiu, Yongmei1 aLuben, Robert, N1 aLunetta, Kathryn, L1 aLynch, Stacey, N1 aMarkus, Marcello, R P1 aMarques-Vidal, Pedro1 aLeach, Irene, Mateo1 aMcArdle, Wendy, L1 aMcCarroll, Steven, A1 aMedland, Sarah, E1 aMiller, Kathryn, A1 aMontgomery, Grant, W1 aMorrison, Alanna, C1 aMüller-Nurasyid, Martina1 aNavarro, Pau1 aNelis, Mari1 aO'Connell, Jeffrey, R1 aO'Donnell, Christopher, J1 aOng, Ken, K1 aNewman, Anne, B1 aPeters, Annette1 aPolasek, Ozren1 aPouta, Anneli1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aRao, Dabeeru, C1 aRing, Susan, M1 aRossin, Elizabeth, J1 aRudan, Diana1 aSanna, Serena1 aScott, Robert, A1 aSehmi, Jaban, S1 aSharp, Stephen1 aShin, Jordan, T1 aSingleton, Andrew, B1 aSmith, Albert, V1 aSoranzo, Nicole1 aSpector, Tim, D1 aStewart, Chip1 aStringham, Heather, M1 aTarasov, Kirill, V1 aUitterlinden, André, G1 aVandenput, Liesbeth1 aHwang, Shih-Jen1 aWhitfield, John, B1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilson, James, F1 aWitteman, Jacqueline, C M1 aWong, Andrew1 aWong, Quenna1 aJamshidi, Yalda1 aZitting, Paavo1 aBoer, Jolanda, M A1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aEkelund, Ulf1 aForouhi, Nita, G1 aFroguel, Philippe1 aHingorani, Aroon1 aIngelsson, Erik1 aKivimaki, Mika1 aKronmal, Richard, A1 aKuh, Diana1 aLind, Lars1 aMartin, Nicholas, G1 aOostra, Ben, A1 aPedersen, Nancy, L1 aQuertermous, Thomas1 aRotter, Jerome, I1 aSchouw, Yvonne, T1 aVerschuren, W, M Monique1 aWalker, Mark1 aAlbanes, Demetrius1 aArnar, David, O1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBoehnke, Michael1 ade Boer, Rudolf, A1 aBouchard, Claude1 aCaulfield, W, L Mark1 aChambers, John, C1 aCurhan, Gary1 aCusi, Daniele1 aEriksson, Johan1 aFerrucci, Luigi1 aGilst, Wiek, H1 aGlorioso, Nicola1 ade Graaf, Jacqueline1 aGroop, Leif1 aGyllensten, Ulf1 aHsueh, Wen-Chi1 aHu, Frank, B1 aHuikuri, Heikki, V1 aHunter, David, J1 aIribarren, Carlos1 aIsomaa, Bo1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKiemeney, Lambertus, A1 avan der Klauw, Melanie, M1 aKooner, Jaspal, S1 aKraft, Peter1 aIacoviello, Licia1 aLehtimäki, Terho1 aLokki, Marja-Liisa, L1 aMitchell, Braxton, D1 aNavis, Gerjan1 aNieminen, Markku, S1 aOhlsson, Claes1 aPoulter, Neil, R1 aQi, Lu1 aRaitakari, Olli, T1 aRimm, Eric, B1 aRioux, John, D1 aRizzi, Federica1 aRudan, Igor1 aSalomaa, Veikko1 aSever, Peter, S1 aShields, Denis, C1 aShuldiner, Alan, R1 aSinisalo, Juha1 aStanton, Alice, V1 aStolk, Ronald, P1 aStrachan, David, P1 aTardif, Jean-Claude1 aThorsteinsdottir, Unnur1 aTuomilehto, Jaako1 avan Veldhuisen, Dirk, J1 aVirtamo, Jarmo1 aViikari, Jorma1 aVollenweider, Peter1 aWaeber, Gérard1 aWiden, Elisabeth1 aCho, Yoon Shin1 aOlsen, Jesper, V1 aVisscher, Peter, M1 aWiller, Cristen1 aFranke, Lude1 aErdmann, Jeanette1 aThompson, John, R1 aPfeufer, Arne1 aSotoodehnia, Nona1 aNewton-Cheh, Christopher1 aEllinor, Patrick, T1 aStricker, Bruno, H Ch1 aMetspalu, Andres1 aPerola, Markus1 aBeckmann, Jacques, S1 aSmith, George Davey1 aStefansson, Kari1 aWareham, Nicholas, J1 aMunroe, Patricia, B1 aSibon, Ody, C M1 aMilan, David, J1 aSnieder, Harold1 aSamani, Nilesh, J1 aLoos, Ruth, J F1 aGlobal BPgen Consortium1 aCARDIoGRAM consortium1 aPR GWAS Consortium1 aQRS GWAS Consortium1 aQT-IGC consortium1 aCHARGE-AF Consortium uhttps://chs-nhlbi.org/node/801501004nas a2200349 4500008004100000022001400041245010500055210006900160260001600229300001100245490000800256653000900264653002400273653001500297653002400312653001900336653002400355653002800379653001100407653001800418653001100436653002600447653000900473653001400482653000900496100002100505700002400526700002300550700002200573700002300595856003600618 2013 eng d a1538-359800aLong-term outcomes of left anterior fascicular block in the absence of overt cardiovascular disease.0 aLongterm outcomes of left anterior fascicular block in the absen c2013 Apr 17 a1587-80 v30910aAged10aAtrial Fibrillation10aBiomarkers10aBundle-Branch Block10aCohort Studies10aElectrocardiography10aEndomyocardial Fibrosis10aFemale10aHeart Failure10aHumans10aKaplan-Meier Estimate10aMale10aPrognosis10aRisk1 aMandyam, Mala, C1 aSoliman, Elsayed, Z1 aHeckbert, Susan, R1 aVittinghoff, Eric1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/607702869nas a2200457 4500008004100000022001400041245013800055210006900193260001300262300001000275490000700285520159500292653002201887653001601909653000901925653002201934653002001956653004001976653001102016653001102027653000902038653001202047653001302059653001102072653001202083653002402095100002202119700002402141700001402165700002002179700001802199700002002217700002102237700002302258700001502281700002302296700002102319700001802340700001702358856003602375 2013 eng d a1943-365400aObesity is associated with a lower resting oxygen saturation in the ambulatory elderly: results from the cardiovascular health study.0 aObesity is associated with a lower resting oxygen saturation in c2013 May a831-70 v583 aBACKGROUND: The contribution of obesity to hypoxemia has not been reported in a community-based study. Our hypothesis was that increasing obesity would be independently associated with lower SpO2 in an ambulatory elderly population.
METHODS: The Cardiovascular Health Study ascertained resting SpO2 in 2,252 subjects over age 64. We used multiple linear regression to estimate the association of body mass index (BMI) with SpO2 and to adjust for potentially confounding factors. Covariates including age, sex, race, smoking, airway obstruction (based on spirometry), self reported diagnosis of emphysema, asthma, heart failure, and left ventricular function (by echocardiography) were evaluated.
RESULTS: Among 2,252 subjects the mean and median SpO2 were 97.6% and 98.0% respectively; 5% of subjects had SpO2 values below 95%. BMI was negatively correlated with SpO2 (Spearman R = -0.27, P < .001). The mean difference in SpO2 between the lowest and highest BMI categories (< 25 kg/m(2) and ≥ 35 kg/m(2)) was 1.33% (95% CI 0.89-1.78%). In multivariable linear regression analysis, SpO2 was significantly inversely associated with BMI (1.4% per 10 units of BMI, 95% CI 1.2-1.6, for whites/others, and 0.87% per 10 units of BMI, 95% CI 0.47-1.27, for African Americans).
CONCLUSIONS: We found a narrow distribution of SpO2 values in a community-based sample of ambulatory elderly. Obesity was a strong independent contributor to a low SpO2, with effects comparable to or greater than other factors clinically associated with lower SpO2.
10aAfrican Americans10aAge Factors10aAged10aAged, 80 and over10aBody Mass Index10aEuropean Continental Ancestry Group10aFemale10aHumans10aMale10aObesity10aOximetry10aOxygen10aSmoking10aWaist Circumference1 aKapur, Vishesh, K1 aWilsdon, Anthony, G1 aAu, David1 aAvdalovic, Mark1 aEnright, Paul1 aFan, Vincent, S1 aHansel, Nadia, N1 aHeckbert, Susan, R1 aJiang, Rui1 aKrishnan, Jerry, A1 aMukamal, Kenneth1 aYende, Sachin1 aBarr, Graham uhttps://chs-nhlbi.org/node/141103017nas a2200493 4500008004100000022001400041245006200055210005700117260001300174300001100187490000700198520168900205653000901894653002401903653001901927653002401946653001101970653001101981653001401992653002102006653000902027653001602036653001702052100002102069700002402090700001902114700002302133700002302156700002202179700002402201700002402225700002502249700001802274700002602292700001902318700001802337700002002355700002202375700002202397700002502419700002002444700002302464856003602487 2013 eng d a1556-387100aThe QT interval and risk of incident atrial fibrillation.0 aQT interval and risk of incident atrial fibrillation c2013 Oct a1562-80 v103 aBACKGROUND: Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.
OBJECTIVE: To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF.
METHODS: We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas.
RESULTS: Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts.
CONCLUSIONS: A prolonged QT interval is associated with an increased risk of incident AF.
10aAged10aAtrial Fibrillation10aCohort Studies10aElectrocardiography10aFemale10aHumans10aIncidence10aLong QT Syndrome10aMale10aMiddle Aged10aRisk Factors1 aMandyam, Mala, C1 aSoliman, Elsayed, Z1 aAlonso, Alvaro1 aDewland, Thomas, A1 aHeckbert, Susan, R1 aVittinghoff, Eric1 aCummings, Steven, R1 aEllinor, Patrick, T1 aChaitman, Bernard, R1 aStocke, Karen1 aApplegate, William, B1 aArking, Dan, E1 aButler, Javed1 aLoehr, Laura, R1 aMagnani, Jared, W1 aMurphy, Rachel, A1 aSatterfield, Suzanne1 aNewman, Anne, B1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/599802377nas a2200349 4500008004100000022001400041245013400055210006900189260001300258300001100271490000700282520138400289653000901673653002401682653003401706653001101740653002201751653001101773653001401784653000901798653001501807653002001822653001701842653001101859653001801870100002001888700002101908700001901929700002001948700002301968856003601991 2013 eng d a1532-541500aRacial differences in the incidence of and risk factors for atrial fibrillation in older adults: the cardiovascular health study.0 aRacial differences in the incidence of and risk factors for atri c2013 Feb a276-800 v613 aThis study examined whether different associations between risk factors and atrial fibrillation (AF) according to race could explain the lower incidence of AF in blacks. Baseline risk factor information was obtained from interviews, clinical examinations, and echocardiography in 4,774 white and 911 black Cardiovascular Health Study participants aged 65 and older without a history of AF at baseline in 1989/90 or 1992/93. Incident AF was determined according to hospital discharge diagnosis or annual study electrocardiogram. Cox regression was used to assess associations between risk factors and race and incident AF. During a mean 11.2 years of follow-up, 1,403 whites and 182 blacks had incident AF. Associations between all examined risk factors were similar in both races, except left ventricular posterior wall thickness, which was more strongly associated with AF in blacks (per 0.2 cm, blacks: hazard ratio (HR) = 1.72, 95% confidence interval (CI) = 1.44-2.06; whites: HR = 1.30, 95% CI = 1.18-1.43). Overall, the relative risk of AF was 25% lower in blacks than whites after adjustment for age and sex (HR = 0.75, 95% CI = 0.64-0.87) and 45% lower after adjustment for all considered risk factors (HR = 0.55, 95% CI = 0.35-0.88). Different associations of the considered risk factors and incident AF by race do not explain the lower incidence of AF in blacks.
10aAged10aAtrial Fibrillation10aContinental Population Groups10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aPrevalence10aRisk Assessment10aRisk Factors10aStroke10aUnited States1 aJensen, Paul, N1 aThacker, Evan, L1 aDublin, Sascha1 aPsaty, Bruce, M1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/585204067nas a2200793 4500008004100000022001400041245014300055210006900198260001600267300001200283490000600295520178900301653002202090653001602112653000902128653002202137653002402159653001902183653002202202653004002224653001102264653001802275653001102293653001702304653001202321653001402333653000902347653001602356653002602372653001602398653003202414653002002446653001202466653001802478100001902496700002202515700001902537700002502556700002402581700002102605700002202626700002202648700002102670700002602691700002402717700002202741700002802763700002702791700002202818700002402840700002202864700002202886700002402908700002202932700002202954700002202976700001902998700001703017700002403034700001903058700001803077700002203095700002403117700002503141700002403166700002303190700002403213856003603237 2013 eng d a2047-998000aSimple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium.0 aSimple risk model predicts incidence of atrial fibrillation in a c2013 Mar 18 ae0001020 v23 aBACKGROUND: Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.
METHODS AND RESULTS: Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19% African Americans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95% CI, 0.664 to 0.747) and calibration was adequate.
CONCLUSION: A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.
10aAfrican Americans10aAge Factors10aAged10aAged, 80 and over10aAtrial Fibrillation10aCohort Studies10aDiabetes Mellitus10aEuropean Continental Ancestry Group10aFemale10aHeart Failure10aHumans10aHypertension10aIceland10aIncidence10aMale10aMiddle Aged10aMyocardial Infarction10aNetherlands10aProportional Hazards Models10aRisk Assessment10aSmoking10aUnited States1 aAlonso, Alvaro1 aKrijthe, Bouwe, P1 aAspelund, Thor1 aStepas, Katherine, A1 aPencina, Michael, J1 aMoser, Carlee, B1 aSinner, Moritz, F1 aSotoodehnia, Nona1 aFontes, João, D1 aJanssens, Cecile, J W1 aKronmal, Richard, A1 aMagnani, Jared, W1 aWitteman, Jacqueline, C1 aChamberlain, Alanna, M1 aLubitz, Steven, A1 aSchnabel, Renate, B1 aAgarwal, Sunil, K1 aMcManus, David, D1 aEllinor, Patrick, T1 aLarson, Martin, G1 aBurke, Gregory, L1 aLauner, Lenore, J1 aHofman, Albert1 aLevy, Daniel1 aGottdiener, John, S1 aKääb, Stefan1 aCouper, David1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aStricker, Bruno, H C1 aGudnason, Vilmundur1 aHeckbert, Susan, R1 aBenjamin, Emelia, J uhttps://chs-nhlbi.org/node/587803479nas a2200553 4500008004100000022001400041245016100055210006900216260001300285300001000298490000600308520190300314653001802217653000902235653002202244653001002266653001902276653001102295653002202306653003402328653001302362653001902375653001102394653000902405653000902414653001602423653003602439653002702475100002502502700001302527700002002540700002102560700001902581700001902600700002202619700002002641700001902661700002302680700001902703700002002722700002302742700001802765700001702783700002302800700002302823700002402846700001902870856003602889 2014 eng d a1942-326800aADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aADAM19 and HTR4 variants and pulmonary function Cohorts for Hear c2014 Jun a350-80 v73 aBACKGROUND: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4.
METHODS AND RESULTS: We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region.
CONCLUSIONS: Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.
10aADAM Proteins10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Diseases10aHumans10aLung10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA1 aLondon, Stephanie, J1 aGao, Wei1 aGharib, Sina, A1 aHancock, Dana, B1 aWilk, Jemma, B1 aHouse, John, S1 aGibbs, Richard, A1 aMuzny, Donna, M1 aLumley, Thomas1 aFranceschini, Nora1 aNorth, Kari, E1 aPsaty, Bruce, M1 aKovar, Christie, L1 aCoresh, Josef1 aZhou, Yanhua1 aHeckbert, Susan, R1 aBrody, Jennifer, A1 aMorrison, Alanna, C1 aDupuis, Josée uhttps://chs-nhlbi.org/node/658002904nas a2200373 4500008004100000022001400041245017000055210006900225260000900294300001200303490000600315520179500321653002102116653002002137653001902157653003402176653001102210653001102221653001402232653000902246653001602255653003002271653000902301653002102310653002402331100001902355700002002374700001902394700001702413700002002430700002102450700002302471856003602494 2014 eng d a1932-620300aAssociation of sick sinus syndrome with incident cardiovascular disease and mortality: the Atherosclerosis Risk in Communities study and Cardiovascular Health Study.0 aAssociation of sick sinus syndrome with incident cardiovascular c2014 ae1096620 v93 aBACKGROUND: Sick sinus syndrome (SSS) is a common indication for pacemaker implantation. Limited information exists on the association of sick sinus syndrome (SSS) with mortality and cardiovascular disease (CVD) in the general population.
METHODS: We studied 19,893 men and women age 45 and older in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), two community-based cohorts, who were without a pacemaker or atrial fibrillation (AF) at baseline. Incident SSS cases were validated by review of medical charts. Incident CVD and mortality were ascertained using standardized protocols. Multivariable Cox models were used to estimate the association of incident SSS with selected outcomes.
RESULTS: During a mean follow-up of 17 years, 213 incident SSS events were identified and validated (incidence, 0.6 events per 1,000 person-years). After adjustment for confounders, SSS incidence was associated with increased mortality (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.14-1.70), coronary heart disease (HR 1.72, 95%CI 1.11-2.66), heart failure (HR 2.87, 95%CI 2.17-3.80), stroke (HR 1.56, 95%CI 0.99-2.46), AF (HR 5.75, 95%CI 4.43-7.46), and pacemaker implantation (HR 53.7, 95%CI 42.9-67.2). After additional adjustment for other incident CVD during follow-up, SSS was no longer associated with increased mortality, coronary heart disease, or stroke, but remained associated with higher risk of heart failure (HR 2.00, 95%CI 1.51-2.66), AF (HR 4.25, 95%CI 3.28-5.51), and pacemaker implantation (HR 25.2, 95%CI 19.8-32.1).
CONCLUSION: Individuals who develop SSS are at increased risk of death and CVD. The mechanisms underlying these associations warrant further investigation.
10aAge Distribution10aAtherosclerosis10aCohort Studies10aContinental Population Groups10aFemale10aHumans10aIncidence10aMale10aMiddle Aged10aResidence Characteristics10aRisk10aSex Distribution10aSick Sinus Syndrome1 aAlonso, Alvaro1 aJensen, Paul, N1 aLopez, Faye, L1 aChen, Lin, Y1 aPsaty, Bruce, M1 aFolsom, Aaron, R1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/654304368nas a2200805 4500008004100000022001400041245016100055210006900216260001300285300001200298490000700310520202900317653000902346653002402355653001502379653002302394653001102417653001102428653001102439653001402450653000902464653003102473653002202504653003002526653002002556653001702576653001802593100002202611700002502633700002102658700002202679700001902701700002202720700002102742700002602763700002402789700002202813700002802835700002702863700002202890700002402912700002702936700002002963700002202983700002203005700002103027700001703048700002203065700002203087700002203109700001903131700001703150700002403167700001903191700001803210700002203228700001903250700002803269700002203297700002003319700002403339700002403363700002503387700002403412700002303436700002403459700002403483700001903507856003603526 2014 eng d a1532-209200aB-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies.0 aBtype natriuretic peptide and Creactive protein in the predictio c2014 Oct a1426-330 v163 aAIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
10aAged10aAtrial Fibrillation10aBiomarkers10aC-Reactive Protein10aEurope10aFemale10aHumans10aIncidence10aMale10aNatriuretic Peptide, Brain10aPeptide Fragments10aPredictive Value of Tests10aRisk Assessment10aRisk Factors10aUnited States1 aSinner, Moritz, F1 aStepas, Katherine, A1 aMoser, Carlee, B1 aKrijthe, Bouwe, P1 aAspelund, Thor1 aSotoodehnia, Nona1 aFontes, João, D1 aJanssens, Cecile, J W1 aKronmal, Richard, A1 aMagnani, Jared, W1 aWitteman, Jacqueline, C1 aChamberlain, Alanna, M1 aLubitz, Steven, A1 aSchnabel, Renate, B1 aVasan, Ramachandran, S1 aWang, Thomas, J1 aAgarwal, Sunil, K1 aMcManus, David, D1 aFranco, Oscar, H1 aYin, Xiaoyan1 aLarson, Martin, G1 aBurke, Gregory, L1 aLauner, Lenore, J1 aHofman, Albert1 aLevy, Daniel1 aGottdiener, John, S1 aKääb, Stefan1 aCouper, David1 aHarris, Tamara, B1 aAstor, Brad, C1 aBallantyne, Christie, M1 aHoogeveen, Ron, C1 aArai, Andrew, E1 aSoliman, Elsayed, Z1 aEllinor, Patrick, T1 aStricker, Bruno, H C1 aGudnason, Vilmundur1 aHeckbert, Susan, R1 aPencina, Michael, J1 aBenjamin, Emelia, J1 aAlonso, Alvaro uhttps://chs-nhlbi.org/node/660102852nas a2200493 4500008004100000022001400041245010800055210006900163260001300232300001300245490000800258520145900266653000901725653002401734653001501758653002101773653002401794653003801818653001101856653001301867653002201880653001101902653001401913653000901927653002201936653001601958653002401974653001701998653001702015653003702032653001802069100002602087700002102113700001702134700002202151700002102173700002002194700001902214700001802233700002402251700002302275700002402298856003602322 2014 eng d a1097-674400aCirculating fibrosis biomarkers and risk of atrial fibrillation: The Cardiovascular Health Study (CHS).0 aCirculating fibrosis biomarkers and risk of atrial fibrillation c2014 May a723-8.e20 v1673 aBACKGROUND: Cardiac fibrosis is thought to play a central role in the pathogenesis of atrial fibrillation (AF). Retrospective studies have suggested that circulating fibrosis biomarkers are associated with AF, but prospective studies are limited.
METHODS: We measured circulating levels of 2 fibrosis biomarkers, procollagen type III, N-terminal propeptide (PIIINP) and transforming growth factor β1 among participants of the CHS, a population-based study of older Americans. We used Cox proportional hazards and competing risks models to examine adjusted risk of incident AF over a median follow-up of 8.8 years.
RESULTS: Levels of PIIINP were assessed in 2,935 participants, of whom 767 developed AF. Compared with the median PIIINP level (4.45 μg/L), adjusted hazard ratios (95% CIs) were 0.85 (0.72-1.00) at the 10th percentile, 0.93 (0.88-0.99) at the 25th percentile, 1.04 (0.95-1.04) at the 75th percentile, and 1.07 (0.90-1.26) at the 90th. Transforming growth factor β1 levels, assessed in 1,538 participants with 408 cases of incident AF, were not associated with AF risk.
CONCLUSION: In older adults, PIIINP levels were associated with risk of incident AF in a complex manner, with an association that appeared to be positive up to median levels but with little relationship beyond that. Further studies are required to confirm and possibly delineate the mechanism for this relationship.
10aAged10aAtrial Fibrillation10aBiomarkers10aCardiomyopathies10aElectrocardiography10aEnzyme-Linked Immunosorbent Assay10aFemale10aFibrosis10aFollow-Up Studies10aHumans10aIncidence10aMale10aPeptide Fragments10aProcollagen10aProspective Studies10aRisk Factors10aTime Factors10aTransforming Growth Factor beta110aUnited States1 aRosenberg, Michael, A1 aMaziarz, Marlena1 aTan, Alex, Y1 aGlazer, Nicole, L1 aZieman, Susan, J1 aKizer, Jorge, R1 aIx, Joachim, H1 aDjoussé, Luc1 aSiscovick, David, S1 aHeckbert, Susan, R1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/633703296nas a2200565 4500008004100000022001400041245008800055210006900143260001300212300001000225490000700235520169900242653000901941653003401950653002401984653001102008653003802019653001502057653001102072653002102083653000902104653001602113653001402129653003602143653002802179653003402207653001702241100002302258700002102281700002002302700002302322700002302345700001202368700001902380700001702399700002302416700002302439700002402462700002002486700001902506700002002525700002002545700002402565700002102589700001902610700001902629700002402648700002202672856003602694 2014 eng d a1531-548700aEvidence of heterogeneity by race/ethnicity in genetic determinants of QT interval.0 aEvidence of heterogeneity by raceethnicity in genetic determinan c2014 Nov a790-80 v253 aBACKGROUND: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.
METHODS: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.
RESULTS: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.
CONCLUSIONS: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.
10aAged10aContinental Population Groups10aElectrocardiography10aFemale10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aLong QT Syndrome10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRisk Factors1 aSeyerle, Amanda, A1 aYoung, Alicia, M1 aJeff, Janina, M1 aMelton, Phillip, E1 aJorgensen, Neal, W1 aLin, Yi1 aCarty, Cara, L1 aDeelman, Ewa1 aHeckbert, Susan, R1 aHindorff, Lucia, A1 aJackson, Rebecca, D1 aMartin, Lisa, W1 aOkin, Peter, M1 aPerez, Marco, V1 aPsaty, Bruce, M1 aSoliman, Elsayed, Z1 aWhitsel, Eric, A1 aNorth, Kari, E1 aLaston, Sandra1 aKooperberg, Charles1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/659803407nas a2200553 4500008004100000022001400041245015800055210006900213260001600282300001200298490000800310520176800318653000902086653002202095653002402117653001602141653001802157653001102175653003102186653002202217653003102239653001802270653001102288653003402299653000902333653001602342653001502358653003202373653003302405653001702438653001802455653003402473653002702507653001402534100002002548700002202568700001602590700002302606700002302629700002502652700001902677700002102696700001502717700001902732700002402751700002202775700002002797856003602817 2014 eng d a1524-453900aFibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS).0 aFibroblast growth factor23 and incident atrial fibrillation the c2014 Jul 22 a298-3070 v1303 aBACKGROUND: Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction.
METHODS AND RESULTS: We tested the associations of circulating FGF-23 concentration with incident AF among 6398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular disease at baseline. Over a median of 7.7 and 8.0 years of follow-up, we observed 291 and 229 incident AF events in MESA and CHS, respectively. In multivariable Cox proportional hazards models, each 2-fold-higher FGF-23 concentration was associated with a 41% higher risk of incident AF in MESA (hazard ratio, 1.41; 95% confidence interval, 1.13-1.76; P=0.003) and a 30% higher risk of incident AF in CHS (hazard ratio, 1.30; 95% confidence interval, 1.05-1.61; P=0.016) after adjustment for potential confounding characteristics, including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (hazard ratio, 1.15 per 0.5 mg/dL; 95% confidence interval, 1.02-1.31; P=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjustment for FGF-23.
CONCLUSION: Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.
10aAged10aAged, 80 and over10aAtrial Fibrillation10aComorbidity10aEthnic Groups10aFemale10aFibroblast Growth Factor 310aFollow-Up Studies10aGlomerular Filtration Rate10aHeart Failure10aHumans10aHypertrophy, Left Ventricular10aMale10aMiddle Aged10aPhosphates10aProportional Hazards Models10aRenal Insufficiency, Chronic10aRisk Factors10aUnited States10aVentricular Dysfunction, Left10aVentricular Remodeling10aVitamin D1 aMathew, Jehu, S1 aSachs, Michael, C1 aKatz, Ronit1 aPatton, Kristen, K1 aHeckbert, Susan, R1 aHoofnagle, Andrew, N1 aAlonso, Alvaro1 aChonchol, Michel1 aDeo, Rajat1 aIx, Joachim, H1 aSiscovick, David, S1 aKestenbaum, Bryan1 ade Boer, Ian, H uhttps://chs-nhlbi.org/node/639902046nas a2200229 4500008004100000022001400041245009800055210006900153260000900222300001000231490000600241520135400247100002401601700002301625700002301648700002201671700002201693700001801715700002001733700002701753856003601780 2014 eng d a1948-175600aGene expression in thiazide diuretic or statin users in relation to incident type 2 diabetes.0 aGene expression in thiazide diuretic or statin users in relation c2014 a22-300 v53 aThiazide diuretics and statins are used to improve cardiovascular outcomes, but may also cause type 2 diabetes (T2DM), although mechanisms are unknown. Gene expression studies may facilitate understanding of these associations. Participants from ongoing population-based studies were sampled for these longitudinal studies of peripheral blood microarray gene expression, and followed to incident diabetes. All sampled subjects were statin or thiazide users. Those who developed diabetes during follow-up comprised cases (44 thiazide users; 19 statin users), and were matched to drug-using controls who did not develop diabetes on several factors. Supervised normalization, surrogate variable analyses removed technical bias and confounding. Differentially-expressed genes were those with a false discovery rate Q-value<0.05. Among thiazide users, diabetes cases had significantly different expression of CCL14 (down-regulated 6%, Q-value=0.0257), compared with controls. Among statin users, diabetes cases had marginal but insignificantly different expression of ZNF532 (up-regulated 15%, Q-value=0.0584), CXORF21 (up-regulated 11%, Q-value=0.0584), and ZNHIT3 (up-regulated 19%, Q-value=0.0959), compared with controls. These genes comprise potential targets for future expression or mechanistic research on medication-related diabetes development.1 aSuchy-Dicey, Astrid1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aMcKnight, Barbara1 aRotter, Jerome, I1 aChen, Yd, Ida1 aPsaty, Bruce, M1 aEnquobahrie, Daniel, A uhttps://chs-nhlbi.org/node/660310059nas a2203157 4500008004100000022001400041245012200055210006900177260001300246300001100259490000700270520116100277653001001438653000901448653002501457653002201482653002701504653002401531653001101555653003801566653003401604653001301638653002101651653001101672653002101683653000901704653001601713653001501729653003601744100001901780700001901799700001601818700001501834700002401849700002401873700002201897700002501919700002001944700001801964700002301982700001902005700002802024700002502052700002202077700001902099700002302118700001802141700003002159700002502189700001902214700002602233700001902259700001802278700002502296700002102321700001902342700001902361700002802380700002102408700001802429700002202447700002202469700001702491700001802508700002002526700002102546700002302567700002302590700001802613700002302631700002002654700002502674700002302699700002302722700002602745700001802771700002202789700002502811700002302836700002502859700002102884700002202905700002202927700002302949700001902972700001902991700001703010700002003027700002003047700002103067700002503088700001803113700002303131700002203154700002403176700002003200700001803220700002203238700003903260700001703299700002103316700002203337700002303359700002003382700002203402700001803424700001903442700002003461700001903481700001803500700002003518700001603538700002803554700002103582700001803603700002303621700002003644700002103664700002203685700003003707700001703737700001703754700002203771700002103793700002403814700002103838700002403859700002203883700001603905700002203921700002203943700002103965700001903986700001904005700001904024700001804043700002404061700001904085700002304104700002204127700002004149700001904169700002204188700002204210700002004232700002004252700001804272700002204290700002604312700002304338700001704361700003104378700002704409700001804436700002404454700001804478700002304496700002004519700002704539700002404566700003004590700001704620700002004637700002004657700001904677700002104696700002404717700002404741700002504765700002304790700002604813700002604839700002704865700002604892700001604918700002204934700002004956700001904976700002504995700001805020700002705038700002405065700001805089700002905107700002805136700002005164700002205184700002105206700001905227700001705246700002805263700003005291700002205321700002005343700001905363700002505382700002305407700002105430700001705451700002405468700001705492700002605509700001705535700002005552700002405572700001905596700001505615700002205630700002805652700001905680700002005699700001805719700002305737700002205760700001905782700001905801700001705820700002605837700002405863700002305887700002405910700002005934700002205954700002405976700002506000700002306025700002006048700002006068700002106088700002106109700001606130700001806146700002606164700002606190700002506216700002406241700001806265700001706283700002306300700002406323700002406347700002006371700002006391700002206411700001806433700002406451700002306475700002106498700002106519700002306540700002106563700001706584700002306601700001906624700002606643700002506669700001806694700002506712700002906737710002006766710002206786710001406808710002206822710002106844856003606865 2014 eng d a1546-171800aGenetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.0 aGenetic association study of QT interval highlights role for cal c2014 Aug a826-360 v463 aThe QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
10aAdult10aAged10aArrhythmias, Cardiac10aCalcium Signaling10aDeath, Sudden, Cardiac10aElectrocardiography10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHeart Ventricles10aHumans10aLong QT Syndrome10aMale10aMiddle Aged10aMyocardium10aPolymorphism, Single Nucleotide1 aArking, Dan, E1 aPulit, Sara, L1 aCrotti, Lia1 aHarst, Pim1 aMunroe, Patricia, B1 aKoopmann, Tamara, T1 aSotoodehnia, Nona1 aRossin, Elizabeth, J1 aMorley, Michael1 aWang, Xinchen1 aJohnson, Andrew, D1 aLundby, Alicia1 aGudbjartsson, Daniel, F1 aNoseworthy, Peter, A1 aEijgelsheim, Mark1 aBradford, Yuki1 aTarasov, Kirill, V1 aDörr, Marcus1 aMüller-Nurasyid, Martina1 aLahtinen, Annukka, M1 aNolte, Ilja, M1 aSmith, Albert, Vernon1 aBis, Joshua, C1 aIsaacs, Aaron1 aNewhouse, Stephen, J1 aEvans, Daniel, S1 aPost, Wendy, S1 aWaggott, Daryl1 aLyytikäinen, Leo-Pekka1 aHicks, Andrew, A1 aEisele, Lewin1 aEllinghaus, David1 aHayward, Caroline1 aNavarro, Pau1 aUlivi, Sheila1 aTanaka, Toshiko1 aTester, David, J1 aChatel, Stéphanie1 aGustafsson, Stefan1 aKumari, Meena1 aMorris, Richard, W1 aNaluai, Åsa, T1 aPadmanabhan, Sandosh1 aKluttig, Alexander1 aStrohmer, Bernhard1 aPanayiotou, Andrie, G1 aTorres, Maria1 aKnoflach, Michael1 aHubacek, Jaroslav, A1 aSlowikowski, Kamil1 aRaychaudhuri, Soumya1 aKumar, Runjun, D1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShuldiner, Alan, R1 aAlonso, Alvaro1 aBader, Joel, S1 aEhret, Georg1 aHuang, Hailiang1 aKao, Linda, W H1 aStrait, James, B1 aMacfarlane, Peter, W1 aBrown, Morris1 aCaulfield, Mark, J1 aSamani, Nilesh, J1 aKronenberg, Florian1 aWilleit, Johann1 aSmith, Gustav1 aGreiser, Karin, H1 aSchwabedissen, Henriette, Meyer Zu1 aWerdan, Karl1 aCarella, Massimo1 aZelante, Leopoldo1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aKolcic, Ivana1 aPolasek, Ozren1 aWright, Alan, F1 aGriffin, Maura1 aDaly, Mark, J1 aArnar, David, O1 aHolm, Hilma1 aThorsteinsdottir, Unnur1 aDenny, Joshua, C1 aRoden, Dan, M1 aZuvich, Rebecca, L1 aEmilsson, Valur1 aPlump, Andrew, S1 aLarson, Martin, G1 aO'Donnell, Christopher, J1 aYin, Xiaoyan1 aBobbo, Marco1 aD'Adamo, Adamo, P1 aIorio, Annamaria1 aSinagra, Gianfranco1 aCarracedo, Angel1 aCummings, Steven, R1 aNalls, Michael, A1 aJula, Antti1 aKontula, Kimmo, K1 aMarjamaa, Annukka1 aOikarinen, Lasse1 aPerola, Markus1 aPorthan, Kimmo1 aErbel, Raimund1 aHoffmann, Per1 aJöckel, Karl-Heinz1 aKälsch, Hagen1 aNöthen, Markus, M1 aHoed, Marcel, den1 aLoos, Ruth, J F1 aThelle, Dag, S1 aGieger, Christian1 aMeitinger, Thomas1 aPerz, Siegfried1 aPeters, Annette1 aPrucha, Hanna1 aSinner, Moritz, F1 aWaldenberger, Melanie1 ade Boer, Rudolf, A1 aFranke, Lude1 avan der Vleuten, Pieter, A1 aBeckmann, Britt, Maria1 aMartens, Eimo1 aBardai, Abdennasser1 aHofman, Nynke1 aWilde, Arthur, A M1 aBehr, Elijah, R1 aDalageorgou, Chrysoula1 aGiudicessi, John, R1 aMedeiros-Domingo, Argelia1 aBarc, Julien1 aKyndt, Florence1 aProbst, Vincent1 aGhidoni, Alice1 aInsolia, Roberto1 aHamilton, Robert, M1 aScherer, Stephen, W1 aBrandimarto, Jeffrey1 aMargulies, Kenneth1 aMoravec, Christine, E1 aM, Fabiola, del Greco1 aFuchsberger, Christian1 aO'Connell, Jeffrey, R1 aLee, Wai, K1 aWatt, Graham, C M1 aCampbell, Harry1 aWild, Sarah, H1 aMokhtari, Nour, E El1 aFrey, Norbert1 aAsselbergs, Folkert, W1 aLeach, Irene, Mateo1 aNavis, Gerjan1 avan den Berg, Maarten, P1 avan Veldhuisen, Dirk, J1 aKellis, Manolis1 aKrijthe, Bouwe, P1 aFranco, Oscar, H1 aHofman, Albert1 aKors, Jan, A1 aUitterlinden, André, G1 aWitteman, Jacqueline, C M1 aKedenko, Lyudmyla1 aLamina, Claudia1 aOostra, Ben, A1 aAbecasis, Goncalo, R1 aLakatta, Edward, G1 aMulas, Antonella1 aOrrù, Marco1 aSchlessinger, David1 aUda, Manuela1 aMarkus, Marcello, R P1 aVölker, Uwe1 aSnieder, Harold1 aSpector, Timothy, D1 aArnlöv, Johan1 aLind, Lars1 aSundström, Johan1 aSyvänen, Ann-Christine1 aKivimaki, Mika1 aKähönen, Mika1 aMononen, Nina1 aRaitakari, Olli, T1 aViikari, Jorma, S1 aAdamkova, Vera1 aKiechl, Stefan1 aBrion, Maria1 aNicolaides, Andrew, N1 aPaulweber, Bernhard1 aHaerting, Johannes1 aDominiczak, Anna, F1 aNyberg, Fredrik1 aWhincup, Peter, H1 aHingorani, Aroon, D1 aSchott, Jean-Jacques1 aBezzina, Connie, R1 aIngelsson, Erik1 aFerrucci, Luigi1 aGasparini, Paolo1 aWilson, James, F1 aRudan, Igor1 aFranke, Andre1 aMühleisen, Thomas, W1 aPramstaller, Peter, P1 aLehtimäki, Terho, J1 aPaterson, Andrew, D1 aParsa, Afshin1 aLiu, Yongmei1 aDuijn, Cornelia, M1 aSiscovick, David, S1 aGudnason, Vilmundur1 aJamshidi, Yalda1 aSalomaa, Veikko1 aFelix, Stephan, B1 aSanna, Serena1 aRitchie, Marylyn, D1 aStricker, Bruno, H1 aStefansson, Kari1 aBoyer, Laurie, A1 aCappola, Thomas, P1 aOlsen, Jesper, V1 aLage, Kasper1 aSchwartz, Peter, J1 aKääb, Stefan1 aChakravarti, Aravinda1 aAckerman, Michael, J1 aPfeufer, Arne1 ade Bakker, Paul, I W1 aNewton-Cheh, Christopher1 aCARe Consortium1 aCOGENT Consortium1 aDCCT/EDIC1 aeMERGE Consortium1 aHRGEN Consortium uhttps://chs-nhlbi.org/node/654402698nas a2200385 4500008004100000022001400041245010500055210006900160260001600229300001100245490000800256520153600264653002201800653000901822653002401831653001601855653001801871653004001889653001101929653003801940653001101978653002501989653000902014653003602023653003202059653001702091100002602108700002202134700002402156700002002180700002302200700002902223700002402252856003602276 2014 eng d a1476-625600aGenetic variants related to height and risk of atrial fibrillation: the cardiovascular health study.0 aGenetic variants related to height and risk of atrial fibrillati c2014 Jul 15 a215-220 v1803 aIncreased height is a known independent risk factor for atrial fibrillation (AF). However, whether genetic determinants of height influence risk is uncertain. In this candidate gene study, we examined the association of 209 height-associated single-nucleotide polymorphisms (SNPs) with incident AF in 3,309 persons of European descent from the Cardiovascular Health Study, a prospective cohort study of older adults (aged ≥ 65 years) enrolled in 1989-1990. After a median follow-up period of 13.2 years, 879 participants developed incident AF. The height-associated SNPs together explained approximately 10% of the variation in height (P = 6.0 × 10(-8)). Using an unweighted genetic height score, we found a nonsignificant association with risk of AF (per allele, hazard ratio = 1.01, 95% confidence interval: 1.00, 1.02; P = 0.06). In weighted analyses, we found that genetically predicted height was strongly associated with AF risk (per 10 cm, hazard ratio = 1.30, 95% confidence interval: 1.03, 1.64; P = 0.03). Importantly, for all models, the inclusion of actual height completely attenuated the genetic height effect. Finally, we identified 1 nonsynonymous SNP (rs1046934) that was independently associated with AF and may warrant future study. In conclusion, we found that genetic determinants of height appear to increase the risk of AF, primarily via height itself. This approach of examining SNPs associated with an intermediate phenotype should be considered as a method for identifying novel genetic targets.
10aAfrican Americans10aAged10aAtrial Fibrillation10aBody Height10aEndonucleases10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aHumans10aLongitudinal Studies10aMale10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aRisk Factors1 aRosenberg, Michael, A1 aKaplan, Robert, C1 aSiscovick, David, S1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aNewton-Cheh, Christopher1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/659507147nas a2202257 4500008004100000022001400041245010000055210006900155260001300224300001100237490000700248520092000255653001901175653002301194653002201217653002901239653001701268653003801285653001801323653003401341653001101375653001801386653002701404653003601431653001401467653002801481653003101509653001501540653001901555100001801574700002601592700002001618700002001638700002301658700001601681700002301697700002601720700001501746700002101761700002001782700002301802700001901825700002501844700002201869700002601891700002501917700001901942700001801961700001901979700002001998700002202018700001802040700002002058700001702078700002402095700003102119700001902150700001902169700002002188700001502208700001802223700002202241700002002263700002002283700001202303700001902315700001602334700002102350700001902371700002202390700001902412700002402431700001602455700001702471700001902488700002002507700002402527700002002551700001802571700001802589700002102607700002702628700001702655700001702672700002702689700001902716700002202735700001702757700002002774700002102794700001802815700001902833700001902852700002002871700002602891700001902917700001902936700002402955700002402979700002203003700001303025700002203038700002003060700002103080700001903101700001903120700001803139700002003157700002003177700001703197700002503214700002803239700002003267700002303287700002203310700001503332700001803347700002303365700001603388700002603404700001703430700001603447700001703463700001903480700002303499700001903522700002003541700002403561700002003585700002103605700002103626700002103647700002203668700001903690700002003709700002103729700002203750700001903772700002003791700002003811700002203831700001803853700002803871700002403899700001703923700002803940700002403968700002103992700001904013700001904032700002204051700001804073700002204091700001904113700001804132700002304150700002504173700002004198700001904218700002404237700001904261700001604280700001904296700002204315700001804337700001904355700001704374700002704391700002104418700001504439700002304454700002204477700002404499700001704523700002504540700002104565700001704586700001904603700002204622700001704644700002404661700002504685700001704710700002204727700001904749700001704768700002204785700002104807700002504828856003604853 2014 eng d a1546-171800aGenome-wide association analysis identifies six new loci associated with forced vital capacity.0 aGenomewide association analysis identifies six new loci associat c2014 Jul a669-770 v463 aForced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
10aCohort Studies10aDatabases, Genetic10aFollow-Up Studies10aForced Expiratory Volume10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLung Diseases10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aPrognosis10aQuantitative Trait Loci10aRespiratory Function Tests10aSpirometry10aVital Capacity1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aGharib, Sina, A1 aWain, Louise, V1 aFranceschini, Nora1 aKoch, Beate1 aPottinger, Tess, D1 aSmith, Albert, Vernon1 aDuan, Qing1 aOldmeadow, Chris1 aLee, Mi, Kyeong1 aStrachan, David, P1 aJames, Alan, L1 aHuffman, Jennifer, E1 aVitart, Veronique1 aRamasamy, Adaikalavan1 aWareham, Nicholas, J1 aKaprio, Jaakko1 aWang, Xin-Qun1 aTrochet, Holly1 aKähönen, Mika1 aFlexeder, Claudia1 aAlbrecht, Eva1 aLopez, Lorna, M1 ade Jong, Kim1 aThyagarajan, Bharat1 aAlves, Alexessander, Couto1 aEnroth, Stefan1 aOmenaas, Ernst1 aJoshi, Peter, K1 aFall, Tove1 aViñuela, Ana1 aLauner, Lenore, J1 aLoehr, Laura, R1 aFornage, Myriam1 aLi, Guo1 aWilk, Jemma, B1 aTang, Wenbo1 aManichaikul, Ani1 aLahousse, Lies1 aHarris, Tamara, B1 aNorth, Kari, E1 aRudnicka, Alicja, R1 aHui, Jennie1 aGu, Xiangjun1 aLumley, Thomas1 aWright, Alan, F1 aHastie, Nicholas, D1 aCampbell, Susan1 aKumar, Rajesh1 aPin, Isabelle1 aScott, Robert, A1 aPietiläinen, Kirsi, H1 aSurakka, Ida1 aLiu, Yongmei1 aHolliday, Elizabeth, G1 aSchulz, Holger1 aHeinrich, Joachim1 aDavies, Gail1 aVonk, Judith, M1 aWojczynski, Mary1 aPouta, Anneli1 aJohansson, Asa1 aWild, Sarah, H1 aIngelsson, Erik1 aRivadeneira, Fernando1 aVölzke, Henry1 aHysi, Pirro, G1 aEiriksdottir, Gudny1 aMorrison, Alanna, C1 aRotter, Jerome, I1 aGao, Wei1 aPostma, Dirkje, S1 aWhite, Wendy, B1 aRich, Stephen, S1 aHofman, Albert1 aAspelund, Thor1 aCouper, David1 aSmith, Lewis, J1 aPsaty, Bruce, M1 aLohman, Kurt1 aBurchard, Esteban, G1 aUitterlinden, André, G1 aGarcia, Melissa1 aJoubert, Bonnie, R1 aMcArdle, Wendy, L1 aMusk, Bill1 aHansel, Nadia1 aHeckbert, Susan, R1 aZgaga, Lina1 avan Meurs, Joyce, B J1 aNavarro, Pau1 aRudan, Igor1 aOh, Yeon-Mok1 aRedline, Susan1 aJarvis, Deborah, L1 aZhao, Jing Hua1 aRantanen, Taina1 aO'Connor, George, T1 aRipatti, Samuli1 aScott, Rodney, J1 aKarrasch, Stefan1 aGrallert, Harald1 aGaddis, Nathan, C1 aStarr, John, M1 aWijmenga, Cisca1 aMinster, Ryan, L1 aLederer, David, J1 aPekkanen, Juha1 aGyllensten, Ulf1 aCampbell, Harry1 aMorris, Andrew, P1 aGläser, Sven1 aHammond, Christopher, J1 aBurkart, Kristin, M1 aBeilby, John1 aKritchevsky, Stephen, B1 aGudnason, Vilmundur1 aHancock, Dana, B1 aWilliams, Dale1 aPolasek, Ozren1 aZemunik, Tatijana1 aKolcic, Ivana1 aPetrini, Marcy, F1 aWjst, Matthias1 aKim, Woo, Jin1 aPorteous, David, J1 aScotland, Generation1 aSmith, Blair, H1 aViljanen, Anne1 aHeliövaara, Markku1 aAttia, John, R1 aSayers, Ian1 aHampel, Regina1 aGieger, Christian1 aDeary, Ian, J1 aBoezen, Marike1 aNewman, Anne1 aJarvelin, Marjo-Riitta1 aWilson, James, F1 aLind, Lars1 aStricker, Bruno, H1 aTeumer, Alexander1 aSpector, Timothy, D1 aMelén, Erik1 aPeters, Marjolein, J1 aLange, Leslie, A1 aBarr, Graham1 aBracke, Ken, R1 aVerhamme, Fien, M1 aSung, Joohon1 aHiemstra, Pieter, S1 aCassano, Patricia, A1 aSood, Akshay1 aHayward, Caroline1 aDupuis, Josée1 aHall, Ian, P1 aBrusselle, Guy, G1 aTobin, Martin, D1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/658204635nas a2200913 4500008004100000022001400041245013400055210006900189260001300258300001100271490000600282520207800288653001002366653000902376653002002385653001302405653001802418653001902436653001102455653001702466653003402483653001302517653001702530653001102547653000902558653002102567653001602588653003602604653003202640653001702672653001102689653002602700653001802726100002202744700001902766700001802785700002002803700001602823700002202839700002302861700002202884700002302906700002002929700002702949700002702976700002003003700002003023700002103043700002403064700002003088700002003108700002103128700001703149700001803166700002403184700002203208700002003230700002203250700002103272700002203293700001803315700002303333700002203356700002103378700002403399700002003423700002203443700002303465700002003488700001803508700002403526700002403550700002203574700002003596700002003616700002703636700002203663856003603685 2014 eng d a1942-326800aGenome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine.0 aGenomewide association study of Larginine and dimethylarginines c2014 Dec a864-720 v73 aBACKGROUND: Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.
METHODS AND RESULTS: This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
CONCLUSIONS: These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.
10aAdult10aAged10aAmidohydrolases10aArginine10aBinding Sites10aCohort Studies10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHEK293 Cells10aHumans10aMale10aMediator Complex10aMiddle Aged10aPolymorphism, Single Nucleotide10aProtein Structure, Tertiary10aRisk Factors10aStroke10aSubstrate Specificity10aTransaminases1 aLüneburg, Nicole1 aLieb, Wolfgang1 aZeller, Tanja1 aChen, Ming-Huei1 aMaas, Renke1 aCarter, Angela, M1 aXanthakis, Vanessa1 aGlazer, Nicole, L1 aSchwedhelm, Edzard1 aSeshadri, Sudha1 aIkram, Mohammad, Arfan1 aLongstreth, William, T1 aFornage, Myriam1 aKönig, Inke, R1 aLoley, Christina1 aOjeda, Francisco, M1 aSchillert, Arne1 aWang, Thomas, J1 aSticht, Heinrich1 aKittel, Anja1 aKönig, Jörg1 aBenjamin, Emelia, J1 aSullivan, Lisa, M1 aBernges, Isabel1 aAnderssohn, Maike1 aZiegler, Andreas1 aGieger, Christian1 aIllig, Thomas1 aMeisinger, Christa1 aWichmann, H-Erich1 aWild, Philipp, S1 aSchunkert, Heribert1 aPsaty, Bruce, M1 aWiggins, Kerri, L1 aHeckbert, Susan, R1 aSmith, Nicholas1 aLackner, Karl1 aLunetta, Kathryn, L1 aBlankenberg, Stefan1 aErdmann, Jeanette1 aMünzel, Thomas1 aGrant, Peter, J1 aVasan, Ramachandran, S1 aBöger, Rainer, H uhttps://chs-nhlbi.org/node/681902966nas a2200397 4500008004100000022001400041245008600055210006900141260001600210300001000226490000700236520183900243653003902082653000902121653002202130653001902152653004002171653001102211653002202222653001102244653001402255653000902269653001602278653002802294653002402322653001702346653002402363100002002387700002402407700001702431700002102448700002102469700002302490700001902513856003602532 2014 eng d a1558-359700aIncidence of and risk factors for sick sinus syndrome in the general population.0 aIncidence of and risk factors for sick sinus syndrome in the gen c2014 Aug 12 a531-80 v643 aBACKGROUND: Little is known about the incidence of and risk factors for sick sinus syndrome (SSS), a common indication for pacemaker implantation.
OBJECTIVES: This study sought to describe the epidemiology of SSS.
METHODS: This analysis included 20,572 participants (mean baseline age 59 years, 43% male) in the ARIC (Atherosclerosis Risk In Communities) study and the CHS (Cardiovascular Health Study), who at baseline were free of prevalent atrial fibrillation and pacemaker therapy, had a heart rate of ≥ 50 beats/min unless using beta blockers, and were identified as of white or black race. Incident SSS cases were identified by hospital discharge International Classification of Disease-revision 9-Clinical Modification code 427.81 and validated by medical record review.
RESULTS: During an average 17 years of follow-up, 291 incident SSS cases were identified (unadjusted rate 0.8 per 1,000 person-years). Incidence increased with age (hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 1.47 to 2.05 per 5-year increment), and blacks had a 41% lower risk of SSS than whites (HR: 0.59; 95% CI: 0.37 to 0.98). Incident SSS was associated with greater baseline body mass index, height, N-terminal pro-B-type natriuretic peptide, and cystatin C, with longer QRS interval, with lower heart rate, and with prevalent hypertension, right bundle branch block, and cardiovascular disease. We project that the annual number of new SSS cases in the United States will increase from 78,000 in 2012 to 172,000 in 2060.
CONCLUSIONS: Blacks have a lower risk of SSS than whites, and several cardiovascular risk factors were associated with incident SSS. With the aging of the population, the number of Americans with SSS will increase dramatically over the next 50 years.
10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aMiddle Aged10aPopulation Surveillance10aProspective Studies10aRisk Factors10aSick Sinus Syndrome1 aJensen, Paul, N1 aGronroos, Noelle, N1 aChen, Lin, Y1 aFolsom, Aaron, R1 adeFilippi, Chris1 aHeckbert, Susan, R1 aAlonso, Alvaro uhttps://chs-nhlbi.org/node/657204762nas a2201117 4500008004100000022001400041245011700055210006900172260001500241300001200256490000800268520162700276653000901903653001201912653002401924653002301948653001601971653001101987653001101998653003002009653001702039653003802056653001302094653002502107653001102132653001002143653000902153653001602162653002002178653002102198653002802219653002302247653002602270653002602296653003002322653001402352653002302366100002202389700002202411700002402433700001902457700001802476700002002494700001902514700001902533700001902552700002202571700002202593700002202615700002202637700001902659700002302678700002302701700003002724700002002754700002002774700002102794700001902815700002302834700002002857700002302877700001902900700002302919700002502942700001802967700002302985700002503008700002203033700001903055700001803074700002103092700002403113700001903137700002803156700002403184700002003208700001803228700002103246700002103267700002603288700002403314700002003338700001903358700002303377700001403400700001703414700001803431700002203449700002503471700002203496700001903518700002403537710002603561710002103587856003603608 2014 eng d a1524-453900aIntegrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.0 aIntegrating genetic transcriptional and functional analyses to i c2014 Oct 7 a1225-350 v1303 aBACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.
METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively).
CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.
10aAged10aAnimals10aAtrial Fibrillation10aChromosome Mapping10aConnexin 4310aEurope10aFemale10aGene Knockdown Techniques10aGenetic Loci10aGenetic Predisposition to Disease10aGenotype10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aMuscle Proteins10aNuclear Proteins10aQuantitative Trait Loci10aRepressor Proteins10aT-Box Domain Proteins10aTranscription Factors10aUbiquitin-Protein Ligases10aZebrafish10aZebrafish Proteins1 aSinner, Moritz, F1 aTucker, Nathan, R1 aLunetta, Kathryn, L1 aOzaki, Kouichi1 aSmith, Gustav1 aTrompet, Stella1 aBis, Joshua, C1 aLin, Honghuang1 aChung, Mina, K1 aNielsen, Jonas, B1 aLubitz, Steven, A1 aKrijthe, Bouwe, P1 aMagnani, Jared, W1 aYe, Jiangchuan1 aGollob, Michael, H1 aTsunoda, Tatsuhiko1 aMüller-Nurasyid, Martina1 aLichtner, Peter1 aPeters, Annette1 aDolmatova, Elena1 aKubo, Michiaki1 aSmith, Jonathan, D1 aPsaty, Bruce, M1 aSmith, Nicholas, L1 aJukema, Wouter1 aChasman, Daniel, I1 aAlbert, Christine, M1 aEbana, Yusuke1 aFurukawa, Tetsushi1 aMacfarlane, Peter, W1 aHarris, Tamara, B1 aDarbar, Dawood1 aDörr, Marcus1 aHolst, Anders, G1 aSvendsen, Jesper, H1 aHofman, Albert1 aUitterlinden, André, G1 aGudnason, Vilmundur1 aIsobe, Mitsuaki1 aMalik, Rainer1 aDichgans, Martin1 aRosand, Jonathan1 aVan Wagoner, David, R1 aBenjamin, Emelia, J1 aMilan, David, J1 aMelander, Olle1 aHeckbert, Susan, R1 aFord, Ian1 aLiu, Yongmei1 aBarnard, John1 aOlesen, Morten, S1 aStricker, Bruno, H C1 aTanaka, Toshihiro1 aKääb, Stefan1 aEllinor, Patrick, T1 aMETASTROKE Consortium1 aAFGen Consortium uhttps://chs-nhlbi.org/node/660005294nas a2201225 4500008004100000022001400041245011300055210006900168260000900237300001200246490000600258520192600264653001002190653003202200653001102232653003102243653001702274653003402291653001102325653002502336653000902361653001602370100001602386700002102402700001802423700002602441700002302467700001702490700002002507700002102527700002002548700002402568700002302592700002202615700002102637700002202658700002402680700002302704700001802727700002402745700002302769700001702792700002202809700002102831700001902852700001702871700001802888700001902906700001502925700001902940700002302959700001302982700001802995700001703013700002103030700002203051700001903073700001903092700002003111700001603131700002103147700001603168700002803184700001803212700001903230700001203249700001503261700002203276700001703298700001703315700001903332700002203351700001903373700002203392700002403414700001503438700001903453700002003472700002903492700002003521700002603541700002203567700001903589700002003608700001703628700001903645700002303664700002203687700002803709700001903737700001903756700002003775700002103795700001903816700001903835700002303854700002303877700002503900700002003925700002103945700002403966700001703990700002504007856003604032 2014 eng d a1932-620300aLarge-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.0 aLargescale genomewide association studies and metaanalyses of lo c2014 ae1007760 v93 aBACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
10aAdult10aChromosomes, Human, Pair 1110aFemale10aGene Expression Regulation10aGenetic Loci10aGenome-Wide Association Study10aHumans10aLongitudinal Studies10aMale10aRespiration1 aTang, Wenbo1 aKowgier, Matthew1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aJoubert, Bonnie, R1 aHodge, Emily1 aGharib, Sina, A1 aSmith, Albert, V1 aRuczinski, Ingo1 aGudnason, Vilmundur1 aMathias, Rasika, A1 aHarris, Tamara, B1 aHansel, Nadia, N1 aLauner, Lenore, J1 aBarnes, Kathleen, C1 aHansen, Joyanna, G1 aAlbrecht, Eva1 aAldrich, Melinda, C1 aAllerhand, Michael1 aBarr, Graham1 aBrusselle, Guy, G1 aCouper, David, J1 aCurjuric, Ivan1 aDavies, Gail1 aDeary, Ian, J1 aDupuis, Josée1 aFall, Tove1 aFoy, Millennia1 aFranceschini, Nora1 aGao, Wei1 aGläser, Sven1 aGu, Xiangjun1 aHancock, Dana, B1 aHeinrich, Joachim1 aHofman, Albert1 aImboden, Medea1 aIngelsson, Erik1 aJames, Alan1 aKarrasch, Stefan1 aKoch, Beate1 aKritchevsky, Stephen, B1 aKumar, Ashish1 aLahousse, Lies1 aLi, Guo1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLohman, Kurt1 aLumley, Thomas1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMusk, Bill1 aNorth, Kari, E1 aPalmer, Lyle, J1 aProbst-Hensch, Nicole, M1 aPsaty, Bruce, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSchulz, Holger1 aSmith, Lewis, J1 aSood, Akshay1 aStarr, John, M1 aStrachan, David, P1 aTeumer, Alexander1 aUitterlinden, André, G1 aVölzke, Henry1 aVoorman, Arend1 aWain, Louise, V1 aWells, Martin, T1 aWilk, Jemma, B1 aWilliams, Dale1 aHeckbert, Susan, R1 aStricker, Bruno, H1 aLondon, Stephanie, J1 aFornage, Myriam1 aTobin, Martin, D1 aO'Connor, George, T1 aHall, Ian, P1 aCassano, Patricia, A uhttps://chs-nhlbi.org/node/660404953nas a2201105 4500008004100000022001400041245009300055210006900148260001500217300001200232490000700244520183400251653001002085653000902095653002202104653003702126653002402163653002302187653003102210653001102241653004002252653001102292653002002303653003802323653002502361653001102386653001002397653000902407653001602416653003602432653002602468100002202494700002402516700001902540700001902559700002002578700001202598700002202610700002302632700001802655700002202673700001802695700001902713700002102732700003002753700001902783700002202802700001902824700002302843700001702866700002402883700001402907700002102921700002202942700001902964700001902983700001903002700002203021700001903043700002203062700002503084700002203109700002203131700002203153700002003175700002003195700001903215700002203234700002603256700002303282700002203305700002003327700002003347700002403367700002303391700002803414700002603442700001703468700001903485700002403504700002203528700002403550700002203574700002003596700001603616700002503632700002303657700002203680700002303702700001903725700001903744700002403763700002403787856003603811 2014 eng d a1558-359700aNovel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.0 aNovel genetic markers associate with atrial fibrillation risk in c2014 Apr 1 a1200-100 v633 aOBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.
BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.
METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).
RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.
CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChromosome Mapping10aChromosomes, Human, Pair 410aEurope10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTranscription Factors1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aLin, Honghuang1 aArking, Dan, E1 aTrompet, Stella1 aLi, Guo1 aKrijthe, Bouwe, P1 aChasman, Daniel, I1 aBarnard, John1 aKleber, Marcus, E1 aDörr, Marcus1 aOzaki, Kouichi1 aSmith, Albert, V1 aMüller-Nurasyid, Martina1 aWalter, Stefan1 aAgarwal, Sunil, K1 aBis, Joshua, C1 aBrody, Jennifer, A1 aChen, Lin, Y1 aEverett, Brendan, M1 aFord, Ian1 aFranco, Oscar, H1 aHarris, Tamara, B1 aHofman, Albert1 aKääb, Stefan1 aMahida, Saagar1 aKathiresan, Sekar1 aKubo, Michiaki1 aLauner, Lenore, J1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aMcKnight, Barbara1 aMcManus, David, D1 aPeters, Annette1 aPsaty, Bruce, M1 aRose, Lynda, M1 aRotter, Jerome, I1 aSilbernagel, Guenther1 aSmith, Jonathan, D1 aSotoodehnia, Nona1 aStott, David, J1 aTaylor, Kent, D1 aTomaschitz, Andreas1 aTsunoda, Tatsuhiko1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aMurabito, Joanne, M1 aSinner, Moritz, F1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aMärz, Winfried1 aChung, Mina1 aAlbert, Christine, M1 aStricker, Bruno, H1 aTanaka, Toshihiro1 aHeckbert, Susan, R1 aJukema, Wouter1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/682004872nas a2201453 4500008004100000022001400041245010900055210006900164260001600233300000900249490000600258520072200264653002100986653003401007653001101041653005101052653002101103653003601124100001801160700002001178700002501198700002301223700001601246700002101262700002301283700001701306700002501323700002401348700002201372700002201394700001901416700001701435700002001452700001201472700002101484700002101505700002801526700002301554700002501577700002001602700002401622700001401646700002601660700002001686700001901706700002401725700001701749700001801766700001901784700002201803700001801825700002201843700001901865700002601884700002101910700002501931700002401956700001801980700002501998700002202023700002102045700001702066700002402083700001602107700001602123700001902139700002202158700001602180700001902196700001902215700001802234700002302252700001902275700002102294700001802315700002102333700002002354700003002374700002702404700001602431700002202447700001802469700001602487700001702503700002302520700001602543700002202559700002102581700002602602700002002628700002502648700002802673700002402701700002302725700002202748700001902770700002302789700002302812700002202835700002002857700002302877700002802900700001902928700002602947700002002973700002102993700002003014700002403034700001703058700002103075700002803096700002203124700002203146700002003168700002303188700002403211700002203235700001903257700002203276700001903298700002303317710004203340856003603382 2014 eng d a2041-172300aPharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.0 aPharmacogenetic metaanalysis of genomewide association studies o c2014 Oct 28 a50680 v53 aStatins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
10aCholesterol, LDL10aGenome-Wide Association Study10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aPharmacogenetics10aPolymorphism, Single Nucleotide1 aPostmus, Iris1 aTrompet, Stella1 aDeshmukh, Harshal, A1 aBarnes, Michael, R1 aLi, Xiaohui1 aWarren, Helen, R1 aChasman, Daniel, I1 aZhou, Kaixin1 aArsenault, Benoit, J1 aDonnelly, Louise, A1 aWiggins, Kerri, L1 aAvery, Christy, L1 aGriffin, Paula1 aFeng, QiPing1 aTaylor, Kent, D1 aLi, Guo1 aEvans, Daniel, S1 aSmith, Albert, V1 ade Keyser, Catherine, E1 aJohnson, Andrew, D1 ade Craen, Anton, J M1 aStott, David, J1 aBuckley, Brendan, M1 aFord, Ian1 aWestendorp, Rudi, G J1 aSlagboom, Eline1 aSattar, Naveed1 aMunroe, Patricia, B1 aSever, Peter1 aPoulter, Neil1 aStanton, Alice1 aShields, Denis, C1 aO'Brien, Eoin1 aShaw-Hawkins, Sue1 aChen, Y-D, Ida1 aNickerson, Deborah, A1 aSmith, Joshua, D1 aDubé, Marie, Pierre1 aBoekholdt, Matthijs1 aHovingh, Kees1 aKastelein, John, J P1 aMcKeigue, Paul, M1 aBetteridge, John1 aNeil, Andrew1 aDurrington, Paul, N1 aDoney, Alex1 aCarr, Fiona1 aMorris, Andrew1 aMcCarthy, Mark, I1 aGroop, Leif1 aAhlqvist, Emma1 aBis, Joshua, C1 aRice, Kenneth1 aSmith, Nicholas, L1 aLumley, Thomas1 aWhitsel, Eric, A1 aStürmer, Til1 aBoerwinkle, Eric1 aNgwa, Julius, S1 aO'Donnell, Christopher, J1 aVasan, Ramachandran, S1 aWei, Wei-Qi1 aWilke, Russell, A1 aLiu, Ching-Ti1 aSun, Fangui1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aPost, Wendy1 aSotoodehnia, Nona1 aArnold, Alice, M1 aStafford, Jeanette, M1 aDing, Jingzhong1 aHerrington, David, M1 aKritchevsky, Stephen, B1 aEiriksdottir, Gudny1 aLauner, Leonore, J1 aHarris, Tamara, B1 aChu, Audrey, Y1 aGiulianini, Franco1 aMacFadyen, Jean, G1 aBarratt, Bryan, J1 aNyberg, Fredrik1 aStricker, Bruno, H1 aUitterlinden, André, G1 aHofman, Albert1 aRivadeneira, Fernando1 aEmilsson, Valur1 aFranco, Oscar, H1 aRidker, Paul, M1 aGudnason, Vilmundur1 aLiu, Yongmei1 aDenny, Joshua, C1 aBallantyne, Christie, M1 aRotter, Jerome, I1 aCupples, Adrienne1 aPsaty, Bruce, M1 aPalmer, Colin, N A1 aTardif, Jean-Claude1 aColhoun, Helen, M1 aHitman, Graham1 aKrauss, Ronald, M1 aJukema, Wouter1 aCaulfield, Mark, J1 aWelcome Trust Case Control Consortium uhttps://chs-nhlbi.org/node/659103072nas a2200493 4500008004100000022001400041245011300055210006900168260001600237300001200253490000600265520167600271653000901947653002201956653002401978653002102002653001602023653001102039653001102050653002502061653000902086653001802095653001802113653003202131653002402163653001702187653001802204653001802222100002202240700002502262700002402287700001802311700002302329700001902352700002202371700002102393700002002414700001902434700002202453700002202475700002102497700002402518856003602542 2014 eng d a2047-998000aPlasma phospholipid saturated fatty acids and incident atrial fibrillation: the Cardiovascular Health Study.0 aPlasma phospholipid saturated fatty acids and incident atrial fi c2014 Jun 26 ae0008890 v33 aBACKGROUND: Prior studies suggest that circulating fatty acids may influence the risk of atrial fibrillation (AF), but little is known about the associations of circulating saturated fatty acids with risk of AF.
METHODS AND RESULTS: The study population included 2899 participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 years or older in the United States who were free of prevalent coronary heart disease and AF in 1992. Cox regression was used to assess the association of all the long-chain saturated fatty acids-palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)-with incident AF. During a median of 11.2 years of follow-up, 707 cases of incident AF occurred. After adjustment for other AF risk factors, higher levels of circulating 16:0 were associated with a higher risk of AF (hazard ratio comparing highest and lowest quartiles: 1.48; 95% CI: 1.18, 1.86). In contrast, higher levels of circulating 18:0, 20:0, 22:0, and 24:0 were each associated with a lower risk of AF. The hazard ratios (95% CI) for AF in the top and bottom quartiles were 0.76 (95% CI: 0.61, 0.95) for 18:0; 0.78 (95% CI: 0.63, 0.97) for 20:0; 0.62 (95% CI: 0.50, 0.78) for 22:0; and 0.68 (95% CI: 0.55, 0.85) for 24:0.
CONCLUSIONS: Results from this prospective cohort study of older adults demonstrate divergent associations of circulating 16:0 versus longer-chain saturated fatty acids with incident AF, highlighting the need to investigate both determinants of these levels and potential pathways of the observed differential risk.
10aAged10aAged, 80 and over10aAtrial Fibrillation10aEicosanoic Acids10aFatty Acids10aFemale10aHumans10aLongitudinal Studies10aMale10aPalmitic Acid10aPhospholipids10aProportional Hazards Models10aProspective Studies10aRisk Factors10aStearic Acids10aUnited States1 aFretts, Amanda, M1 aMozaffarian, Dariush1 aSiscovick, David, S1 aDjoussé, Luc1 aHeckbert, Susan, R1 aKing, Irena, B1 aMcKnight, Barbara1 aSitlani, Colleen1 aSacks, Frank, M1 aSong, Xiaoling1 aSotoodehnia, Nona1 aSpiegelman, Donna1 aWallace, Erin, R1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/639704219nas a2200913 4500008004100000022001400041245008500055210006900140260001300209300001100222490000700233520168500240653001601925653000901941653002201950653002101972653002501993653001902018653004002037653001102077653003802088653003402126653001302160653001102173653000902184653001602193653003602209653002402245653001702269653001402286653001602300653001102316100003002327700002002357700001902377700002202396700002002418700002002438700001502458700001602473700002102489700003002510700002202540700002002562700002102582700001802603700002102621700002002642700001602662700002302678700001902701700001802720700002202738700002002760700002102780700002102801700002302822700001702845700002602862700002402888700001602912700002602928700001902954700001902973700002802992700002403020700002303044700001603067700001803083700002003101700002103121700002003142700002003162700002203182700002003204700002303224700002203247856003603269 2014 eng d a1524-462800aPredicting stroke through genetic risk functions: the CHARGE Risk Score Project.0 aPredicting stroke through genetic risk functions the CHARGE Risk c2014 Feb a403-120 v453 aBACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.
METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.
RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).
CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.
10aAge Factors10aAged10aAged, 80 and over10aArea Under Curve10aCase-Control Studies10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRegression Analysis10aRisk Factors10aROC Curve10aSex Factors10aStroke1 aIbrahim-Verbaas, Carla, A1 aFornage, Myriam1 aBis, Joshua, C1 aChoi, Seung, Hoan1 aPsaty, Bruce, M1 aMeigs, James, B1 aRao, Madhu1 aNalls, Mike1 aFontes, João, D1 aO'Donnell, Christopher, J1 aKathiresan, Sekar1 aEhret, Georg, B1 aFox, Caroline, S1 aMalik, Rainer1 aDichgans, Martin1 aSchmidt, Helena1 aLahti, Jari1 aHeckbert, Susan, R1 aLumley, Thomas1 aRice, Kenneth1 aRotter, Jerome, I1 aTaylor, Kent, D1 aFolsom, Aaron, R1 aBoerwinkle, Eric1 aRosamond, Wayne, D1 aShahar, Eyal1 aGottesman, Rebecca, F1 aKoudstaal, Peter, J1 aAmin, Najaf1 aWieberdink, Renske, G1 aDehghan, Abbas1 aHofman, Albert1 aUitterlinden, André, G1 aDeStefano, Anita, L1 aDebette, Stephanie1 aXue, Luting1 aBeiser, Alexa1 aWolf, Philip, A1 aDeCarli, Charles1 aIkram, Arfan, M1 aSeshadri, Sudha1 aMosley, Thomas, H1 aLongstreth, W T1 aDuijn, Cornelia, M1 aLauner, Lenore, J uhttps://chs-nhlbi.org/node/622004324nas a2200793 4500008004100000022001400041245017800055210006900233260001300302300001100315490000600326520200100332653001002333653000902343653002202352653001002374653001902384653001102403653002202414653003402436653001302470653002802483653001902511653001102530653000902541653001602550653004002566653003602606653002702642100002202669700002302691700001902714700001902733700001902752700001702771700001802788700002402806700001602830700002002846700001902866700001902885700002302904700001902927700002402946700002502970700002202995700002403017700001903041700002903060700003003089700002403119700002403143700002003167700002203187700002203209700002203231700002203253700002103275700002003296700002103316700002103337700002103358700002003379700002203399710002203421710004103443710001003484856003603494 2014 eng d a1942-326800aSequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.0 aSequencing of SCN5A identifies rare and common variants associat c2014 Jun a365-730 v73 aBACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.
METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).
CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.
10aAdult10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Conduction System10aHeart Diseases10aHumans10aMale10aMiddle Aged10aNAV1.5 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA1 aMagnani, Jared, W1 aBrody, Jennifer, A1 aPrins, Bram, P1 aArking, Dan, E1 aLin, Honghuang1 aYin, Xiaoyan1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aZhang, Feng1 aSpector, Tim, D1 aAlonso, Alvaro1 aBis, Joshua, C1 aHeckbert, Susan, R1 aLumley, Thomas1 aSitlani, Colleen, M1 aCupples, Adrienne, L1 aLubitz, Steven, A1 aSoliman, Elsayed, Z1 aPulit, Sara, L1 aNewton-Cheh, Christopher1 aO'Donnell, Christopher, J1 aEllinor, Patrick, T1 aBenjamin, Emelia, J1 aMuzny, Donna, M1 aGibbs, Richard, A1 aSantibanez, Jireh1 aTaylor, Herman, A1 aRotter, Jerome, I1 aLange, Leslie, A1 aPsaty, Bruce, M1 aJackson, Rebecca1 aRich, Stephen, S1 aBoerwinkle, Eric1 aJamshidi, Yalda1 aSotoodehnia, Nona1 aCHARGE Consortium1 aNHLBI Exome Sequencing Project (ESP)1 aUK10K uhttps://chs-nhlbi.org/node/658303990nas a2200757 4500008004100000022001400041245017100055210006900226260001300295300001100308490000600319520184400325653001002169653000902179653002202188653001002210653001902220653001102239653002202250653003402272653001302306653001902319653001102338653000902349653001602358653003602374653002002410653002702430100001902457700001402476700002302490700001902513700001902532700001902551700002202570700002102592700002402613700002102637700001802658700001802676700002002694700002302714700003002737700002302767700001602790700001702806700001902823700001402842700001602856700002402872700001902896700002402915700001802939700002202957700001902979700001702998700002403015700002403039700002303063700002003086700002003106700002503126700002403151700002103175856003603196 2014 eng d a1942-326800aStrategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aStrategies to design and analyze targeted sequencing data cohort c2014 Jun a335-430 v73 aBACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.
METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.
CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.
10aAdult10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Diseases10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aResearch Design10aSequence Analysis, DNA1 aLin, Honghuang1 aWang, Min1 aBrody, Jennifer, A1 aBis, Joshua, C1 aDupuis, Josée1 aLumley, Thomas1 aMcKnight, Barbara1 aRice, Kenneth, M1 aSitlani, Colleen, M1 aReid, Jeffrey, G1 aBressler, Jan1 aLiu, Xiaoming1 aDavis, Brian, C1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aKovar, Christie, L1 aDinh, Huyen1 aWu, Yuanqing1 aNewsham, Irene1 aChen, Han1 aBroka, Andi1 aDeStefano, Anita, L1 aGupta, Mayetri1 aLunetta, Kathryn, L1 aLiu, Ching-Ti1 aWhite, Charles, C1 aXing, Chuanhua1 aZhou, Yanhua1 aBenjamin, Emelia, J1 aSchnabel, Renate, B1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aMuzny, Donna, M1 aCupples, Adrienne, L1 aMorrison, Alanna, C1 aBoerwinkle, Eric uhttps://chs-nhlbi.org/node/657803677nas a2200613 4500008004100000022001400041245016900055210006900224260001300293300001000306490000700316520181200323653000902135653002402144653001102168653003802179653002202217653003402239653002502273653001102298653002702309653000902336653001602345653003602361653002902397100001902426700002202445700002302467700001902490700002402509700002202533700002202555700002202577700002202599700002202621700002202643700002102665700002002686700002202706700001902728700002202747700001702769700002302786700002402809700001902833700002102852700001902873700002302892700001902915700002402934700002402958710004502982856003603027 2014 eng d a1556-387100aTargeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.0 aTargeted sequencing in candidate genes for atrial fibrillation t c2014 Mar a452-70 v113 aBACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.
OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.
METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.
RESULTS: One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).
CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.
10aAged10aAtrial Fibrillation10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHomeodomain Proteins10aHumans10aLinkage Disequilibrium10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptors, Interleukin-61 aLin, Honghuang1 aSinner, Moritz, F1 aBrody, Jennifer, A1 aArking, Dan, E1 aLunetta, Kathryn, L1 aRienstra, Michiel1 aLubitz, Steven, A1 aMagnani, Jared, W1 aSotoodehnia, Nona1 aMcKnight, Barbara1 aMcManus, David, D1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aBis, Joshua, C1 aGibbs, Richard, A1 aMuzny, Donna1 aKovar, Christie, L1 aMorrison, Alanna, C1 aGupta, Mayetri1 aFolsom, Aaron, R1 aKääb, Stefan1 aHeckbert, Susan, R1 aAlonso, Alvaro1 aEllinor, Patrick, T1 aBenjamin, Emelia, J1 aCHARGE Atrial Fibrillation Working Group uhttps://chs-nhlbi.org/node/614903375nas a2200565 4500008004100000022001400041245012200055210006900177260001300246300001200259490000600271520178500277653001602062653000902078653001002087653002402097653001502121653003202136653002402168653002802192653001102220653003802231653001102269653001402280653001502294653000902309653001402318653003602332653002402368653002002392653001702412653001502429653001302444653001702457100002202474700002302496700002002519700002802539700001402567700001602581700001302597700002202610700002002632700002502652700002802677700002202705700002302727700002302750856003602773 2014 eng d a1941-308400aTelomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.0 aTelomere length and the risk of atrial fibrillation insights int c2014 Dec a1026-320 v73 aBACKGROUND: Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients.
METHODS AND RESULTS: Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 ± 0.20 versus 1.02 ± 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup.
CONCLUSIONS: Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.
10aAge Factors10aAged10aAging10aAtrial Fibrillation10aCalifornia10aCardiac Surgical Procedures10aCellular Senescence10aCross-Sectional Studies10aFemale10aGenetic Predisposition to Disease10aHumans10aIncidence10aLeukocytes10aMale10aPhenotype10aPolymorphism, Single Nucleotide10aProspective Studies10aRisk Assessment10aRisk Factors10aTelomerase10aTelomere10aTime Factors1 aRoberts, Jason, D1 aDewland, Thomas, A1 aLongoria, James1 aFitzpatrick, Annette, L1 aZiv, Elad1 aHu, Donglei1 aLin, Jue1 aGlidden, David, V1 aPsaty, Bruce, M1 aBurchard, Esteban, G1 aBlackburn, Elizabeth, H1 aOlgin, Jeffrey, E1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/659402466nas a2200421 4500008004100000022001400041245012200055210006900177260001300246300001000259490000700269520126700276653000901543653002201552653002001574653001501594653001101609653001801620653001101638653001401649653002501663653000901688653001601697653003101713653002201744653002401766653001701790653001501807653002701822100002101849700002201870700001701892700003001909700002301939700001801962700002801980856003602008 2014 eng d a1477-037700aTroponin T, NT-proBNP, and venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE).0 aTroponin T NTproBNP and venous thromboembolism the Longitudinal c2014 Feb a33-410 v193 aIncreased levels of plasma troponins and natriuretic peptides are markers of cardiac dysfunction associated with increased risk of cardiovascular disease. Little information exists on cardiac dysfunction and occurrence of venous thromboembolism (VTE). In two prospective epidemiological cohorts, we tested the hypothesis that high-sensitivity troponin T (TnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) are associated positively with VTE occurrence. The Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS) measured plasma TnT and NT-proBNP in 13,719 men or women with no history of venous thrombosis, coronary heart disease, or heart failure and followed them for approximately 10 years for VTE occurrence (n = 348 VTEs). In both ARIC and CHS, TnT was associated positively with incidence of total VTE and provoked VTE, but not with unprovoked VTE: age, race, and sex-adjusted hazard ratios for total VTE in the pooled analysis were 1.00, 0.85, 1.36, 1.51, and 1.98 (p-trend <0.0001) across five categories of TnT. In contrast, the association of NT-proBNP with VTE was positive in ARIC (hazard ratios approximately 2.5-fold for the highest versus lowest NT-proBNP quintiles), but non-existent in CHS.
10aAged10aAged, 80 and over10aAtherosclerosis10aBiomarkers10aFemale10aHeart Failure10aHumans10aIncidence10aLongitudinal Studies10aMale10aMiddle Aged10aNatriuretic Peptide, Brain10aPeptide Fragments10aProspective Studies10aRisk Factors10aTroponin T10aVenous Thromboembolism1 aFolsom, Aaron, R1 aLutsey, Pamela, L1 aNambi, Vijay1 adeFilippi, Christopher, R1 aHeckbert, Susan, R1 aCushman, Mary1 aBallantyne, Christie, M uhttps://chs-nhlbi.org/node/623503390nas a2200517 4500008004100000022001400041245012400055210006900179260001300248300001000261490000700271520190100278653000902179653002402188653001002212653002102222653002802243653002702271653002402298653001102322653001602333653001902349653001102368653001802379653003102397653000902428653001602437653003002453653002402483653002402507653001702531653002202548100001802570700002002588700002002608700001902628700002102647700002302668700002202691700002602713700002302739700002402762700002602786700002402812856003602836 2015 eng d a1524-462800aAssociation between left atrial abnormality on ECG and vascular brain injury on MRI in the Cardiovascular Health Study.0 aAssociation between left atrial abnormality on ECG and vascular c2015 Mar a711-60 v463 aBACKGROUND AND PURPOSE: Emerging evidence suggests that atrial disease is associated with vascular brain injury in the absence of atrial fibrillation.
METHODS: The Cardiovascular Health Study prospectively enrolled community-dwelling adults aged ≥65 years. Among participants who underwent MRI, we examined associations of ECG left atrial abnormality with brain infarcts and leukoaraiosis. P-wave terminal force in lead V1 was the primary measure of left atrial abnormality; P-wave area and duration were secondary predictors. We excluded participants with atrial fibrillation before or on their index ECG. Primary outcomes were incident infarcts and worsening leukoaraiosis from initial to follow-up scan ≈5 years later. Secondary outcomes were prevalent infarcts and degree of leukoaraiosis on initial MRI. Relative risk (RR) and linear regression models were adjusted for vascular risk factors.
RESULTS: Among 3129 participants with ≥1 scan, each SD increase in P-wave terminal force in lead V1 was associated with a 0.05-point (95% confidence interval [CI], 0.0003-0.10) higher baseline white matter grade on a 10-point scale. P-wave terminal force in lead V1 was associated with prevalent infarcts of any type (RR per SD, 1.09; 95% CI, 1.04-1.16) and more so with prevalent nonlacunar infarcts (RR per SD, 1.22; 95% CI, 1.08-1.38). Among 1839 participants with 2 scans, P-wave terminal force in lead V1 was associated with worsening leukoaraiosis (RR per SD, 1.09; 95% CI, 1.01-1.18), but not with incident infarcts (RR per SD, 1.06; 95% CI, 0.93-1.20). Sensitivity analyses adjusting for incident atrial fibrillation found similar results. P-wave area and duration were not associated with outcomes.
CONCLUSIONS: ECG left atrial abnormality is associated with vascular brain injury in the absence of documented atrial fibrillation.
10aAged10aAtrial Fibrillation10aBrain10aBrain Infarction10aCardiovascular Diseases10aCerebrovascular Trauma10aElectrocardiography10aFemale10aHeart Atria10aHeart Diseases10aHumans10aLinear Models10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aPredictive Value of Tests10aProspective Studies10aRegression Analysis10aRisk Factors10aTreatment Outcome1 aKamel, Hooman1 aBartz, Traci, M1 aLongstreth, W T1 aOkin, Peter, M1 aThacker, Evan, L1 aPatton, Kristen, K1 aStein, Phyllis, K1 aGottesman, Rebecca, F1 aHeckbert, Susan, R1 aKronmal, Richard, A1 aElkind, Mitchell, S V1 aSoliman, Elsayed, Z uhttps://chs-nhlbi.org/node/666805255nas a2200949 4500008004100000022001400041245015700055210006900212260000900281300001300290490000700303520251800310653002202828653000902850653002802859653002802887653004002915653001102955653003402966653001103000653001703011653001403028653000903042653001603051653003603067653002203103100001903125700002103144700001603165700002203181700002603203700001603229700002103245700002303266700001603289700002003305700002203325700002203347700002103369700002303390700002303413700002003436700002203456700002303478700002103501700002203522700002003544700002103564700002203585700001803607700002003625700002503645700002203670700002303692700001703715700002103732700002303753700002403776700002003800700002103820700002203841700002503863700002803888700002203916700001403938700001903952700001903971700002003990700002604010700002404036700002704060700001904087700002404106700002204130700001604152700001904168700002304187700002104210700002004231700001804251856003604269 2015 eng d a1932-620300aDrug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.0 aDrugGene Interactions of Antihypertensive Medications and Risk o c2015 ae01404960 v103 aBACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.
METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).
RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.
10aAfrican Americans10aAged10aAntihypertensive Agents10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aHypertension10aIncidence10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTreatment Outcome1 aBis, Joshua, C1 aSitlani, Colleen1 aIrvin, Ryan1 aAvery, Christy, L1 aSmith, Albert, Vernon1 aSun, Fangui1 aEvans, Daniel, S1 aMusani, Solomon, K1 aLi, Xiaohui1 aTrompet, Stella1 aKrijthe, Bouwe, P1 aHarris, Tamara, B1 aQuibrera, Miguel1 aBrody, Jennifer, A1 aDemissie, Serkalem1 aDavis, Barry, R1 aWiggins, Kerri, L1 aTranah, Gregory, J1 aLange, Leslie, A1 aSotoodehnia, Nona1 aStott, David, J1 aFranco, Oscar, H1 aLauner, Lenore, J1 aStürmer, Til1 aTaylor, Kent, D1 aCupples, Adrienne, L1 aEckfeldt, John, H1 aSmith, Nicholas, L1 aLiu, Yongmei1 aWilson, James, G1 aHeckbert, Susan, R1 aBuckley, Brendan, M1 aIkram, Arfan, M1 aBoerwinkle, Eric1 aChen, Yii-Der Ida1 ade Craen, Anton, J M1 aUitterlinden, André, G1 aRotter, Jerome, I1 aFord, Ian1 aHofman, Albert1 aSattar, Naveed1 aSlagboom, Eline1 aWestendorp, Rudi, G J1 aGudnason, Vilmundur1 aVasan, Ramachandran, S1 aLumley, Thomas1 aCummings, Steven, R1 aTaylor, Herman, A1 aPost, Wendy1 aJukema, Wouter1 aStricker, Bruno, H1 aWhitsel, Eric, A1 aPsaty, Bruce, M1 aArnett, Donna uhttps://chs-nhlbi.org/node/687503293nas a2200541 4500008004100000022001400041245011700055210006900172260001300241300001200254490000800266520179700274653001602071653001602087653000902103653002202112653001002134653002402144653001502168653001102183653001102194653001402205653001802219653000902237653002602246653003102272653002202303653001402325653003202339653002402371653002002395653001702415653001702432653001802449653001802467100001902485700002002504700001802524700001902542700002402561700002102585700002402606700002202630700002302652700002002675700002002695856003602715 2015 eng d a1468-201X00aHigher circulating adiponectin levels are associated with increased risk of atrial fibrillation in older adults.0 aHigher circulating adiponectin levels are associated with increa c2015 Sep a1368-740 v1013 aBACKGROUND: Adiponectin has cardioprotective properties, suggesting that lower levels seen in obesity and diabetes could heighten risk of atrial fibrillation (AF). Among older adults, however, higher adiponectin has been linked to greater incidence of adverse outcomes associated with AF, although recent reports have shown this association to be U-shaped. We postulated that higher adiponectin would be linked to increased risk for AF in older adults in a U-shaped manner.
METHODS: We examined the associations of total and high-molecular-weight (HMW) adiponectin with incident AF among individuals free of prevalent cardiovascular disease (CVD) participating in a population-based cohort study of older adults (n=3190; age=74±5 years).
RESULTS: During median follow-up of 11.4 years, there were 886 incident AF events. Adjusted cubic splines showed a positive and linear association between adiponectin and incident AF. After adjusting for potential confounders, including amino-terminal pro-B-type natriuretic peptide 1-76, the HR (95% CI) for AF per SD increase in total adiponectin was 1.14 (1.05 to 1.24), while that for HMW adiponectin was 1.17 (1.08 to 1.27). Additional adjustment for putative mediators, including subclinical CVD, diabetes, lipids and inflammation, did not significantly affect these estimates.
CONCLUSIONS: The present findings demonstrate that higher, not lower, levels of adiponectin are independently associated with increased risk of AF in older adults despite its documented cardiometabolic benefits. Additional work is necessary to determine if adiponectin is a marker of failed counter-regulatory pathways or whether this hormone is directly harmful in the setting of or as a result of advanced age.
10aAdiponectin10aAge Factors10aAged10aAged, 80 and over10aAging10aAtrial Fibrillation10aBiomarkers10aFemale10aHumans10aIncidence10aLinear Models10aMale10aMultivariate Analysis10aNatriuretic Peptide, Brain10aPeptide Fragments10aPrognosis10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aTime Factors10aUnited States10aUp-Regulation1 aMacheret, Fima1 aBartz, Traci, M1 aDjoussé, Luc1 aIx, Joachim, H1 aMukamal, Kenneth, J1 aZieman, Susan, J1 aSiscovick, David, S1 aTracy, Russell, P1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/680104486nas a2200925 4500008004100000022001400041245007500055210006900130260001500199300001200214490000700226520186200233653002302095653001202118653002302130653004002153653003802193653003402231653001302265653001102278653001802289653000902307653000902316653003602325653000902361653001402370653003602384653002402420100002002444700001802464700002602482700002502508700001902533700002002552700002302572700001902595700002102614700001602635700001802651700001902669700001902688700002502707700001902732700002702751700002102778700001602799700002402815700002602839700002602865700002402891700001702915700002202932700002002954700002302974700001802997700001903015700001803034700002103052700001903073700001903092700002303111700002303134700002603157700001903183700001703202700002703219700002403246700002003270700002503290700001903315700001903334700002203353700002003375700001703395700002203412700002103434700002503455710004403480856003603524 2015 eng d a1460-208300aIntegrative pathway genomics of lung function and airflow obstruction.0 aIntegrative pathway genomics of lung function and airflow obstru c2015 Dec 1 a6836-480 v243 aChronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.
10aAirway Obstruction10aAnimals10aCell Proliferation10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenomics10aHumans10aImmune System10aLung10aMale10aMetabolic Networks and Pathways10aMice10aPhenotype10aPolymorphism, Single Nucleotide10aSignal Transduction1 aGharib, Sina, A1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aBirkland, Timothy, P1 aWilk, Jemma, B1 aWain, Louise, V1 aBrody, Jennifer, A1 aObeidat, Ma'en1 aHancock, Dana, B1 aTang, Wenbo1 aRawal, Rajesh1 aBoezen, Marike1 aImboden, Medea1 aHuffman, Jennifer, E1 aLahousse, Lies1 aAlves, Alexessander, C1 aManichaikul, Ani1 aHui, Jennie1 aMorrison, Alanna, C1 aRamasamy, Adaikalavan1 aSmith, Albert, Vernon1 aGudnason, Vilmundur1 aSurakka, Ida1 aVitart, Veronique1 aEvans, David, M1 aStrachan, David, P1 aDeary, Ian, J1 aHofman, Albert1 aGläser, Sven1 aWilson, James, F1 aNorth, Kari, E1 aZhao, Jing Hua1 aHeckbert, Susan, R1 aJarvis, Deborah, L1 aProbst-Hensch, Nicole1 aSchulz, Holger1 aBarr, Graham1 aJarvelin, Marjo-Riitta1 aO'Connor, George, T1 aKähönen, Mika1 aCassano, Patricia, A1 aHysi, Pirro, G1 aDupuis, Josée1 aHayward, Caroline1 aPsaty, Bruce, M1 aHall, Ian, P1 aParks, William, C1 aTobin, Martin, D1 aLondon, Stephanie, J1 aCHARGE Consortium; SpiroMeta Consortium uhttps://chs-nhlbi.org/node/686006153nas a2201525 4500008004100000022001400041245009600055210006900151260001300220300001200233490000600245520187500251653000902126653002202135653002302157653003402180653001102214653001702225653003402242653001102276653000902287653002702296653001602323653002002339653001102359653001702370100002902387700002302416700001902439700002302458700001802481700002002499700002302519700002002542700002002562700001902582700002402601700002602625700002102651700002402672700002402696700002302720700002702743700002002770700002102790700002202811700002102833700002202854700001602876700002002892700002902912700002202941700002502963700002202988700001803010700001803028700002403046700002003070700002603090700002003116700002403136700002603160700002503186700001903211700002303230700001903253700001703272700001703289700001903306700003003325700002203355700001903377700001703396700002403413700002203437700002203459700002403481700002003505700002103525700001603546700002003562700002103582700001903603700002003622700002103642700002203663700002703685700002003712700002503732700001903757700002303776700002503799700002003824700002203844700002503866700002203891700002803913700002103941700002003962700002303982700002404005700001604029700002804045700002304073700001804096700001804114700002304132700001804155700002404173700002104197700002304218700001604241700001404257700002004271700001904291700002004310700002404330700002204354700002204376700002004398700002404418700002304442700002204465700002204487700001904509700002304528700002004551700002004571856003604591 2015 eng d a1942-326800aMultiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.0 aMultiethnic genomewide association study of cerebral white matte c2015 Apr a398-4090 v83 aBACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.
METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).
CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
10aAged10aAged, 80 and over10aChromosomes, Human10aContinental Population Groups10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aModels, Genetic10aStroke10aWhite Matter1 aVerhaaren, Benjamin, F J1 aDebette, Stephanie1 aBis, Joshua, C1 aSmith, Jennifer, A1 aIkram, Kamran1 aAdams, Hieab, H1 aBeecham, Ashley, H1 aRajan, Kumar, B1 aLopez, Lorna, M1 aBarral, Sandra1 avan Buchem, Mark, A1 avan der Grond, Jeroen1 aSmith, Albert, V1 aHegenscheid, Katrin1 aAggarwal, Neelum, T1 ade Andrade, Mariza1 aAtkinson, Elizabeth, J1 aBeekman, Marian1 aBeiser, Alexa, S1 aBlanton, Susan, H1 aBoerwinkle, Eric1 aBrickman, Adam, M1 aBryan, Nick1 aChauhan, Ganesh1 aChen, Christopher, P L H1 aChouraki, Vincent1 ade Craen, Anton, J M1 aCrivello, Fabrice1 aDeary, Ian, J1 aDeelen, Joris1 aDe Jager, Philip, L1 aDufouil, Carole1 aElkind, Mitchell, S V1 aEvans, Denis, A1 aFreudenberger, Paul1 aGottesman, Rebecca, F1 aGuðnason, Vilmundur1 aHabes, Mohamad1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHilal, Saima1 aHofer, Edith1 aHofman, Albert1 aIbrahim-Verbaas, Carla, A1 aKnopman, David, S1 aLewis, Cora, E1 aLiao, Jiemin1 aLiewald, David, C M1 aLuciano, Michelle1 avan der Lugt, Aad1 aMartinez, Oliver, O1 aMayeux, Richard1 aMazoyer, Bernard1 aNalls, Mike1 aNauck, Matthias1 aNiessen, Wiro, J1 aOostra, Ben, A1 aPsaty, Bruce, M1 aRice, Kenneth, M1 aRotter, Jerome, I1 avon Sarnowski, Bettina1 aSchmidt, Helena1 aSchreiner, Pamela, J1 aSchuur, Maaike1 aSidney, Stephen, S1 aSigurdsson, Sigurdur1 aSlagboom, Eline1 aStott, David, J M1 avan Swieten, John, C1 aTeumer, Alexander1 aTöglhofer, Anna, Maria1 aTraylor, Matthew1 aTrompet, Stella1 aTurner, Stephen, T1 aTzourio, Christophe1 aUh, Hae-Won1 aUitterlinden, André, G1 aVernooij, Meike, W1 aWang, Jing, J1 aWong, Tien, Y1 aWardlaw, Joanna, M1 aWindham, Gwen1 aWittfeld, Katharina1 aWolf, Christiane1 aWright, Clinton, B1 aYang, Qiong1 aZhao, Wei1 aZijdenbos, Alex1 aJukema, Wouter1 aSacco, Ralph, L1 aKardia, Sharon, L R1 aAmouyel, Philippe1 aMosley, Thomas, H1 aLongstreth, W T1 aDeCarli, Charles, C1 aDuijn, Cornelia, M1 aSchmidt, Reinhold1 aLauner, Lenore, J1 aGrabe, Hans, J1 aSeshadri, Sudha, S1 aIkram, Arfan, M1 aFornage, Myriam uhttps://chs-nhlbi.org/node/668302704nas a2200421 4500008004100000022001400041245015100055210006900206260001300275300001200288490000700300520145600307653002201763653000901785653001201794653004001806653001401846653001101860653002001871653001101891653001401902653002501916653000901941653001601950653003601966653003202002653002402034653001702058653001802075653002702093100002102120700001802141700002502159700002302184700001802207700002102225856003602246 2015 eng d a1096-865200aProspective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE).0 aProspective study of circulating factor XI and incident venous t c2015 Nov a1047-510 v903 aElevated plasma concentrations of coagulation factor XI may increase risk of venous thromboembolism (VTE), but prospective data are limited. We studied prospectively the associations of plasma factor XI and a key F11 genetic variant with incident VTE in whites and African-Americans. We measured factor XI in 16,299 participants, initially free of VTE, in two prospective population cohorts. We also measured the F11 single nucleotide polymorphism rs4241824, which a genome-wide association study had linked to factor XI concentration. During follow-up, we identified 606 VTEs. The age, race, sex, and study-adjusted hazard ratio of VTE increased across factor XI quintiles (P < 0.001 for trend), and the hazard ratio was 1.51 (95% CI 1.16, 1.97) for the highest versus lowest quintile overall, and was 1.42 (95% CI 1.03, 1.95) in whites and 1.72 (95% CI 1.08, 2.73) in African-Americans. In whites, the F11 variant was associated with both factor XI concentration and VTE incidence (1.15-fold greater incidence of VTE per risk allele). In African-Americans, these associations were absent. In conclusion, this cohort study documented that an elevated plasma factor XI concentration is a risk factor for VTE over extended follow-up, not only in whites but also in African-Americans. In whites, the association of the F11 genetic variant with VTE suggests a causal relation, but we did not observe this genetic relation in African-Americans.
10aAfrican Americans10aAged10aAlleles10aEuropean Continental Ancestry Group10aFactor XI10aFemale10aGene Expression10aHumans10aIncidence10aLongitudinal Studies10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aProspective Studies10aRisk Factors10aUnited States10aVenous Thromboembolism1 aFolsom, Aaron, R1 aTang, Weihong1 aRoetker, Nicholas, S1 aHeckbert, Susan, R1 aCushman, Mary1 aPankow, James, S uhttps://chs-nhlbi.org/node/693003265nas a2200445 4500008004100000022001400041245016200055210006900217260001300286300001100299490000700310520197100317653000902288653002402297653001502321653002402336653001102360653001802371653001102389653001402400653002502414653000902439653001602448653002002464653001702484653002402501653001502525653001802540100002202558700002002580700002402600700002202624700002302646700002402669700002002693700002402713700001902737700002702756856003602783 2015 ENG d a1556-387100aSerial measures of cardiac troponin T levels by a highly sensitive assay and incident atrial fibrillation in a prospective cohort of ambulatory older adults.0 aSerial measures of cardiac troponin T levels by a highly sensiti c2015 May a879-850 v123 aBACKGROUND: Various mechanisms in cardiac remodeling related to atrial fibrillation (AF) lead to elevated circulating cardiac troponin levels, but little is known about such elevations upstream to AF onset.
OBJECTIVE: The purpose of this study was to study the association between circulating troponin levels as assessed by a highly sensitive cardiac troponin T (hs-cTnT) assay and incident atrial fibrillation (AF).
METHODS: In a large prospective cohort of ambulatory older adults [the Cardiovascular Health Study (CHS)], hs-cTnT levels were measured in sera that were collected at enrollment from 4262 participants without AF (2871 with follow-up measurements). Incident AF was identified by electrocardiograms during CHS visits, hospital discharge diagnoses, and Medicare files, including outpatient and physician claims diagnoses.
RESULTS: Over median follow-up of 11.2 years (interquartile range 6.1-16.5), 1363 participants (32.0%) developed AF. Higher baseline levels of hs-cTnT were associated with incident AF in covariate-adjusted analyses accounting for demographics, traditional risk factors, and incident heart failure in time-dependent analyzes (hazard ratio for 3rd tertile vs undetectable 1.75, 95% confidence interval 1.48-2.08). This association was statistically significant in analyses that additionally adjusted for biomarkers of inflammation and hemodynamic strain (hazard ratio for 3rd tertile vs undetectable 1.38, 95% confidence interval 1.16-1.65). Significant associations were also found when hs-cTnT levels were treated as a continuous variable and when examining change from baseline of hs-cTnT levels and incident AF.
CONCLUSION: The findings show a significant association of circulating troponin levels in ambulatory older adults with incident AF beyond that of traditional risk factors, incident heart failure, and biomarkers of inflammation and hemodynamic strain.
10aAged10aAtrial Fibrillation10aBiomarkers10aElectrocardiography10aFemale10aHeart Failure10aHumans10aIncidence10aLongitudinal Studies10aMale10aOutpatients10aRisk Assessment10aRisk Factors10aStatistics as Topic10aTroponin T10aUnited States1 aHussein, Ayman, A1 aBartz, Traci, M1 aGottdiener, John, S1 aSotoodehnia, Nona1 aHeckbert, Susan, R1 aLloyd-Jones, Donald1 aKizer, Jorge, R1 aChristenson, Robert1 aWazni, Oussama1 aDeFilippi, Christopher uhttps://chs-nhlbi.org/node/670203153nas a2200529 4500008004100000022001400041245012000055210006900175260001300244300001000257490000800267520166400275653000901939653002201948653001901970653002401989653001102013653002202024653001502046653001102061653001402072653001802086653000902104653002602113653003702139653001402176653003202190653002402222653000902246653001702255653000902272653001502281100002002296700002402316700002202340700001802362700002402380700002402404700002702428700002402455700002202479700002302501700002202524700002102546700002002567856003602587 2015 eng d a1468-201X00aVariation in resting heart rate over 4 years and the risks of myocardial infarction and death among older adults.0 aVariation in resting heart rate over 4 years and the risks of my c2015 Jan a132-80 v1013 aOBJECTIVE: Resting heart rate (RHR) is an established predictor of myocardial infarction (MI) and mortality, but the relationship between variation in RHR over a period of several years and health outcomes is unclear. We evaluated the relationship between long-term variation in RHR and the risks of incident MI and mortality among older adults.
METHODS: 1991 subjects without cardiovascular disease from the Cardiovascular Health Study were included. RHR was taken from resting ECGs at the first five annual study visits. RHR mean, trend and variation were estimated with linear regression. Subjects were followed for incident MI and death until December 2010. HRs for RHR mean, trend and variation are reported for differences of 10 bpm, 2 bpm/year and 2 bpm, respectively.
RESULTS: 262 subjects had an incident MI event (13%) and 1326 died (67%) during 12 years of median follow-up. In primary analyses adjusted for cardiovascular risk factors, RHR mean (HR 1.12; 95% CI 1.05 to 1.20) and variation (HR 1.08; 95% CI 1.03 to 1.13) were associated with the risk of death while trend was not. None of the RHR variables were significantly associated with the risk of incident MI events; however, CIs were wide and the MI associations with RHR variables were not significantly different from the mortality associations. Adjusting for additional variables did not affect estimates, and there were no significant interactions with sex.
CONCLUSIONS: Variation in RHR over a period of several years represents a potential predictor of long-term mortality among older persons free of cardiovascular disease.
10aAged10aAged, 80 and over10aCause of Death10aElectrocardiography10aFemale10aFollow-Up Studies10aHeart Rate10aHumans10aIncidence10aLinear Models10aMale10aMyocardial Infarction10aOutcome Assessment (Health Care)10aPrognosis10aProportional Hazards Models10aProspective Studies10aRest10aRisk Factors10aTime10aWashington1 aFloyd, James, S1 aSitlani, Colleen, M1 aWiggins, Kerri, L1 aWallace, Erin1 aSuchy-Dicey, Astrid1 aAbbasi, Siddique, A1 aCarnethon, Mercedes, R1 aSiscovick, David, S1 aSotoodehnia, Nona1 aHeckbert, Susan, R1 aMcKnight, Barbara1 aRice, Kenneth, M1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/656103175nas a2200409 4500008004100000022001400041245006600055210006500121260001600186300001000202490000700212520203900219653000902258653002202267653002102289653003602310653001102346653001602357653001802373653001102391653000902402653001702411653001802428653003602446100002302482700002302505700002202528700002102550700002302571700002402594700002202618700002002640700002202660700002402682700002302706856003602729 2015 eng d a1558-359700aVentricular Ectopy as a Predictor of Heart Failure and Death.0 aVentricular Ectopy as a Predictor of Heart Failure and Death c2015 Jul 14 a101-90 v663 aBACKGROUND: Studies of patients presenting for catheter ablation suggest that premature ventricular contractions (PVCs) are a modifiable risk factor for congestive heart failure (CHF). The relationship among PVC frequency, incident CHF, and mortality in the general population remains unknown.
OBJECTIVES: The goal of this study was to determine whether PVC frequency ascertained using a 24-h Holter monitor is a predictor of a decrease in the left ventricular ejection fraction (LVEF), incident CHF, and death in a population-based cohort.
METHODS: We studied 1,139 Cardiovascular Health Study (CHS) participants who were randomly assigned to 24-h ambulatory electrocardiography (Holter) monitoring and who had a normal LVEF and no history of CHF. PVC frequency was quantified using Holter studies, and LVEF was measured from baseline and 5-year echocardiograms. Participants were followed for incident CHF and death.
RESULTS: Those in the upper quartile versus the lowest quartile of PVC frequency had a multivariable-adjusted, 3-fold greater odds of a 5-year decrease in LVEF (odds ratio [OR]: 3.10; 95% confidence interval [CI]: 1.42 to 6.77; p = 0.005), a 48% increased risk of incident CHF (HR: 1.48; 95% CI: 1.08 to 2.04; p = 0.02), and a 31% increased risk of death (HR: 1.31; 95% CI: 1.06 to 1.63; p = 0.01) during a median follow-up of >13 years. Similar statistically significant results were observed for PVCs analyzed as a continuous variable. The specificity for the 15-year risk of CHF exceeded 90% when PVCs included at least 0.7% of ventricular beats. The population-level risk for incident CHF attributed to PVCs was 8.1% (95% CI: 1.2% to 14.9%).
CONCLUSIONS: In a population-based sample, a higher frequency of PVCs was associated with a decrease in LVEF, an increase in incident CHF, and increased mortality. Because of the capacity to prevent PVCs through medical or ablation therapy, PVCs may represent a modifiable risk factor for CHF and death.
10aAged10aCatheter Ablation10aEchocardiography10aElectrocardiography, Ambulatory10aFemale10aForecasting10aHeart Failure10aHumans10aMale10aRisk Factors10aStroke Volume10aVentricular Premature Complexes1 aDukes, Jonathan, W1 aDewland, Thomas, A1 aVittinghoff, Eric1 aMandyam, Mala, C1 aHeckbert, Susan, R1 aSiscovick, David, S1 aStein, Phyllis, K1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aGottdiener, John, S1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/676707420nas a2202053 4500008004100000022001400041245005000055210004800105260001600153300001200169490000700181520170000188100001501888700002401903700001801927700001801945700001701963700002401980700001802004700002402022700002202046700002202068700002202090700002102112700002202133700002802155700001902183700002002202700001902222700001802241700002002259700003002279700002102309700001802330700002202348700002202370700002602392700001802418700001902436700002202455700002502477700002302502700001602525700002502541700002502566700001902591700001802610700001902628700001702647700002402664700002002688700002102708700002602729700001702755700002502772700002502797700002602822700002402848700002002872700001402892700002202906700002202928700001702950700002102967700002302988700002103011700002403032700001903056700002003075700002003095700002103115700002003136700002003156700001803176700002503194700002203219700001703241700002303258700001703281700002203298700001703320700001903337700002503356700001503381700002203396700002103418700002003439700001903459700001603478700001803494700001903512700001903531700002103550700001903571700002403590700002303614700001803637700002003655700002003675700002003695700001803715700002503733700002603758700001903784700002303803700002503826700001703851700002503868700002203893700002303915700002403938700002403962700002203986700002504008700002404033700002204057700002304079700002404102700002404126700002004150700003204170700002104202700002404223700002004247700002304267700001704290700002804307700002804335700002304363700001904386700002204405700002304427700002204450700001704472700002604489700003204515700002104547700002004568700002804588700001504616700002304631700002404654700002004678700002004698700001604718700002104734700002704755700002804782700002304810700002004833700001904853700001804872700002204890700002104912700002504933700001904958700002104977700001904998700001905017700002405036700002205060700002305082700002305105700002905128700002105157700002205178700002005200700001605220700002905236700001805265700002205283700002505305856003605330 2016 eng d a1558-359700a52 Genetic Loci Influencing Myocardial Mass.0 a52 Genetic Loci Influencing Myocardial Mass c2016 Sep 27 a1435-480 v683 aBACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.
OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.
METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.
RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo.
CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
1 aHarst, Pim1 avan Setten, Jessica1 aVerweij, Niek1 aVogler, Georg1 aFranke, Lude1 aMaurano, Matthew, T1 aWang, Xinchen1 aLeach, Irene, Mateo1 aEijgelsheim, Mark1 aSotoodehnia, Nona1 aHayward, Caroline1 aSorice, Rossella1 aMeirelles, Osorio1 aLyytikäinen, Leo-Pekka1 aPolasek, Ozren1 aTanaka, Toshiko1 aArking, Dan, E1 aUlivi, Sheila1 aTrompet, Stella1 aMüller-Nurasyid, Martina1 aSmith, Albert, V1 aDörr, Marcus1 aKerr, Kathleen, F1 aMagnani, Jared, W1 aM, Fabiola, del Greco1 aZhang, Weihua1 aNolte, Ilja, M1 aSilva, Claudia, T1 aPadmanabhan, Sandosh1 aTragante, Vinicius1 aEsko, Tõnu1 aAbecasis, Goncalo, R1 aAdriaens, Michiel, E1 aAndersen, Karl1 aBarnett, Phil1 aBis, Joshua, C1 aBodmer, Rolf1 aBuckley, Brendan, M1 aCampbell, Harry1 aCannon, Megan, V1 aChakravarti, Aravinda1 aChen, Lin, Y1 aDelitala, Alessandro1 aDevereux, Richard, B1 aDoevendans, Pieter, A1 aDominiczak, Anna, F1 aFerrucci, Luigi1 aFord, Ian1 aGieger, Christian1 aHarris, Tamara, B1 aHaugen, Eric1 aHeinig, Matthias1 aHernandez, Dena, G1 aHillege, Hans, L1 aHirschhorn, Joel, N1 aHofman, Albert1 aHubner, Norbert1 aHwang, Shih-Jen1 aIorio, Annamaria1 aKähönen, Mika1 aKellis, Manolis1 aKolcic, Ivana1 aKooner, Ishminder, K1 aKooner, Jaspal, S1 aKors, Jan, A1 aLakatta, Edward, G1 aLage, Kasper1 aLauner, Lenore, J1 aLevy, Daniel1 aLundby, Alicia1 aMacfarlane, Peter, W1 aMay, Dalit1 aMeitinger, Thomas1 aMetspalu, Andres1 aNappo, Stefania1 aNaitza, Silvia1 aNeph, Shane1 aNord, Alex, S1 aNutile, Teresa1 aOkin, Peter, M1 aOlsen, Jesper, V1 aOostra, Ben, A1 aPenninger, Josef, M1 aPennacchio, Len, A1 aPers, Tune, H1 aPerz, Siegfried1 aPeters, Annette1 aPinto, Yigal, M1 aPfeufer, Arne1 aPilia, Maria, Grazia1 aPramstaller, Peter, P1 aPrins, Bram, P1 aRaitakari, Olli, T1 aRaychaudhuri, Soumya1 aRice, Ken, M1 aRossin, Elizabeth, J1 aRotter, Jerome, I1 aSchafer, Sebastian1 aSchlessinger, David1 aSchmidt, Carsten, O1 aSehmi, Jobanpreet1 aSilljé, Herman, H W1 aSinagra, Gianfranco1 aSinner, Moritz, F1 aSlowikowski, Kamil1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aSpiering, Wilko1 aStamatoyannopoulos, John, A1 aStolk, Ronald, P1 aStrauch, Konstantin1 aTan, Sian-Tsung1 aTarasov, Kirill, V1 aTrinh, Bosco1 aUitterlinden, André, G1 avan den Boogaard, Malou1 aDuijn, Cornelia, M1 aGilst, Wiek, H1 aViikari, Jorma, S1 aVisscher, Peter, M1 aVitart, Veronique1 aVölker, Uwe1 aWaldenberger, Melanie1 aWeichenberger, Christian, X1 aWestra, Harm-Jan1 aWijmenga, Cisca1 aWolffenbuttel, Bruce, H1 aYang, Jian1 aBezzina, Connie, R1 aMunroe, Patricia, B1 aSnieder, Harold1 aWright, Alan, F1 aRudan, Igor1 aBoyer, Laurie, A1 aAsselbergs, Folkert, W1 avan Veldhuisen, Dirk, J1 aStricker, Bruno, H1 aPsaty, Bruce, M1 aCiullo, Marina1 aSanna, Serena1 aLehtimäki, Terho1 aWilson, James, F1 aBandinelli, Stefania1 aAlonso, Alvaro1 aGasparini, Paolo1 aJukema, Wouter1 aKääb, Stefan1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aHeckbert, Susan, R1 ade Boer, Rudolf, A1 aNewton-Cheh, Christopher1 aHicks, Andrew, A1 aChambers, John, C1 aJamshidi, Yalda1 aVisel, Axel1 aChristoffels, Vincent, M1 aIsaacs, Aaron1 aSamani, Nilesh, J1 ade Bakker, Paul, I W uhttps://chs-nhlbi.org/node/726202806nas a2200385 4500008004100000022001400041245021100055210006900266260000900335300001300344490000700357520165000364653000902014653002102023653002402044653002802068653001102096653001102107653000902118653001602127653001202143653001202155653001102167100002002178700001902198700002002217700002202237700002402259700002202283700002002305700001902325700002302344700001702367856003602384 2016 eng d a1932-620300aAssociation of Smoking, Alcohol, and Obesity with Cardiovascular Death and Ischemic Stroke in Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS).0 aAssociation of Smoking Alcohol and Obesity with Cardiovascular D c2016 ae01470650 v113 aAtrial fibrillation (AF) is associated with an increased risk of ischemic stroke and cardiovascular (CV) death. Whether modifiable lifestyle risk factors are associated with these CV outcomes in AF is unknown. Among Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS) participants with incident AF, we estimated the risk of composite endpoint of ischemic stroke or CV death associated with candidate modifiable risk factor (smoking, heavy alcohol consumption, or high body mass index [BMI]), and computed the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) of incorporating each factor into the CHA2DS2-VASc. Among 1222 ARIC (mean age: 63.4) and 756 CHS (mean age: 79.1) participants with incident AF, during mean follow-up of 6.9 years and 5.7 years, there were 332 and 335 composite events respectively. Compared with never smokers, current smokers had a higher incidence of the composite endpoint in ARIC [HR: 1.65 (1.21-2.26)] but not in CHS [HR: 1.05 (0.69-1.61)]. In ARIC, the addition of current smoking did not improve risk prediction over and above the CHA2DS2-VASc. No significant associations were observed with alcohol consumption or BMI with CVD outcomes in AF patients from either cohort. Smoking is associated with an increased risk of ischemic stroke or CV death in ARIC, which comprised mostly middle-aged to young-old (65-74 years), but not in CHS, which comprised mostly middle-old or oldest-old (≥75 years) adults with AF. However, addition of smoking to the CHA2DS2-VASc score did not improve risk prediction of these outcomes.
10aAged10aAlcohol Drinking10aAtrial Fibrillation10aCardiovascular Diseases10aFemale10aHumans10aMale10aMiddle Aged10aObesity10aSmoking10aStroke1 aKwon, Younghoon1 aNorby, Faye, L1 aJensen, Paul, N1 aAgarwal, Sunil, K1 aSoliman, Elsayed, Z1 aLip, Gregory, Y H1 aLongstreth, W T1 aAlonso, Alvaro1 aHeckbert, Susan, R1 aChen, Lin, Y uhttps://chs-nhlbi.org/node/695002093nas a2200205 4500008004100000022001400041245015100055210006900206260001300275300001100288490000800299520142100307100001801728700002201746700002301768700001901791700002001810700002101830856003601851 2016 eng d a1879-247200aBody size measures, hemostatic and inflammatory markers and risk of venous thrombosis: The Longitudinal Investigation of Thromboembolism Etiology.0 aBody size measures hemostatic and inflammatory markers and risk c2016 Aug a127-320 v1443 aOBJECTIVE: Obesity is an important venous thrombosis (VT) risk factor but the reasons for this are unclear.
MATERIALS AND METHODS: In a cohort of 20,914 individuals aged 45 and older without prior VT, we calculated the relative risk (RR) of VT over 12.6years follow-up according to baseline body size measures, and studied whether associations were mediated by biomarkers of hemostasis and inflammation that are related to adiposity.
RESULTS: Greater levels of all body size measures (weight, height, waist, hip circumference, calf circumference, body-mass index, waist-hip ratio, fat mass and fat-free mass) were associated with increased risk of VT, with 4th versus 1st quartile RRs of 1.5-3.0. There were no multiplicative interactions of biomarkers with obesity status. Adjustment for biomarkers associated with VT risk and body size (factors VII and VIII, von Willebrand factor, partial thromboplastin time, D-dimer, C-reactive protein and factor XI) only marginally lowered, or did not impact, the RRs associated with body size measures.
CONCLUSIONS: Greater body size, by multiple measures, is a risk factor for VT. Associations were not mediated by circulating levels of studied biomarkers suggesting that body size relates to VT because of physical factors associated with blood flow, not the hypercoagulability or inflammation associated with adiposity.
1 aCushman, Mary1 aO'Meara, Ellen, S1 aHeckbert, Susan, R1 aZakai, Neil, A1 aRosamond, Wayne1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/725202377nas a2200205 4500008004100000022001400041245006000055210005900115260001300174490000600187520178700193100001901980700002201999700002302021700002302044700002202067700002302089700002302112856003602135 2016 eng d a2047-998000aConsumption of Caffeinated Products and Cardiac Ectopy.0 aConsumption of Caffeinated Products and Cardiac Ectopy c2016 Jan0 v53 aBACKGROUND: Premature cardiac contractions are associated with increased morbidity and mortality. Though experts associate premature atrial contractions (PACs) and premature ventricular contractions (PVCs) with caffeine, there are no data to support this relationship in the general population. As certain caffeinated products may have cardiovascular benefits, recommendations against them may be detrimental.
METHODS AND RESULTS: We studied Cardiovascular Health Study participants with a baseline food frequency assessment, 24-hour ambulatory electrocardiography (Holter) monitoring, and without persistent atrial fibrillation. Frequencies of habitual coffee, tea, and chocolate consumption were assessed using a picture-sort food frequency survey. The main outcomes were PACs/h and PVCs/hour. Among 1388 participants (46% male, mean age 72 years), 840 (61%) consumed ≥1 caffeinated product per day. The median numbers of PACs and PVCs/h and interquartile ranges were 3 (1-12) and 1 (0-7), respectively. There were no differences in the number of PACs or PVCs/h across levels of coffee, tea, and chocolate consumption. After adjustment for potential confounders, more frequent consumption of these products was not associated with ectopy. In examining combined dietary intake of coffee, tea, and chocolate as a continuous measure, no relationships were observed after multivariable adjustment: 0.48% fewer PACs/h (95% CI -4.60 to 3.64) and 2.87% fewer PVCs/h (95% CI -8.18 to 2.43) per 1-serving/week increase in consumption.
CONCLUSIONS: In the largest study to evaluate dietary patterns and quantify cardiac ectopy using 24-hour Holter monitoring, we found no relationship between chronic consumption of caffeinated products and ectopy.
1 aDixit, Shalini1 aStein, Phyllis, K1 aDewland, Thomas, A1 aDukes, Jonathan, W1 aVittinghoff, Eric1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/699203463nas a2200325 4500008004100000022001400041245010200055210006900157260001600226300001100242490000800253520250800261100001502769700001902784700001602803700002202819700001902841700003002860700002202890700001702912700002302929700002102952700002402973700001702997700002303014700002103037700002403058700001903082856003603101 2016 eng d a1524-453900aDevelopment and Validation of a Sudden Cardiac Death Prediction Model for the General Population.0 aDevelopment and Validation of a Sudden Cardiac Death Prediction c2016 Sep 13 a806-160 v1343 aBACKGROUND: Most sudden cardiac death (SCD) events occur in the general population among persons who do not have any prior history of clinical heart disease. We sought to develop a predictive model of SCD among US adults.
METHODS: We evaluated a series of demographic, clinical, laboratory, electrocardiographic, and echocardiographic measures in participants in the ARIC study (Atherosclerosis Risk in Communities) (n=13 677) and the CHS (Cardiovascular Health Study) (n=4207) who were free of baseline cardiovascular disease. Our initial objective was to derive a SCD prediction model using the ARIC cohort and validate it in CHS. Independent risk factors for SCD were first identified in the ARIC cohort to derive a 10-year risk model of SCD. We compared the prediction of SCD with non-SCD and all-cause mortality in both the derivation and validation cohorts. Furthermore, we evaluated whether the SCD prediction equation was better at predicting SCD than the 2013 American College of Cardiology/American Heart Association Cardiovascular Disease Pooled Cohort risk equation.
RESULTS: There were a total of 345 adjudicated SCD events in our analyses, and the 12 independent risk factors in the ARIC study included age, male sex, black race, current smoking, systolic blood pressure, use of antihypertensive medication, diabetes mellitus, serum potassium, serum albumin, high-density lipoprotein, estimated glomerular filtration rate, and QTc interval. During a 10-year follow-up period, a model combining these risk factors showed good to excellent discrimination for SCD risk (c-statistic 0.820 in ARIC and 0.745 in CHS). The SCD prediction model was slightly better in predicting SCD than the 2013 American College of Cardiology/American Heart Association Pooled Cohort risk equations (c-statistic 0.808 in ARIC and 0.743 in CHS). Only the SCD prediction model, however, demonstrated similar and accurate prediction for SCD using both the original, uncalibrated score and the recalibrated equation. Finally, in the echocardiographic subcohort, a left ventricular ejection fraction <50% was present in only 1.1% of participants and did not enhance SCD prediction.
CONCLUSIONS: Our study is the first to derive and validate a generalizable risk score that provides well-calibrated, absolute risk estimates across different risk strata in an adult population of white and black participants without a clinical diagnosis of cardiovascular disease.
1 aDeo, Rajat1 aNorby, Faye, L1 aKatz, Ronit1 aSotoodehnia, Nona1 aAdabag, Selcuk1 adeFilippi, Christopher, R1 aKestenbaum, Bryan1 aChen, Lin, Y1 aHeckbert, Susan, R1 aFolsom, Aaron, R1 aKronmal, Richard, A1 aKonety, Suma1 aPatton, Kristen, K1 aSiscovick, David1 aShlipak, Michael, G1 aAlonso, Alvaro uhttps://chs-nhlbi.org/node/724302330nas a2200229 4500008004100000022001400041245006900055210006800124260001500192300001000207490000800217520165900225100002201884700002201906700002301928700002101951700002201972700002401994700002302018700002302041856003602064 2016 eng d a1879-191300aElectrocardiographic Predictors of Incident Atrial Fibrillation.0 aElectrocardiographic Predictors of Incident Atrial Fibrillation c2016 Sep 1 a714-90 v1183 aAtrial fibrillation (AF) is likely secondary to multiple different pathophysiological mechanisms that are increasingly but incompletely understood. Motivated by the hypothesis that 3 previously described electrocardiographic predictors of AF identify distinct AF mechanisms, we sought to determine if these electrocardiographic findings independently predict incident disease. Among Cardiovascular Health Study participants without prevalent AF, we determined whether left anterior fascicular block (LAFB), a prolonged QTC, and atrial premature complexes (APCs) each predicted AF after adjusting for each other. We then calculated the attributable risk in the exposed for each electrocardiographic marker. LAFB and QTC intervals were assessed on baseline 12-lead electrocardiogram (n = 4,696). APC count was determined using 24-hour Holter recordings obtained in a random subsample (n = 1,234). After adjusting for potential confounders and each electrocardiographic marker, LAFB (hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.1 to 3.9, p = 0.023), a prolonged QTC (HR 2.5, 95% CI 1.4 to 4.3, p = 0.002), and every doubling of APC count (HR 1.2, 95% CI 1.1 to 1.3, p <0.001) each remained independently predictive of incident AF. The attributable risk of AF in the exposed was 35% (95% CI 13% to 52%) for LAFB, 25% (95% CI 0.6% to 44%) for a prolonged QTC, and 34% (95% CI 26% to 42%) for APCs. In conclusion, in a community-based cohort, 3 previously established electrocardiogram-derived AF predictors were each independently associated with incident AF, suggesting that they may represent distinct mechanisms underlying the disease.
1 aNguyen, Kaylin, T1 aVittinghoff, Eric1 aDewland, Thomas, A1 aMandyam, Mala, C1 aStein, Phyllis, K1 aSoliman, Elsayed, Z1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/712904382nas a2200853 4500008004100000022001400041245015400055210006900209260001600278520191500294100002102209700002202230700001902252700001202271700001802283700001902301700002002320700002002340700002202360700001902382700001902401700002402420700001902444700001902463700001902482700001402501700001902515700002402534700001502558700002202573700001802595700002302613700001902636700002302655700001902678700001802697700002002715700002202735700001502757700001702772700002002789700002202809700002102831700001702852700001702869700002302886700002902909700001902938700002002957700001902977700002202996700002403018700002403042700002103066700002503087700002303112700002403135700002803159700002203187700002603209700002103235700001803256700002003274700002303294700002203317700002003339700002103359700002303380700002103403700002003424700002203444710002603466856003603492 2016 eng d a1460-208300aFine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.0 aFinemapping novel loci identification and SNP association transf c2016 Aug 293 aThe electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.
1 aEvans, Daniel, S1 aAvery, Christy, L1 aNalls, Mike, A1 aLi, Guo1 aBarnard, John1 aSmith, Erin, N1 aTanaka, Toshiko1 aButler, Anne, M1 aBuxbaum, Sarah, G1 aAlonso, Alvaro1 aArking, Dan, E1 aBerenson, Gerald, S1 aBis, Joshua, C1 aBuyske, Steven1 aCarty, Cara, L1 aChen, Wei1 aChung, Mina, K1 aCummings, Steven, R1 aDeo, Rajat1 aEaton, Charles, B1 aFox, Ervin, R1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHindorff, Lucia, A1 aHsueh, Wen-Chi1 aIsaacs, Aaron1 aJamshidi, Yalda1 aKerr, Kathleen, F1 aLiu, Felix1 aLiu, Yongmei1 aLohman, Kurt, K1 aMagnani, Jared, W1 aMaher, Joseph, F1 aMehra, Reena1 aMeng, Yan, A1 aMusani, Solomon, K1 aNewton-Cheh, Christopher1 aNorth, Kari, E1 aPsaty, Bruce, M1 aRedline, Susan1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aSchork, Nicholas, J1 aShohet, Ralph, V1 aSingleton, Andrew, B1 aSmith, Jonathan, D1 aSoliman, Elsayed, Z1 aSrinivasan, Sathanur, R1 aTaylor, Herman, A1 aVan Wagoner, David, R1 aWilson, James, G1 aYoung, Taylor1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aEvans, Michele, K1 aFerrucci, Luigi1 aMurray, Sarah, S1 aTranah, Gregory, J1 aWhitsel, Eric, A1 aReiner, Alex, P1 aSotoodehnia, Nona1 aCHARGE QRS Consortium uhttps://chs-nhlbi.org/node/725903570nas a2200349 4500008004100000022001400041245011100055210006900166260001500235300001100250490000600261520253900267100002202806700001602828700002302844700001902867700002302886700002202909700001702931700002002948700002202968700002202990700002003012700002503032700001903057700002903076700002203105700002003127700001403147700002303161856003603184 2016 eng d a2380-659100aGenetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals.0 aGenetic Investigation Into the Differential Risk of Atrial Fibri c2016 Jul 1 a442-500 v13 aIMPORTANCE: White persons have a higher risk of atrial fibrillation (AF) compared with black individuals despite a lower prevalence of risk factors. This difference may be due, at least in part, to genetic factors.
OBJECTIVES: To determine whether 9 single-nucleotide polymorphisms (SNPs) associated with AF account for this paradoxical differential racial risk for AF and to use admixture mapping to search genome-wide for loci that may account for this phenomenon.
DESIGN, SETTING, AND PARTICIPANTS: Genome-wide admixture analysis and candidate SNP study involving 3 population-based cohort studies that were initiated between 1987 and 1997, including the Cardiovascular Health Study (CHS) (n = 4173), the Atherosclerosis Risk in Communities (ARIC) (n = 12 341) study, and the Health, Aging, and Body Composition (Health ABC) (n = 1015) study. In all 3 studies, race was self-identified. Cox proportional hazards regression models and the proportion of treatment effect method were used to determine the impact of 9 AF-risk SNPs among participants from CHS and the ARIC study. The present study began July 1, 2012, and was completed in 2015.
MAIN OUTCOMES AND MEASURES: Incident AF systematically ascertained using clinic visit electrocardiograms, hospital discharge diagnosis codes, death certificates, and Medicare claims data.
RESULTS: A single SNP, rs10824026 (chromosome 10: position 73661450), was found to significantly mediate the higher risk for AF in white participants compared with black participants in CHS (11.4%; 95% CI, 2.9%-29.9%) and ARIC (31.7%; 95% CI, 16.0%-53.0%). Admixture mapping was performed in a meta-analysis of black participants within CHS (n = 811), ARIC (n = 3112), and Health ABC (n = 1015). No loci that reached the prespecified statistical threshold for genome-wide significance were identified.
CONCLUSIONS AND RELEVANCE: The rs10824026 SNP on chromosome 10q22 mediates a modest proportion of the increased risk of AF among white individuals compared with black individuals, potentially through an effect on gene expression levels of MYOZ1. No additional genetic variants accounting for a significant portion of the differential racial risk of AF were identified with genome-wide admixture mapping, suggesting that additional genetic or environmental influences beyond single SNPs in isolation may account for the paradoxical racial risk of AF among white individuals and black individuals.
1 aRoberts, Jason, D1 aHu, Donglei1 aHeckbert, Susan, R1 aAlonso, Alvaro1 aDewland, Thomas, A1 aVittinghoff, Eric1 aLiu, Yongmei1 aPsaty, Bruce, M1 aOlgin, Jeffrey, E1 aMagnani, Jared, W1 aHuntsman, Scott1 aBurchard, Esteban, G1 aArking, Dan, E1 aBibbins-Domingo, Kirsten1 aHarris, Tamara, B1 aPerez, Marco, V1 aZiv, Elad1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/716505079nas a2201093 4500008004100000022001400041245015000055210006900205260000900274300001300283490000700296520193900303653000902242653001902251653002502270653002802295653001102323653003802334653003402372653001102406653000902417653001602426653002602442653003602468653002402504100001902528700001902547700002202566700002602588700002402614700002502638700002002663700002302683700001902706700001702725700002402742700002002766700002202786700002102808700002802829700002302857700001402880700001802894700002002912700002802932700002402960700002702984700002303011700001903034700001903053700002303072700002203095700002403117700002303141700002003164700002403184700002303208700001803231700002403249700002103273700002403294700002003318700001603338700001503354700002203369700001903391700002003410700001903430700001703449700002203466700001903488700002603507700001903533700002003552700001803572700002403590700001703614700002003631700002603651700002203677700001703699700001703716700001803733700001903751700001903770700002003789700002403809700002103833700002403854700002003878700002103898700003003919856003603949 2016 eng d a1932-620300aGenome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.0 aGenomeWide Association Study for Incident Myocardial Infarction c2016 ae01449970 v113 aBACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.
METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.
RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).
CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
10aAged10aCohort Studies10aCooperative Behavior10aCoronary Artery Disease10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aProspective Studies1 aDehghan, Abbas1 aBis, Joshua, C1 aWhite, Charles, C1 aSmith, Albert, Vernon1 aMorrison, Alanna, C1 aCupples, Adrienne, L1 aTrompet, Stella1 aChasman, Daniel, I1 aLumley, Thomas1 aVölker, Uwe1 aBuckley, Brendan, M1 aDing, Jingzhong1 aJensen, Majken, K1 aFolsom, Aaron, R1 aKritchevsky, Stephen, B1 aGirman, Cynthia, J1 aFord, Ian1 aDörr, Marcus1 aSalomaa, Veikko1 aUitterlinden, André, G1 aEiriksdottir, Gudny1 aVasan, Ramachandran, S1 aFranceschini, Nora1 aCarty, Cara, L1 aVirtamo, Jarmo1 aDemissie, Serkalem1 aAmouyel, Philippe1 aArveiler, Dominique1 aHeckbert, Susan, R1 aFerrieres, Jean1 aDucimetiere, Pierre1 aSmith, Nicholas, L1 aWang, Ying, A1 aSiscovick, David, S1 aRice, Kenneth, M1 aWiklund, Per-Gunnar1 aTaylor, Kent, D1 aEvans, Alun1 aKee, Frank1 aRotter, Jerome, I1 aKarvanen, Juha1 aKuulasmaa, Kari1 aHeiss, Gerardo1 aKraft, Peter1 aLauner, Lenore, J1 aHofman, Albert1 aMarkus, Marcello, R P1 aRose, Lynda, M1 aSilander, Kaisa1 aWagner, Peter1 aBenjamin, Emelia, J1 aLohman, Kurt1 aStott, David, J1 aRivadeneira, Fernando1 aHarris, Tamara, B1 aLevy, Daniel1 aLiu, Yongmei1 aRimm, Eric, B1 aJukema, Wouter1 aVölzke, Henry1 aRidker, Paul, M1 aBlankenberg, Stefan1 aFranco, Oscar, H1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aO'Donnell, Christopher, J uhttps://chs-nhlbi.org/node/700402724nas a2200265 4500008004100000022001400041245013800055210006900193260001300262300000900275490000800284520189600292100002202188700002302210700002202233700002402255700001902279700001702298700002002315700002202335700001902357700002302376700002302399856003602422 2016 eng d a1097-674400aImpact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.0 aImpact of genetic variants on the upstream efficacy of reninangi c2016 May a9-170 v1753 aBACKGROUND: Renin-angiotensin system (RAS) inhibition via angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce the risk of developing atrial fibrillation (AF) in certain populations, but the evidence is conflicting. Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with AF, potentially identifying clinically relevant subtypes of the disease. We sought to investigate the impact of carrier status of 9 AF-associated SNPs on the efficacy of RAS inhibition for the primary prevention of AF.
METHODS: We performed SNP-RAS inhibitor interaction testing with unadjusted and adjusted Cox proportional hazards models using a discovery (Cardiovascular Health Study) and a replication (Atherosclerosis Risk in Communities) cohort. Additive genetic models were used for the SNP analyses, and 2-tailed P values <.05 were considered statistically significant.
RESULTS: Among 2,796 Cardiovascular Health Study participants, none of the 9 a priori identified candidate SNPs exhibited a significant SNP-drug interaction. Two of the 9 SNPs, rs2106261 (16q22) and rs6666258 (1q21), revealed interaction relationships that neared statistical significance (with point estimates in the same direction for angiotensin-converting enzyme inhibitor only and angiotensin II receptor blocker only analyses), but neither association could be replicated among 8,604 participants in Atherosclerosis Risk in Communities.
CONCLUSIONS: Our study failed to identify AF-associated SNP genetic subtypes of AF that derive increased benefit from upstream RAS inhibition for AF prevention. Future studies should continue to investigate the impact of genotype on the response to AF treatment strategies in an effort to develop personalized approaches to therapy and prevention.
1 aRoberts, Jason, D1 aDewland, Thomas, A1 aGlidden, David, V1 aHoffmann, Thomas, J1 aArking, Dan, E1 aChen, Lin, Y1 aPsaty, Bruce, M1 aOlgin, Jeffrey, E1 aAlonso, Alvaro1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/716603069nas a2200457 4500008004100000022001400041245009800055210006900153260001300222300001100235490000700246520178800253653003102041653000902072653002202081653002402103653002602127653002402153653001102177653002502188653001102213653001402224653001402238653002502252653000902277653001302286653001502299653002402314653001802338653001802356100002102374700002402395700002402419700001902443700002402462700002302486700002202509700002102531700002302552856003602575 2016 eng d a1532-541500aIncident Atrial Fibrillation and Disability-Free Survival in the Cardiovascular Health Study.0 aIncident Atrial Fibrillation and DisabilityFree Survival in the c2016 Apr a838-430 v643 aOBJECTIVES: To assess the associations between incident atrial fibrillation (AF) and disability-free survival and risk of disability.
DESIGN: Prospective cohort study.
SETTING: Cardiovascular Health Study.
PARTICIPANTS: Individuals aged 65 and older and enrolled in fee-for-service Medicare followed between 1991 and 2009 (MN = 4,046). Individuals with prevalent AF, activity of daily living (ADL) disability, or a history of stroke or heart failure at baseline were excluded.
MEASUREMENTS: Incident AF was identified according to annual study electrocardiogram, hospital discharge diagnosis, or Medicare claims. Disability-free survival was defined as survival free of ADL disability (any difficulty or inability in bathing, dressing, eating, using the toilet, walking around the home, or getting out of a bed or chair). ADLs were assessed at annual study visits or in a telephone interview. Association between incident AF and disability-free survival or risk of disability was estimated using Cox proportional hazards models.
RESULTS: Over an average of 7.0 years of follow-up, 660 individuals (16.3%) developed incident AF, and 3,112 (77%) became disabled or died. Incident AF was associated with shorter disability-free survival (hazard ratio (HR) for death or ADL disability = 1.71, 95% confidence interval (CI) = 1.55-1.90) and a higher risk of ADL disability (HR = 1.36, 95% CI = 1.18-1.58) than in individuals with no history of AF. This association persisted after adjustment for interim stroke and heart failure.
CONCLUSION: These results suggest that AF is a risk factor for shorter functional longevity in older adults, independent of other risk factors and comorbid conditions.
10aActivities of Daily Living10aAged10aAged, 80 and over10aAtrial Fibrillation10aDisability Evaluation10aElectrocardiography10aFemale10aGeriatric Assessment10aHumans10aIncidence10aLongevity10aLongitudinal Studies10aMale10aMedicare10aPrevalence10aProspective Studies10aSurvival Rate10aUnited States1 aWallace, Erin, R1 aSiscovick, David, S1 aSitlani, Colleen, M1 aDublin, Sascha1 aMitchell, Pamela, H1 aOdden, Michelle, C1 aHirsch, Calvin, H1 aThielke, Stephen1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/700201946nas a2200193 4500008004100000022001400041245010100055210007000156260001300226300000900239490000800248520136100256100001701617700002301634700001801657700002001675700002101695856003601716 2016 eng d a1879-247200aLack of association of plasma gamma prime (γ') fibrinogen with incident cardiovascular disease.0 aLack of association of plasma gamma prime γ fibrinogen with inci c2016 Jul a50-20 v1433 aINTRODUCTION: The association of gamma prime (γ') fibrinogen; a fibrinogen γ chain variant generated via alternative mRNA processing, with cardiovascular disease (CVD) remains equivocal. We prospectively examine the association of plasma γ' fibrinogen with the incidence of multiple cardiovascular disease (CVD) endpoints, independent of established CVD risk factors and total fibrinogen.
MATERIALS AND METHODS: We measured plasma γ' fibrinogen on plasma samples collected in 1992-1993 from adults ≥65years (n=3219) enrolled in the Cardiovascular Health Study, who were followed through 2013 for incident CVD events.
RESULTS AND CONCLUSIONS: In multivariable Cox models adjusted for traditional CVD risk factors and total fibrinogen, the hazard ratio per 1 standard deviation (10.7mg/dl) increment of γ' fibrinogen was 1.02 (95%CI: 0.95-1.10) for coronary heart disease; 0.88 (0.77-1.00) for ischemic stroke; 1.07 (0.87-1.32) for peripheral artery disease; 1.00 (0.92-1.08) for heart failure and 1.01 (0.92-1.10) for CVD mortality. Likewise, we failed to show a statistically significant association of γ'/total fibrinogen ratio with any CVD endpoint. These results suggest that among the elderly, γ' fibrinogen does not add much to CVD prediction beyond traditional risk factors and total fibrinogen level.
1 aAppiah, Duke1 aHeckbert, Susan, R1 aCushman, Mary1 aPsaty, Bruce, M1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/711802847nas a2200397 4500008004100000022001400041245006700055210006600122260001300188300001500201490000800216520175400224653003901978653000902017653002402026653001902050653001302069653002202082653001702104653001102121653002602132653001602158653001202174653000902186653002202195653001802217653002702235100002302262700002202285700001702307700001802324700002302342700002702365700002102392856003602413 2016 eng d a1555-716200aLifetime Risk of Venous Thromboembolism in Two Cohort Studies.0 aLifetime Risk of Venous Thromboembolism in Two Cohort Studies c2016 Mar a339.e19-260 v1293 aBACKGROUND: Greater public awareness of venous thromboembolism may be an important next step for optimizing venous thromboembolism prevention and treatment. "Lifetime risk" is an easily interpretable way of presenting risk information. Therefore, we sought to calculate the lifetime risk of venous thromboembolism (deep vein thrombosis or pulmonary embolism) using data from 2 large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study.
METHODS: We followed participants aged 45-64 years in ARIC (n = 14,185) and ≥65 in CHS (n = 5414) at baseline visits (1987-1989 in ARIC, 1989-1990 and 1992-1993 in CHS) for incident venous thromboembolism (n = 728 in ARIC through 2011 and n = 172 in CHS through 2001). We estimated lifetime risks and 95% confidence intervals of incident venous thromboembolism using a modified Kaplan-Meier method, accounting for the competing risk of death from other causes.
RESULTS: At age 45 years, the remaining lifetime risk of venous thromboembolism in ARIC was 8.1% (95% confidence interval, 7.1-8.7). High-risk groups were African Americans (11.5% lifetime risk), those with obesity (10.9%), heterozygous for the factor V Leiden (17.1%), or with sickle cell trait or disease (18.2%). Lifetime risk estimates differed by cohort; these differences were explained by differences in time period of venous thromboembolism ascertainment.
CONCLUSIONS: At least 1 in 12 middle-aged adults will develop venous thromboembolism in their remaining lifetime. This estimate of lifetime risk may be useful to promote awareness of venous thromboembolism and guide decisions at both clinical and policy levels.
10aAfrican Continental Ancestry Group10aAged10aAnemia, Sickle Cell10aCohort Studies10aFactor V10aFollow-Up Studies10aHeterozygote10aHumans10aKaplan-Meier Estimate10aMiddle Aged10aObesity10aRisk10aSickle Cell Trait10aUnited States10aVenous Thromboembolism1 aBell, Elizabeth, J1 aLutsey, Pamela, L1 aBasu, Saonli1 aCushman, Mary1 aHeckbert, Susan, R1 aLloyd-Jones, Donald, M1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/690602456nas a2200289 4500008004100000022001400041245013300055210006900188260001500257300001300272490000800285520155700293100002001850700001801870700001901888700001801907700002401925700001901949700002101968700002401989700002402013700002602037700002402063700002302087700002002110856003602130 2016 eng d a1476-625600aMeasures of Body Size and Composition and Risk of Incident Atrial Fibrillation in Older People: The Cardiovascular Health Study.0 aMeasures of Body Size and Composition and Risk of Incident Atria c2016 Jun 1 a998-10070 v1833 aVarious anthropometric measures, including height, have been associated with atrial fibrillation (AF). This raises questions about the appropriateness of using ratio measures such as body mass index (BMI), which contains height squared in its denominator, in the evaluation of AF risk. Among older adults, the optimal anthropometric approach to risk stratification of AF remains uncertain. Anthropometric and bioelectrical impedance measures were obtained from 4,276 participants (mean age = 72.4 years) free of cardiovascular disease in the Cardiovascular Health Study. During follow-up (1989-2008), 1,050 cases of AF occurred. BMI showed a U-shaped association, whereas height, weight, waist circumference, hip circumference, fat mass, and fat-free mass were linearly related to incident AF. The strongest adjusted association occurred for height (per each 1-standard-deviation increment, hazard ratio = 1.38, 95% confidence interval: 1.25, 1.51), which exceeded all other measures, including weight (hazard ratio = 1.21, 95% confidence interval: 1.13, 1.29). Combined assessment of log-transformed weight and height showed regression coefficients that departed from the 1 to -2 ratio inherent in BMI, indicating a loss of predictive information. Risk estimates for AF tended to be stronger for hip circumference than for waist circumference and for fat-free mass than for fat mass, which was explained largely by height. These findings highlight the prominent role of body size and the inadequacy of BMI as determinants of AF in older adults.
1 aKaras, Maria, G1 aYee, Laura, M1 aBiggs, Mary, L1 aDjoussé, Luc1 aMukamal, Kenneth, J1 aIx, Joachim, H1 aZieman, Susan, J1 aSiscovick, David, S1 aGottdiener, John, S1 aRosenberg, Michael, A1 aKronmal, Richard, A1 aHeckbert, Susan, R1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/712304724nas a2201189 4500008004100000022001400041245009300055210006900148260001300217300001200230490000700242520135800249100001801607700002101625700002001646700002501666700002201691700001901713700002301732700002801755700002501783700002101808700001701829700001601846700002201862700002101884700001601905700002001921700002101941700002301962700002201985700002102007700002402028700002102052700002402073700001902097700002502116700002402141700002102165700002502186700002402211700002402235700001402259700001702273700002202290700002302312700001902335700001802354700002502372700002302397700001802420700001702438700001902455700002202474700002402496700001702520700002602537700002002563700001802583700003002601700001602631700001802647700002702665700001802692700002102710700002602731700001902757700001702776700002202793700002202815700002002837700002302857700002102880700002202901700001902923700002002942700002302962700001802985700002803003700001603031700002603047700002103073700002203094700002203116700002803138700002203166700002503188700002103213700002403234700001903258700002303277700002003300700002003320700002603340700002203366700002403388700002303412700001903435700002203454700002203476856003603498 2016 eng d a1468-624400aMeta-analysis of genome-wide association studies of HDL cholesterol response to statins.0 aMetaanalysis of genomewide association studies of HDL cholestero c2016 Dec a835-8450 v533 aBACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.
METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.
CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
1 aPostmus, Iris1 aWarren, Helen, R1 aTrompet, Stella1 aArsenault, Benoit, J1 aAvery, Christy, L1 aBis, Joshua, C1 aChasman, Daniel, I1 ade Keyser, Catherine, E1 aDeshmukh, Harshal, A1 aEvans, Daniel, S1 aFeng, QiPing1 aLi, Xiaohui1 aSmit, Roelof, A J1 aSmith, Albert, V1 aSun, Fangui1 aTaylor, Kent, D1 aArnold, Alice, M1 aBarnes, Michael, R1 aBarratt, Bryan, J1 aBetteridge, John1 aBoekholdt, Matthijs1 aBoerwinkle, Eric1 aBuckley, Brendan, M1 aChen, Y-D, Ida1 ade Craen, Anton, J M1 aCummings, Steven, R1 aDenny, Joshua, C1 aDubé, Marie, Pierre1 aDurrington, Paul, N1 aEiriksdottir, Gudny1 aFord, Ian1 aGuo, Xiuqing1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHofman, Albert1 aHovingh, Kees1 aKastelein, John, J P1 aLauner, Leonore, J1 aLiu, Ching-Ti1 aLiu, Yongmei1 aLumley, Thomas1 aMcKeigue, Paul, M1 aMunroe, Patricia, B1 aNeil, Andrew1 aNickerson, Deborah, A1 aNyberg, Fredrik1 aO'Brien, Eoin1 aO'Donnell, Christopher, J1 aPost, Wendy1 aPoulter, Neil1 aVasan, Ramachandran, S1 aRice, Kenneth1 aRich, Stephen, S1 aRivadeneira, Fernando1 aSattar, Naveed1 aSever, Peter1 aShaw-Hawkins, Sue1 aShields, Denis, C1 aSlagboom, Eline1 aSmith, Nicholas, L1 aSmith, Joshua, D1 aSotoodehnia, Nona1 aStanton, Alice1 aStott, David, J1 aStricker, Bruno, H1 aStürmer, Til1 aUitterlinden, André, G1 aWei, Wei-Qi1 aWestendorp, Rudi, G J1 aWhitsel, Eric, A1 aWiggins, Kerri, L1 aWilke, Russell, A1 aBallantyne, Christie, M1 aColhoun, Helen, M1 aCupples, Adrienne, L1 aFranco, Oscar, H1 aGudnason, Vilmundur1 aHitman, Graham1 aPalmer, Colin, N A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aStafford, Jeanette, M1 aStein, Charles, M1 aTardif, Jean-Claude1 aCaulfield, Mark, J1 aJukema, Wouter1 aRotter, Jerome, I1 aKrauss, Ronald, M uhttps://chs-nhlbi.org/node/735805480nas a2201321 4500008004100000022001400041245007700055210006900132260001600201520175400217100002301971700001901994700002402013700001902037700001802056700002102074700002302095700001702118700002002135700001802155700001702173700002002190700002002210700002802230700002502258700001802283700002402301700001702325700002402342700002102366700002002387700001902407700001302426700003102439700001602470700001702486700002302503700001802526700002202544700002502566700002002591700002102611700001902632700001902651700002102670700002102691700002202712700002202734700002302756700001902779700001802798700001902816700001802835700001902853700002002872700002402892700001902916700002202935700002002957700001902977700002502996700002203021700002303043700002003066700002303086700001903109700002603128700002203154700002103176700002003197700001603217700002503233700002303258700002303281700002203304700002603326700002103352700002203373700002003395700002203415700002003437700002303457700002803480700002203508700002203530700001703552700002303569700002503592700001803617700002403635700002103659700002103680700002103701700002203722700001803744700001903762700002203781700002403803700002203827700002003849700002903869700002003898700002103918700002203939700002103961700002303982700001904005700002204024700002404046700003004070710002204100856003604122 2016 eng d a1942-326800aMultiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.0 aMultiethnic ExomeWide Association Study of Subclinical Atheroscl c2016 Nov 213 aBACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.
METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).
CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.
1 aNatarajan, Pradeep1 aBis, Joshua, C1 aBielak, Lawrence, F1 aCox, Amanda, J1 aDörr, Marcus1 aFeitosa, Mary, F1 aFranceschini, Nora1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aIsaacs, Aaron1 aJhun, Min, A1 aKavousi, Maryam1 aLi-Gao, Ruifang1 aLyytikäinen, Leo-Pekka1 aMarioni, Riccardo, E1 aSchminke, Ulf1 aStitziel, Nathan, O1 aTada, Hayato1 avan Setten, Jessica1 aSmith, Albert, V1 aVojinovic, Dina1 aYanek, Lisa, R1 aYao, Jie1 aYerges-Armstrong, Laura, M1 aAmin, Najaf1 aBaber, Usman1 aBorecki, Ingrid, B1 aCarr, Jeffrey1 aChen, Yii-Der Ida1 aCupples, Adrienne, L1 ade Jong, Pim, A1 ade Koning, Harry1 ade Vos, Bob, D1 aDemirkan, Ayse1 aFuster, Valentin1 aFranco, Oscar, H1 aGoodarzi, Mark, O1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHoffmann, Udo1 aHofman, Albert1 aIšgum, Ivana1 aJukema, Wouter1 aKähönen, Mika1 aKardia, Sharon, L R1 aKral, Brian, G1 aLauner, Lenore, J1 aMassaro, Joseph1 aMehran, Roxana1 aMitchell, Braxton, D1 aMosley, Thomas, H1 ade Mutsert, Renée1 aNewman, Anne, B1 aNguyen, Khanh-Dung1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aOudkerk, Matthijs1 aPankow, James, S1 aPeloso, Gina, M1 aPost, Wendy1 aProvince, Michael, A1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aReilly, Dermot, F1 aRivadeneira, Fernando1 aRosendaal, Frits1 aSartori, Samantha1 aTaylor, Kent, D1 aTeumer, Alexander1 aTrompet, Stella1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Lugt, Aad1 aVölker, Uwe1 aWardlaw, Joanna, M1 aWassel, Christina, L1 aWeiss, Stefan1 aWojczynski, Mary, K1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBowden, Donald, W1 aDeary, Ian, J1 aDehghan, Abbas1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aLehtimäki, Terho1 aMathias, Rasika1 aMook-Kanamori, Dennis, O1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRotter, Jerome, I1 aWilson, James, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aKathiresan, Sekar1 aPeyser, Patricia, A1 aO'Donnell, Christopher, J1 aCHARGE Consortium uhttps://chs-nhlbi.org/node/725702191nas a2200205 4500008004100000022001400041245008400055210006900139260001300208300001100221490000700232520158100239100002301820700002201843700001801865700002301883700002201906700002101928856003601949 2016 eng d a1941-722500aOrthostatic Hypotension and Risk of Venous Thromboembolism in 2 Cohort Studies.0 aOrthostatic Hypotension and Risk of Venous Thromboembolism in 2 c2016 May a634-400 v293 aBACKGROUND: Although venous stasis is a risk factor for venous thromboembolism (VTE) and orthostatic hypotension (OH) can cause venous stasis, to our knowledge no study has examined the relationship between OH and VTE risk. We sought to quantify the association between OH and VTE (deep vein thrombosis or pulmonary embolism) using data from 2 large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) Study. We hypothesized that OH was positively associated with incident VTE.
METHODS: We measured OH-defined as a drop in systolic blood pressure (SBP) of at least 20 mm Hg or diastolic blood pressure (DBP) of at least 10 mm Hg within 3 minutes of standing-in participants aged 45-64 years in ARIC (n = 12,480) and ≥65 years in CHS (n = 5,027) at baseline visits (1987-1989 in ARIC; 1989-1990 and 1992-1993 in CHS), and followed participants for incident VTE (n = 568 in ARIC through 2011 and n = 148 in CHS through 2001). We calculated adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs) for incident VTE in relation to OH status.
RESULTS: In CHS, there was a positive association between OH status and incident VTE (HR for VTE = 1.74 (95% CI: 1.20-2.51)). In contrast, there was no association between OH and VTE in the ARIC study (HR for VTE = 0.97 (95% CI: 0.70-1.33)).
CONCLUSIONS: Community-dwelling older adults with OH had a moderately increased risk of VTE. These results were not seen in a population-based middle-aged cohort.
1 aBell, Elizabeth, J1 aAgarwal, Sunil, K1 aCushman, Mary1 aHeckbert, Susan, R1 aLutsey, Pamela, L1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/680702162nas a2200217 4500008004100000022001400041245014400055210007000199260001300269300000900282490000800291520145900299100002101758700001801779700002301797700002301820700002601843700001801869700002101887856003601908 2016 eng d a1879-247200aProspective study of γ' fibrinogen and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE).0 aProspective study of γ fibrinogen and incident venous thromboemb c2016 Mar a44-90 v1393 aINTRODUCTION: Epidemiological studies generally have not found plasma total fibrinogen to be a risk factor for venous thromboembolism (VTE), but several have reported associations between variants in the fibrinogen gamma gene (FGG) and VTE. A case-control study in whites suggested plasma γ' fibrinogen concentration may be associated inversely with VTE, but this was not replicated in African Americans.
OBJECTIVE: To examine the prospective association between γ' fibrinogen concentrations and occurrence of VTE.
METHODS: We used the Longitudinal Investigation of Thromboembolism Etiology (LITE), involving two pooled population-based cohorts in the United States including 16,234 participants. The cohorts comprised white and African American men and women, aged 50years and older at study onset in the early 1990s. We identified VTEs during follow-up and documented they met standardized diagnostic criteria.
RESULTS: During two decades of follow-up, neither γ' fibrinogen nor total fibrinogen nor their ratio was associated with VTE overall (n=521 VTEs), in subgroups defined by race, or in other subgroups. In both race groups, the minor allele of FGG rs2066865 was associated with lower γ' fibrinogen concentrations, but this allele was not associated with VTE.
CONCLUSIONS: A lower plasma concentration of γ' fibrinogen in healthy adults does not appear to increase VTE risk.
1 aFolsom, Aaron, R1 aTang, Weihong1 aGeorge, Kristen, M1 aHeckbert, Susan, R1 aMacLehose, Richard, F1 aCushman, Mary1 aPankow, James, S uhttps://chs-nhlbi.org/node/699303259nas a2200481 4500008004100000022001400041245010400055210006900159260001600228300001100244490000800255520187600263653001802139653002802157653001102185653002202196653001902218653002002237653002402257653001102281653002702292653004502319653001102364653000902375653002602384653001302410653001702423653002102440653002202461653001802483100002002501700002302521700002102544700002202565700002802587700002302615700002202638700001602660700002402676700002102700700002002721856003602741 2016 ENG d a1524-453900aStudy of Cardiovascular Health Outcomes in the Era of Claims Data: The Cardiovascular Health Study.0 aStudy of Cardiovascular Health Outcomes in the Era of Claims Dat c2016 Jan 12 a156-640 v1333 aBACKGROUND: Increasingly, the diagnostic codes from administrative claims data are being used as clinical outcomes.
METHODS AND RESULTS: Data from the Cardiovascular Health Study (CHS) were used to compare event rates and risk factor associations between adjudicated hospitalized cardiovascular events and claims-based methods of defining events. The outcomes of myocardial infarction (MI), stroke, and heart failure were defined in 3 ways: the CHS adjudicated event (CHS[adj]), selected International Classification of Diseases, Ninth Edition diagnostic codes only in the primary position for Medicare claims data from the Center for Medicare & Medicaid Services (CMS[1st]), and the same selected diagnostic codes in any position (CMS[any]). Conventional claims-based methods of defining events had high positive predictive values but low sensitivities. For instance, the positive predictive value of International Classification of Diseases, Ninth Edition code 410.x1 for a new acute MI in the first position was 90.6%, but this code identified only 53.8% of incident MIs. The observed event rates for CMS[1st] were low. For MI, the incidence was 14.9 events per 1000 person-years for CHS[adj] MI, 8.6 for CMS[1st] MI, and 12.2 for CMS[any] MI. In general, cardiovascular disease risk factor associations were similar across the 3 methods of defining events. Indeed, traditional cardiovascular disease risk factors were also associated with all first hospitalizations not resulting from an MI.
CONCLUSIONS: The use of diagnostic codes from claims data as clinical events, especially when restricted to primary diagnoses, leads to an underestimation of event rates. Additionally, claims-based events data represent a composite end point that includes the outcome of interest and selected (misclassified) nonevent hospitalizations.
10aBlood Glucose10aCardiovascular Diseases10aFemale10aFollow-Up Studies10aHealth Surveys10aHospitalization10aHospitals, Veterans10aHumans10aInsurance Claim Review10aInternational Classification of Diseases10aLipids10aMale10aManaged Care Programs10aMedicare10aRisk Factors10aSampling Studies10aTreatment Outcome10aUnited States1 aPsaty, Bruce, M1 aDelaney, Joseph, A1 aArnold, Alice, M1 aCurtis, Lesley, H1 aFitzpatrick, Annette, L1 aHeckbert, Susan, R1 aMcKnight, Barbara1 aIves, Diane1 aGottdiener, John, S1 aKuller, Lewis, H1 aLongstreth, W T uhttps://chs-nhlbi.org/node/693203189nas a2200433 4500008004100000022001400041245005100055210005000106260001300156300001300169490000700182520196300189100002202152700002302174700002502197700002202222700001802244700003002262700001902292700002102311700002202332700001902354700002502373700002102398700002602419700001702445700002002462700002002482700002402502700002202526700002402548700002402572700002302596700001902619700002402638700001902662710003802681856003602719 2016 eng d a1553-740400aWhole Exome Sequencing in Atrial Fibrillation.0 aWhole Exome Sequencing in Atrial Fibrillation c2016 Sep ae10062840 v123 aAtrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.
1 aLubitz, Steven, A1 aBrody, Jennifer, A1 aBihlmeyer, Nathan, A1 aRoselli, Carolina1 aWeng, Lu-Chen1 aChristophersen, Ingrid, E1 aAlonso, Alvaro1 aBoerwinkle, Eric1 aGibbs, Richard, A1 aBis, Joshua, C1 aCupples, Adrienne, L1 aMohler, Peter, J1 aNickerson, Deborah, A1 aMuzny, Donna1 aPerez, Marco, V1 aPsaty, Bruce, M1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aLunetta, Kathryn, L1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aArking, Dan, E1 aEllinor, Patrick, T1 aLin, Honghuang1 aNHLBI GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/725001904nas a2200577 4500008004100000022001400041245010300055210006900158260001600227300001400243490000700257100002300264700002400287700001900311700002600330700002200356700002500378700002000403700002000423700002400443700002000467700002200487700002700509700001900536700002400555700002300579700002100602700001800623700002200641700002800663700003000691700002100721700002100742700002400763700002300787700002300810700002100833700002500854700002700879700002100906700002200927700002100949700002100970700002000991700002501011710006501036710008501101710005101186710005301237856003601290 2017 eng d a1546-171800aAnalysis commons, a team approach to discovery in a big-data environment for genetic epidemiology.0 aAnalysis commons a team approach to discovery in a bigdata envir c2017 Oct 27 a1560-15630 v491 aBrody, Jennifer, A1 aMorrison, Alanna, C1 aBis, Joshua, C1 aO'Connell, Jeffrey, R1 aBrown, Michael, R1 aHuffman, Jennifer, E1 aAmes, Darren, C1 aCarroll, Andrew1 aConomos, Matthew, P1 aGabriel, Stacey1 aGibbs, Richard, A1 aGogarten, Stephanie, M1 aGupta, Namrata1 aJaquish, Cashell, E1 aJohnson, Andrew, D1 aLewis, Joshua, P1 aLiu, Xiaoming1 aManning, Alisa, K1 aPapanicolaou, George, J1 aPitsillides, Achilleas, N1 aRice, Kenneth, M1 aSalerno, William1 aSitlani, Colleen, M1 aSmith, Nicholas, L1 aHeckbert, Susan, R1 aLaurie, Cathy, C1 aMitchell, Braxton, D1 aVasan, Ramachandran, S1 aRich, Stephen, S1 aRotter, Jerome, I1 aWilson, James, G1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aCupples, Adrienne, L1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium1 aTOPMed Hematology and Hemostasis Working Group1 aCHARGE Analysis and Bioinformatics Working Group uhttps://chs-nhlbi.org/node/755302588nas a2200253 4500008004100000022001400041245008900055210006900144260001300213300001400226490000700240520182000247100002802067700002202095700002202117700002402139700002402163700002302187700002202210700002002232700002302252700002302275856003602298 2017 eng d a1556-387100aAtrial ectopy as a mediator of the association between race and atrial fibrillation.0 aAtrial ectopy as a mediator of the association between race and c2017 Dec a1856-18610 v143 aBACKGROUND: Blacks have a lower risk of atrial fibrillation (AF) despite having more AF risk factors, but the mechanism remains unknown. Premature atrial contraction (PAC) burden is a recently identified risk factor for AF.
OBJECTIVE: The purpose of this study was to determine whether the burden of PACs explains racial differences in AF risk.
METHODS: PAC burden (number per hour) was assessed by 24-hour ambulatory electrocardiographic (ECG) monitoring in a randomly selected subset of patients in the Cardiovascular Health Study. Participants were followed prospectively for the development of AF, diagnosed by study ECG and hospital admission records.
RESULTS: Among 938 participants (median age 73 years; 34% black; 58% female), 206 (22%) developed AF over a median follow-up of 11.0 years (interquartile range 6.1-13.4). After adjusting for age, sex, body mass index, coronary disease, congestive heart failure, diabetes, hypertension, alcohol consumption, smoking status, and study site, black race was associated with a 42% lower risk of AF (hazard ratio 0.58, 95% confidence interval [CI] 0.40-0.85; P = .005). The baseline PAC burden was 2.10 times (95% CI 1.57-2.83; P <.001) higher in whites than blacks. There was no detectable difference in premature ventricular contraction (PVC) burden by race. PAC burden mediated 19.5% (95% CI 6.3-52.5) of the adjusted association between race and AF.
CONCLUSION: On average, whites exhibited more PACs than blacks, and this difference statistically explains a modest proportion of the differential risk of AF by race. The differential PAC burden, without differences in PVCs, by race suggests that identifiable common exposures or genetic influences might be important to atrial pathophysiology.
1 aChristensen, Matthew, A1 aNguyen, Kaylin, T1 aStein, Phyllis, K1 aFohtung, Raymond, B1 aSoliman, Elsayed, Z1 aDewland, Thomas, A1 aVittinghoff, Eric1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/755506088nas a2201561 4500008004100000022001400041245007200055210006900127260001600196520173100212100002801943700002101971700002401992700001802016700002002034700002202054700002502076700001602101700001802117700001802135700001802153700002002171700002002191700001502211700002302226700003002249700001902279700001302298700002102311700002802332700002002360700002402380700002002404700001902424700001802443700002102461700002102482700002102503700001702524700002202541700001902563700001902582700002002601700002502621700002302646700002202669700002402691700002102715700002402736700002202760700002202782700001702804700002302821700001902844700002202863700002302885700001902908700002002927700002002947700002402967700001802991700002203009700001203031700001303043700002103056700001503077700002503092700002103117700002203138700002103160700002203181700002703203700001703230700002503247700002003272700002303292700001803315700002003333700001503353700002303368700002603391700002203417700001603439700001903455700001703474700002203491700002403513700002403537700002203561700002603583700002003609700002103629700002403650700002103674700001803695700002403713700001703737700002603754700001603780700002803796700001903824700001903843700002103862700002003883700002303903700002403926700001903950700002703969700002203996700002204018700002404040700001804064700002204082700001904104700002204123700002304145700002304168700001804191700002904209700002004238700001904258700002204277700001804299700002404317700002204341700001904363700002404382700001504406700002204421700002304443700002404466856003604490 2017 eng d a1460-208300aDiscovery of novel heart rate-associated loci using the Exome Chip.0 aDiscovery of novel heart rateassociated loci using the Exome Chi c2017 Apr 033 aBackground Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.
1 avan den Berg, Marten, E1 aWarren, Helen, R1 aCabrera, Claudia, P1 aVerweij, Niek1 aMifsud, Borbala1 aHaessler, Jeffrey1 aBihlmeyer, Nathan, A1 aFu, Yi-Ping1 aWeiss, Stefan1 aLin, Henry, J1 aGrarup, Niels1 aLi-Gao, Ruifang1 aPistis, Giorgio1 aShah, Nabi1 aBrody, Jennifer, A1 aMüller-Nurasyid, Martina1 aLin, Honghuang1 aMei, Hao1 aSmith, Albert, V1 aLyytikäinen, Leo-Pekka1 aHall, Leanne, M1 avan Setten, Jessica1 aTrompet, Stella1 aPrins, Bram, P1 aIsaacs, Aaron1 aRadmanesh, Farid1 aMarten, Jonathan1 aEntwistle, Aiman1 aKors, Jan, A1 aSilva, Claudia, T1 aAlonso, Alvaro1 aBis, Joshua, C1 ade Boer, Rudolf1 ade Haan, Hugoline, G1 ade Mutsert, Renée1 aDedoussis, George1 aDominiczak, Anna, F1 aDoney, Alex, S F1 aEllinor, Patrick, T1 aEppinga, Ruben, N1 aFelix, Stephan, B1 aGuo, Xiuqing1 aHagemeijer, Yanick1 aHansen, Torben1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHuang, Paul, L1 aHwang, Shih-Jen1 aKähönen, Mika1 aKanters, Jørgen, K1 aKolcic, Ivana1 aLauner, Lenore, J1 aLi, Man1 aYao, Jie1 aLinneberg, Allan1 aLiu, Simin1 aMacfarlane, Peter, W1 aMangino, Massimo1 aMorris, Andrew, D1 aMulas, Antonella1 aMurray, Alison, D1 aNelson, Christopher, P1 aOrrù, Marco1 aPadmanabhan, Sandosh1 aPeters, Annette1 aPorteous, David, J1 aPoulter, Neil1 aPsaty, Bruce, M1 aQi, Lihong1 aRaitakari, Olli, T1 aRivadeneira, Fernando1 aRoselli, Carolina1 aRudan, Igor1 aSattar, Naveed1 aSever, Peter1 aSinner, Moritz, F1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aStanton, Alice, V1 aStirrups, Kathleen, E1 aTaylor, Kent, D1 aTobin, Martin, D1 aUitterlinden, Andre1 aVaartjes, Ilonca1 aHoes, Arno, W1 avan der Meer, Peter1 aVölker, Uwe1 aWaldenberger, Melanie1 aXie, Zhijun1 aZoledziewska, Magdalena1 aTinker, Andrew1 aPolasek, Ozren1 aRosand, Jonathan1 aJamshidi, Yalda1 aDuijn, Cornelia, M1 aZeggini, Eleftheria1 aJukema, Wouter1 aAsselbergs, Folkert, W1 aSamani, Nilesh, J1 aLehtimäki, Terho1 aGudnason, Vilmundur1 aWilson, James1 aLubitz, Steven, A1 aKääb, Stefan1 aSotoodehnia, Nona1 aCaulfield, Mark, J1 aPalmer, Colin, N A1 aSanna, Serena1 aMook-Kanamori, Dennis, O1 aDeloukas, Panos1 aPedersen, Oluf1 aRotter, Jerome, I1 aDörr, Marcus1 aO'Donnell, Chris, J1 aHayward, Caroline1 aArking, Dan, E1 aKooperberg, Charles1 aHarst, Pim1 aEijgelsheim, Mark1 aStricker, Bruno, H1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/736302652nas a2200265 4500008004100000022001400041245009100055210006900146260001600215490000600231520185100237100002202088700002202110700002302132700002302155700002402178700002202202700002402224700001902248700001702267700002002284700002302304700002302327856003602350 2017 eng d a2047-998000aEctopy on a Single 12-Lead ECG, Incident Cardiac Myopathy, and Death in the Community.0 aEctopy on a Single 12Lead ECG Incident Cardiac Myopathy and Deat c2017 Aug 030 v63 aBACKGROUND: Atrial fibrillation and heart failure are 2 of the most common diseases, yet ready means to identify individuals at risk are lacking. The 12-lead ECG is one of the most accessible tests in medicine. Our objective was to determine whether a premature atrial contraction observed on a standard 12-lead ECG would predict atrial fibrillation and mortality and whether a premature ventricular contraction would predict heart failure and mortality.
METHODS AND RESULTS: We utilized the CHS (Cardiovascular Health) Study, which followed 5577 participants for a median of 12 years, as the primary cohort. The ARIC (Atherosclerosis Risk in Communities Study), the replication cohort, captured data from 15 792 participants over a median of 22 years. In the CHS, multivariable analyses revealed that a baseline 12-lead ECG premature atrial contraction predicted a 60% increased risk of atrial fibrillation (hazard ratio, 1.6; 95% CI, 1.3-2.0; P<0.001) and a premature ventricular contraction predicted a 30% increased risk of heart failure (hazard ratio, 1.3; 95% CI, 1.0-1.6; P=0.021). In the negative control analyses, neither predicted incident myocardial infarction. A premature atrial contraction was associated with a 30% increased risk of death (hazard ratio, 1.3; 95% CI, 1.1-1.5; P=0.008) and a premature ventricular contraction was associated with a 20% increased risk of death (hazard ratio, 1.2; 95% CI, 1.0-1.3; P=0.044). Similarly statistically significant results for each analysis were also observed in ARIC.
CONCLUSIONS: Based on a single standard ECG, a premature atrial contraction predicted incident atrial fibrillation and death and a premature ventricular contraction predicted incident heart failure and death, suggesting that this commonly used test may predict future disease.
1 aNguyen, Kaylin, T1 aVittinghoff, Eric1 aDewland, Thomas, A1 aDukes, Jonathan, W1 aSoliman, Elsayed, Z1 aStein, Phyllis, K1 aGottdiener, John, S1 aAlonso, Alvaro1 aChen, Lin, Y1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/748903262nas a2200313 4500008004100000022001400041245020200055210006900257260001600326300001400342490000700356520223900363100001802602700002202620700001902642700002402661700002002685700001502705700001602720700002202736700001702758700003002775700002002805700002402825700002202849700001802871700002302889856003602912 2017 eng d a1555-905X00aeGFR and Albuminuria in Relation to Risk of Incident Atrial Fibrillation: A Meta-Analysis of the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study.0 aeGFR and Albuminuria in Relation to Risk of Incident Atrial Fibr c2017 Sep 07 a1386-13980 v123 aBACKGROUND AND OBJECTIVES: The incidence of atrial fibrillation is high in ESRD, but limited data are available on the incidence of atrial fibrillation across a broad range of kidney function. Thus, we examined the association of eGFR and urine albumin-to-creatinine ratio with risk of incident atrial fibrillation.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We meta-analyzed three prospective cohorts: the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Cox regression models were performed examining the association of eGFR and urine albumin-to-creatinine ratio with incident atrial fibrillation adjusting for demographics and comorbidity. In additional analyses, we adjusted for measures of subclinical cardiovascular disease (by electrocardiogram and cardiac imaging) and interim heart failure and myocardial infarction events.
RESULTS: In the meta-analyzed study population of 16,769 participants without prevalent atrial fibrillation, across categories of decreasing eGFR (eGFR>90 [reference], 60-89, 45-59, 30-44, and <30 ml/min per 1.73 m(2)), there was a stepwise increase in the adjusted risk of incident atrial fibrillation: hazard ratios (95% confidence intervals) were 1.00, 1.09 (0.97 to 1.24), 1.17 (1.00 to 1.38), 1.59 (1.28 to 1.98), and 2.03 (1.40 to 2.96), respectively. There was a stepwise increase in the adjusted risk of incident atrial fibrillation across categories of increasing urine albumin-to-creatinine ratio (urine albumin-to-creatinine ratio <15 [reference], 15-29, 30-299, and ≥300 mg/g): hazard ratios (95% confidence intervals) were 1.00, 1.04 (0.83 to 1.30), 1.47 (1.20 to 1.79), and 1.76 (1.18 to 2.62), respectively. The associations were consistent after adjustment for subclinical cardiovascular disease measures and interim heart failure and myocardial infarction events.
CONCLUSIONS: In this meta-analysis of three cohorts, reduced eGFR and elevated urine albumin-to-creatinine ratio were significantly associated with greater risk of incident atrial fibrillation, highlighting the need for further studies to understand mechanisms linking kidney disease with atrial fibrillation.
1 aBansal, Nisha1 aZelnick, Leila, R1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 ade Boer, Ian, H1 aDeo, Rajat1 aKatz, Ronit1 aKestenbaum, Bryan1 aMathew, Jehu1 aRobinson-Cohen, Cassianne1 aSarnak, Mark, J1 aShlipak, Michael, G1 aSotoodehnia, Nona1 aYoung, Bessie1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/746404297nas a2200889 4500008004100000022001400041245007400055210006900129260001300198490000700211520176700218653002501985653001502010653001502025653002402040653001702064653003402081653001302115653001602128653001102144653004002155653004002195653002602235100003002261700002202291700001702313700001802330700001802348700001902366700002602385700002202411700002202433700001502455700002202470700001902492700002202511700001802533700003002551700002302581700001902604700002002623700002202643700001702665700002202682700002302704700002202727700002102749700002302770700002602793700001702819700002602836700002002862700002202882700002402904700002402928700002002952700001902972700002402991700002203015700002003037700002403057700001903081700002003100700002203120700002203142700001803164700001203182700001903194700002403213700001903237700002103256700002303277700002403300700002303324700002403347856003603371 2017 eng d a1942-326800aFifteen Genetic Loci Associated With the Electrocardiographic P Wave.0 aFifteen Genetic Loci Associated With the Electrocardiographic P c2017 Aug0 v103 aBACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.
METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.
CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.
10aArrhythmias, Cardiac10aCaveolin 110aCaveolin 210aElectrocardiography10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHeart Atria10aHumans10aNAV1.5 Voltage-Gated Sodium Channel10aNAV1.8 Voltage-Gated Sodium Channel10aT-Box Domain Proteins1 aChristophersen, Ingrid, E1 aMagnani, Jared, W1 aYin, Xiaoyan1 aBarnard, John1 aWeng, Lu-Chen1 aArking, Dan, E1 aNiemeijer, Maartje, N1 aLubitz, Steven, A1 aAvery, Christy, L1 aDuan, Qing1 aFelix, Stephan, B1 aBis, Joshua, C1 aKerr, Kathleen, F1 aIsaacs, Aaron1 aMüller-Nurasyid, Martina1 aMüller, Christian1 aNorth, Kari, E1 aReiner, Alex, P1 aTinker, Lesley, F1 aKors, Jan, A1 aTeumer, Alexander1 aPetersmann, Astrid1 aSinner, Moritz, F1 aBůzková, Petra1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aVölker, Uwe1 aWaldenberger, Melanie1 aPeters, Annette1 aMeitinger, Thomas1 aLimacher, Marian, C1 aWilhelmsen, Kirk, C1 aPsaty, Bruce, M1 aHofman, Albert1 aUitterlinden, Andre1 aKrijthe, Bouwe, P1 aZhang, Zhu-Ming1 aSchnabel, Renate, B1 aKääb, Stefan1 aDuijn, Cornelia1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aDörr, Marcus1 aLi, Yun1 aChung, Mina, K1 aSoliman, Elsayed, Z1 aAlonso, Alvaro1 aWhitsel, Eric, A1 aStricker, Bruno, H1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/755702350nas a2200253 4500008004100000022001400041245010700055210006900162260001300231300001200244490000600256520157700262100002601839700002301865700001901888700002001907700002801927700001701955700002201972700002701994700001802021700002102039856003602060 2017 eng d a2475-037900aGalectin-3 and Venous Thromboembolism Incidence: the Atherosclerosis Risk in Communities (ARIC) Study.0 aGalectin3 and Venous Thromboembolism Incidence the Atheroscleros c2017 Oct a223-2300 v13 aBackground: The inflammatory biomarker galectin-3 contributes to pathologic conditions such as heart failure and stimulates murine thrombogenesis. Its association with venous thromboembolism (VTE) has been sparsely studied.
Objectives: To assess the prospective association of plasma galectin-3 and the LGALS3 rs4644 SNP with VTE incidence.
Methods: We measured plasma galectin-3 in 9,916 participants in the Atherosclerosis Risk in Communities (ARIC) study cohort in 1996 - 1998 and identified VTEs through 2013. Using Cox regression, we estimated the hazard ratio associating galectin-3 with incident VTE over a median of 13.9 years. Replication was sought in the Cardiovascular Health Study (CHS).
Results: ARIC included 21.8% blacks and 56.2% females with mean baseline age of 62.7 years. The incidence rate of VTE (n=389 events) increased across quintiles of galectin-3, with hazard ratios (95% CI) of 1 (reference), 1.13 (0.80 - 1.61), 1.00 (0.70 - 1.43), 1.36 (0.96 - 1.91), and 1.55 (1.09 - 2.19) (p-trend = 0.005), adjusted for age, sex, race, body mass index, diabetes status, and renal function. Results did not replicate in the CHS (124 VTE), but meta-analysis of both studies yielded a pooled hazard ratio (95% CI) for 1 SD increment in log galectin-3 of 1.10 (1.00 - 1.22). In ARIC, the C allele of rs4644 in the LGALS3 gene was associated with higher galectin-3 level, and in whites, with an increased rate of VTE.
Conclusion: Galectin-3 levels were associated positively with VTE incidence.
1 aFashanu, Oluwaseun, E1 aHeckbert, Susan, R1 aAguilar, David1 aJensen, Paul, N1 aBallantyne, Christie, M1 aBasu, Saonli1 aHoogeveen, Ron, C1 aDeFilippi, Christopher1 aCushman, Mary1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/751804213nas a2200973 4500008004100000022001400041245013200055210006900187260001600256300001000272490000600282520142300288100001801711700002401729700003001753700002601783700002701809700002001836700001801856700001901874700002801893700002201921700002401943700001801967700002201985700002002007700002202027700001802049700001802067700002302085700002202108700002602130700002202156700002202178700002402200700001902224700002102243700002302264700002102287700002402308700002602332700002302358700002002381700002202401700002002423700002002443700001702463700002502480700001902505700002202524700001302546700001702559700003002576700002402606700002302630700001802653700002202671700001402693700001802707700002102725700002802746700001702774700002202791700001902813700001902832700002402851700001902875700001702894700001802911700001902929700002302948700002402971700002202995700002003017700001803037700002203055700001503077700001903092700002303111700002203134700002503156700002203181856003603203 2017 eng d a2045-232200aGenetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.0 aGenetic Interactions with Age Sex Body Mass Index and Hypertensi c2017 Sep 12 a113030 v73 aIt is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
1 aWeng, Lu-Chen1 aLunetta, Kathryn, L1 aMüller-Nurasyid, Martina1 aSmith, Albert, Vernon1 aThériault, Sébastien1 aWeeke, Peter, E1 aBarnard, John1 aBis, Joshua, C1 aLyytikäinen, Leo-Pekka1 aKleber, Marcus, E1 aMartinsson, Andreas1 aLin, Henry, J1 aRienstra, Michiel1 aTrompet, Stella1 aKrijthe, Bouwe, P1 aDörr, Marcus1 aKlarin, Derek1 aChasman, Daniel, I1 aSinner, Moritz, F1 aWaldenberger, Melanie1 aLauner, Lenore, J1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aAlonso, Alvaro1 aParé, Guillaume1 aTeixeira, Pedro, L1 aDenny, Joshua, C1 aShoemaker, Benjamin1 aVan Wagoner, David, R1 aSmith, Jonathan, D1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aTaylor, Kent, D1 aKähönen, Mika1 aNikus, Kjell1 aDelgado, Graciela, E1 aMelander, Olle1 aEngström, Gunnar1 aYao, Jie1 aGuo, Xiuqing1 aChristophersen, Ingrid, E1 aEllinor, Patrick, T1 aGeelhoed, Bastiaan1 aVerweij, Niek1 aMacfarlane, Peter1 aFord, Ian1 aHeeringa, Jan1 aFranco, Oscar, H1 aUitterlinden, André, G1 aVölker, Uwe1 aTeumer, Alexander1 aRose, Lynda, M1 aKääb, Stefan1 aGudnason, Vilmundur1 aArking, Dan, E1 aConen, David1 aRoden, Dan, M1 aChung, Mina, K1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aLehtimäki, Terho1 aMärz, Winfried1 aSmith, Gustav1 aRotter, Jerome, I1 aHarst, Pim1 aJukema, Wouter1 aStricker, Bruno, H1 aFelix, Stephan, B1 aAlbert, Christine, M1 aLubitz, Steven, A uhttps://chs-nhlbi.org/node/759504391nas a2201129 4500008004100000022001400041245013100055210006900186260001300255300001200268490000700280520110800287100002001395700001701415700002301432700001801455700001701473700002501490700002001515700001701535700002501552700001901577700002501596700001901621700002301640700002301663700002001686700002201706700002001728700002301748700002101771700002001792700002301812700002001835700002001855700001801875700002001893700002201913700001601935700002401951700002101975700002401996700002002020700001602040700002002056700002602076700001902102700002402121700001902145700001802164700002002182700001702202700002002219700002402239700001902263700002402282700002402306700002102330700001802351700002102369700001702390700001902407700002502426700001502451700001902466700001902485700002202504700002302526700002802549700002802577700002402605700002602629700002302655700001602678700002002694700001802714700002102732700002502753700002102778700001802799700002402817700002302841700002202864700002002886700002102906700002402927700001902951700002002970710002702990710002603017710002803043710002903071710005403100710002803154710004303182856003603225 2017 eng d a1546-171800aGenetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.0 aGenetic loci associated with chronic obstructive pulmonary disea c2017 Mar a426-4320 v493 aChronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.
1 aHobbs, Brian, D1 ade Jong, Kim1 aLamontagne, Maxime1 aBossé, Yohan1 aShrine, Nick1 aArtigas, Maria Soler1 aWain, Louise, V1 aHall, Ian, P1 aJackson, Victoria, E1 aWyss, Annah, B1 aLondon, Stephanie, J1 aNorth, Kari, E1 aFranceschini, Nora1 aStrachan, David, P1 aBeaty, Terri, H1 aHokanson, John, E1 aCrapo, James, D1 aCastaldi, Peter, J1 aChase, Robert, P1 aBartz, Traci, M1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aGharib, Sina, A1 aZanen, Pieter1 aLammers, Jan, W1 aOudkerk, Matthijs1 aGroen, H, J1 aLocantore, Nicholas1 aTal-Singer, Ruth1 aRennard, Stephen, I1 aVestbo, Jørgen1 aTimens, Wim1 aParé, Peter, D1 aLatourelle, Jeanne, C1 aDupuis, Josée1 aO'Connor, George, T1 aWilk, Jemma, B1 aKim, Woo, Jin1 aLee, Mi, Kyeong1 aOh, Yeon-Mok1 aVonk, Judith, M1 ade Koning, Harry, J1 aLeng, Shuguang1 aBelinsky, Steven, A1 aTesfaigzi, Yohannes1 aManichaikul, Ani1 aWang, Xin-Qun1 aRich, Stephen, S1 aBarr, Graham1 aSparrow, David1 aLitonjua, Augusto, A1 aBakke, Per1 aGulsvik, Amund1 aLahousse, Lies1 aBrusselle, Guy, G1 aStricker, Bruno, H1 aUitterlinden, André, G1 aAmpleford, Elizabeth, J1 aBleecker, Eugene, R1 aWoodruff, Prescott, G1 aMeyers, Deborah, A1 aQiao, Dandi1 aLomas, David, A1 aYim, Jae-Joon1 aKim, Deog, Kyeom1 aHawrylkiewicz, Iwona1 aSliwinski, Pawel1 aHardin, Megan1 aFingerlin, Tasha, E1 aSchwartz, David, A1 aPostma, Dirkje, S1 aMacNee, William1 aTobin, Martin, D1 aSilverman, Edwin, K1 aBoezen, Marike1 aCho, Michael, H1 aCOPDGene Investigators1 aECLIPSE Investigators1 aLifeLines Investigators1 aSPIROMICS Research Group1 aInternational COPD Genetics Network Investigators1 aUK BiLEVE Investigators1 aInternational COPD Genetics Consortium uhttps://chs-nhlbi.org/node/734506994nas a2202101 4500008004100000022001400041245009900055210006900154260001600223300001000239490000600249520104500255100001901300700001901319700002301338700002201361700001701383700001601400700002801416700002201444700001901466700001801485700002201503700002701525700002201552700002301574700001901597700002001616700001801636700002201654700002301676700002201699700002001721700002801741700002801769700002201797700002001819700002701839700003001866700001901896700001701915700002201932700002201954700001801976700001701994700002102011700002702032700002202059700002302081700002202104700001902126700001702145700001802162700002002180700002202200700002502222700002102247700001802268700002102286700002002307700002302327700002202350700002702372700002102399700002102420700002402441700001902465700002102484700002002505700002102525700001902546700002502565700001902590700002602609700002602635700002102661700001902682700002402701700002002725700002602745700001902771700002102790700002002811700002402831700001702855700001802872700002402890700002102914700002202935700001302957700001202970700001902982700002403001700001803025700002503043700002203068700002003090700002203110700003903132700002103171700001803192700002203210700001903232700001803251700002003269700001703289700001903306700002403325700001703349700002003366700002003386700002003406700002303426700002703449700002203476700002103498700002203519700002303541700002403564700002203588700002103610700002203631700002303653700003203676700002403708700002203732700002003754700002803774700002403802700002003826700002203846700002503868700002203893700002803915700002403943700001803967700002603985700002404011700002304035700001704058700002004075700002304095700001804118700002204136700002304158700001504181700002104196700002004217700002704237700001904264700002004283700001904303700002404322700001504346700002204361700001504383700002804398700002404426700002904450700002004479700002504499700002204524700002204546700001904568700002204587700001704609700002304626700002204649700002604671700002704697700002704724700002304751700002104774700002204795700002004817700001904837856003604856 2017 eng d a2041-172300aGenetic loci associated with heart rate variability and their effects on cardiac disease risk.0 aGenetic loci associated with heart rate variability and their ef c2017 Jun 14 a158050 v83 aReduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals. METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries. CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results. Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery. Several in vitro and animal studies have showed that inflammatory markers play a role in bone remodeling and pathogenesis of osteoporosis. Additionally, some human longitudinal studies showed suggestive associations between elevated inflammatory markers and increased risk of nontraumatic fractures. We examined several inflammatory markers and multiple fracture types in a single study of older individuals with extensive follow-up. We assessed the association of four inflammatory markers with the risk of incident hip fractures among 5265 participants of the Cardiovascular Health Study (CHS) and a composite endpoint of incident fractures of the hip, pelvis, humerus, or proximal forearm in 4477 participants. Among CHS participants followed between 1992 and 2009, we observed 480 incident hip fractures during a median follow-up of 11 years. In the composite fracture analysis cohort of 4477 participants, we observed 711 fractures during a median follow-up of 7 years. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for hip fracture associated with doubling of IL-6 were HR 1.15 (95% CI, 1.02 to 1.30) overall and HR 1.17 (95% CI, 1.01 to 1.35) in women. We also observed a positive association between each unit increase in white blood cell (WBC) count and risk of hip fracture: HR 1.04 (95% CI, 1.01 to 1.06) overall and HR 1.06 (95% CI, 0.95 to 1.20) in women. We observed no significant associations between any of the four inflammatory markers and a composite fracture endpoint. Our findings suggest that chronic inflammatory and immune processes may be related to higher rates of incident hip fractures. © 2017 American Society for Bone and Mineral Research. BACKGROUND: Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF. METHODS: We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF. RESULTS: Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease. CONCLUSIONS: In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF. BACKGROUND: Multiple prospective studies have established an association between inflammation and higher risk of atrial fibrillation (AF), but the association between lipoprotein-associated phospholipase A (Lp-PLA) mass and activity and incident AF has not been extensively evaluated. METHODS: Using data from 10,794 Atherosclerosis Risk In Communities (ARIC) study participants aged 53-75 years, 5,181 Cardiovascular Health Study (CHS) participants aged 65 to 100 years, and 5,425 Multi-Ethnic Study of Atherosclerosis (MESA) participants aged 45-84 years, we investigated the association between baseline Lp-PLA levels and the risk of developing AF. Incident AF was identified in each cohort by follow-up visit electrocardiograms, hospital discharge coding of AF, or Medicare claims data. RESULTS: Over a mean of 13.1, 11.5, and 10.0 years of follow-up, 1,439 (13%), 2,084 (40%), and 615 (11%) incident AF events occurred in ARIC, CHS, and MESA, respectively. In adjusted analyses, each SD increment in Lp-PLA activity was associated with incident AF in both ARIC (hazard ratio [HR] 1.13, 95% CI 1.06-1.20) and MESA (HR 1.24, 95% CI 1.05-1.46). Each SD increment in Lp-PLA mass was also associated with incident AF in MESA (HR 1.25, 95% CI 1.11-1.41). No significant associations were observed among CHS participants. CONCLUSIONS: Although higher Lp-PLA mass and activity were associated with development of AF in ARIC and MESA, this relationship was not observed in CHS, a cohort of older individuals. BACKGROUND AND PURPOSE: Emerging evidence suggests that an underlying atrial cardiopathy may result in thromboembolism before atrial fibrillation (AF) develops. We examined the association between various markers of atrial cardiopathy and the risk of ischemic stroke. METHODS: The CHS (Cardiovascular Health Study) prospectively enrolled community-dwelling adults ≥65 years of age. For this study, we excluded participants diagnosed with stroke or AF before baseline. Exposures were several markers of atrial cardiopathy: baseline P-wave terminal force in ECG lead V, left atrial dimension on echocardiogram, and N terminal pro B type natriuretic peptide (NT-proBNP), as well as incident AF. Incident AF was ascertained from 12-lead electrocardiograms at annual study visits for the first decade after study enrollment and from inpatient and outpatient Medicare data throughout follow-up. The primary outcome was incident ischemic stroke. We used Cox proportional hazards models that included all 4 atrial cardiopathy markers along with adjustment for demographic characteristics and established vascular risk factors. RESULTS: Among 3723 participants who were free of stroke and AF at baseline and who had data on all atrial cardiopathy markers, 585 participants (15.7%) experienced an incident ischemic stroke during a median 12.9 years of follow-up. When all atrial cardiopathy markers were combined in 1 Cox model, we found significant associations with stroke for P-wave terminal force in ECG lead V (hazard ratio per 1000 μV*ms 1.04; 95% confidence interval, 1.001-1.08), log-transformed NT-proBNP (hazard ratio per doubling of NT-proBNP, 1.09; 95% confidence interval, 1.03-1.16), and incident AF (hazard ratio, 2.04; 95% confidence interval, 1.67-2.48) but not left atrial dimension (hazard ratio per cm, 0.96; 95% confidence interval, 0.84-1.10). CONCLUSIONS: In addition to clinically apparent AF, other evidence of abnormal atrial substrate is associated with subsequent ischemic stroke. This finding is consistent with the hypothesis that thromboembolism from the left atrium may occur in the setting of several different manifestations of atrial disease. BACKGROUND: Atrial fibrillation (AF) is an important public health problem across race/ethnic groups. Data from US cohort studies initiated in the 1980s suggest a higher prevalence of AF risk factors among African-Americans (AAs) than whites, but lower AF incidence. The Jackson Heart Study (JHS) is a community-based study of 5306 AAs recruited starting in 2000. HYPOTHESIS: Demographic, anthropometric, cardiovascular, and/or electrocardiographic factors are associated with AF incidence in JHS. METHODS: Using baseline participant characteristics and incident AF identified through hospital surveillance, study electrocardiogram, and Medicare claims, we estimated age- and sex-specific AF incidence rates, compared them with rates in AA participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS), and examined associations of cardiovascular risk factors with AF. RESULTS: A total of 66 participants had prevalent AF at baseline. Over an average follow-up of 8.5 years, 242 cases of incident AF were identified. Age- and sex-specific AF incidence rates in JHS were similar to those among AAs in MESA and appeared slightly lower than those among AAs in CHS. In an age- and sex-adjusted model, associations with incident AF were observed for modifiable risk factors: high body weight (HR = 1.23 per 15 kg, 95%CI 1.13-1.35), systolic blood pressure (HR = 1.29 per 20 mmHg, 95%CI 1.13-1.47), and current smoking (HR = 1.80, 95%CI 1.27-2.55). Risk estimates associated with these risk factors were only slightly attenuated after multivariable adjustments. CONCLUSIONS: These findings underscore the potential additional benefits of interventions for weight management, control of hypertension, and smoking cessation for the prevention of AF among AAs. BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus. CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health. BACKGROUND: Genetic variants at the / locus are strongly associated with electrocardiographic PR and QRS intervals. While is the canonical cardiac sodium channel gene, the role of in cardiac conduction is less well characterized. METHODS: We sequenced the locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology. RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium ( =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, =1.52×10) and QRS intervals (rs6599251, QRS β=-0.73; =1.2×10), respectively. Although these variants were not associated with or expression in human atrial tissue (n=490), they were in high linkage disequilibrium ( ≥0.72) with a common missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, =0.03, and I962V+V1073A, 22.4±0.8%, =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, =0.03). CONCLUSIONS: Our findings suggest an association between genetic variation in , the late sodium current, and alterations in cardiac conduction. Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA. Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk. Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community. BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. RESULTS: At 17q25, we confirmed the association of multiple common variants in , , and (<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in (lead, rs34136221; =4.5×10) partially independent of known common signal (=1.4×10). We further identified a locus at 2q33 containing common variants in , , and (lead, rs2351524; =1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency variants (=2.8×10). CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH. BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes. BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest. The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10) and multi-trait analysis (P = 2.9 × 10) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes. Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. Background: Atrial fibrillation is increasingly prevalent as the US population ages and is associated with significant morbidity and mortality. Care for patients with atrial fibrillation can be costly, US health care costs are comparatively high, and there are few cost estimates available that incorporate detailed measurement of comorbidities and their effects on costs. Methods and Results: In the Cardiovascular Health Study and the Framingham Heart Study, participants aged 65 years or older with newly diagnosed atrial fibrillation were matched on age and follow-up time to referents free of atrial fibrillation. The total clinical and hospital medical costs paid by Medicare Parts A and B (drug costs from Medicare Part D costs were not included) in the year prior to diagnosis (or matching) were compared with costs in the following year. Estimates were adjusted for other medical conditions and adjusted to 2009 dollars. In the Cardiovascular Health Study, 513 participants were diagnosed with new-onset atrial fibrillation and survived 30 days post-atrial fibrillation diagnosis, and 513 referents (as a control cohort) were identified, with a mean age of 77 years. In the Framingham Heart Study, we identified 336 participants diagnosed with atrial fibrillation, who survived 30 days post-atrial fibrillation diagnosis and matched these participants to 336 referents. We compared these new-onset atrial fibrillation participants with referents, using a difference in difference design to account for both time trends and differences between the two groups. The adjusted incremental cost for participants with atrial fibrillation, compared with referents, was US$18,060 (95% confidence interval: US$14,965-US$21,155) in the Cardiovascular Health Study and US$20,012 (95% confidence interval: US$15,057-US$24,966) in the Framingham Heart Study. The pooled estimate was US$18,601 (95% confidence interval: US$15,981-US$21,234). Conclusion: Atrial fibrillation was associated with increased costs in the year after diagnosis in two community-based cohorts, even after careful accounting for age, time period, and systematically measured comorbidities. BACKGROUND: Heart failure (HF) is associated with cognitive impairment. However, we know little about the time course of cognitive change after HF diagnosis, the importance of comorbid atrial fibrillation, or the role of ejection fraction. We sought to determine the associations of incident HF with rates of cognitive decline and whether these differed by atrial fibrillation status or reduced versus preserved ejection fraction. METHODS AND RESULTS: Participants were 4864 men and women aged ≥65 years without a history of HF and free of clinical stroke in the CHS (Cardiovascular Health Study)-a community-based prospective cohort study in the United States, with cognition assessed annually from 1989/1990 through 1998/1999. We identified 496 participants with incident HF by review of hospital discharge summaries and Medicare claims data, with adjudication according to standard criteria. Global cognitive ability was measured by the Modified Mini-Mental State Examination. In adjusted models, 5-year decline in model-predicted mean Modified Mini-Mental State Examination score was 10.2 points (95% confidence interval, 8.6-11.8) after incident HF diagnosed at 80 years of age, compared with a mean 5-year decline of 5.8 points (95% confidence interval, 5.3-6.2) from 80 to 85 years of age without HF. The association was stronger at older ages than at younger ages, did not vary significantly in the presence versus absence of atrial fibrillation (=0.084), and did not vary significantly by reduced versus preserved ejection fraction (=0.734). CONCLUSIONS: Decline in global cognitive ability tends to be faster after HF diagnosis than without HF. Clinical and public health implications of this finding warrant further attention. Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease. Background Premature ventricular contractions (PVCs) predict heart failure and death. Data regarding modifiable risk factors for PVCs are scarce. Methods and Results We studied 1424 Cardiovascular Health Study participants randomly assigned to 24-hour Holter monitoring. Demographics, comorbidities, habits, and echocardiographic measurements were examined as predictors of PVC frequency and, among 845 participants, change in PVC frequency 5 years later. Participants exhibited a median of 0.6 (interquartile range, 0.1-7.1) PVCs per hour. Of the more directly modifiable characteristics and after multivariable adjustment, every SD increase in systolic blood pressure was associated with 9% more PVCs (95% confidence interval [CI], 2%-17%; P=0.01), regularly performing no or low-intensity exercise compared with more physical activity was associated with ≈15% more PVCs (95% CI, 3-25%; P=0.02), and those with a history of smoking exhibited an average of 18% more PVCs (95% CI, 3-36%; P=0.02) than did never smokers. After 5 years, PVC frequency increased from a median of 0.5 (IQR, 0.1-4.7) to 1.2 (IQR, 0.1-13.8) per hour ( P<0.0001). Directly modifiable predictors of 5-year increase in PVCs, described as the odds per each quintile increase in PVCs, included increased diastolic blood pressure (odds ratio per SD increase, 1.16; 95% CI, 1.02-1.31; P=0.02) and a history of smoking (OR, 1.31; 95% CI, 1.02-1.68; P=0.04). Conclusions Enhancing physical activity, smoking cessation, and aggressive control of blood pressure may represent fruitful strategies to mitigate PVC frequency and PVC-associated adverse outcomes. We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms. Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy. Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF. Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci. Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development. We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition. BACKGROUND: Decline in serum androgens is common among older men and has been associated with cardiovascular disease, although its role in risk of atrial fibrillation (AF) has not been well defined. HYPOTHESIS: Low serum androgens are associated with an increased risk of AF. METHODS: We examined the prospective associations between testosterone, its more active metabolite dihydrotestosterone (DHT), and sex-hormone binding globulin (SHBG) with risk of AF among 1019 otherwise healthy men of average age 76.3±4.9 years in the Cardiovascular Health Study. RESULTS: After median follow-up of 9.5 years, 304 (30%) men developed AF. We detected a nonlinear association with risk of incident AF in both free and total DHT, in which subjects with the lowest levels had a higher risk of incident AF. After adjustment for demographics, clinical risk factors, left atrial diameter, and serum NT-proBNP levels, men with free DHT less than 0.16 ng/dL were at increased risk compared with men with higher levels (HR 1.48, CI 1.01-2.17, p<0.05). Sensitivity analyses confirmed that the increased risk was not cutpoint-specific, with a significant association noted up to cutpoints less than ~0.2 ng/dL. We also detected a complex nonlinear association between SHBG and incident AF, in which subjects in the middle quintile (52.9 - 65.3 nmol/L) had increased risk. CONCLUSION: Among older men, low free DHT is associated with an increased risk of incident atrial fibrillation. Further studies are needed to explore mechanisms for this association. BACKGROUND: The relationship between sleep disruption, independent of obstructive sleep apnea (OSA), and atrial fibrillation (AF) is unknown. OBJECTIVE: The purpose of this study was to determine whether poor sleep itself is a risk factor for AF. METHODS: We first performed an analysis of participants in the Health eHeart Study and validated those findings in the longitudinal Cardiovascular Health Study, including a subset of patients undergoing polysomnography. To determine whether the observed relationships readily translated to medical practice, we examined 2005-2009 data from the California Healthcare Cost and Utilization Project. RESULTS: Among 4553 Health eHeart participants, the 526 with AF exhibited more frequent nighttime awakening (odd ratio [OR] 1.47; 95% confidence interval [CI] 1.14-1.89; P = .003). In 5703 Cardiovascular Health Study participants followed for a median 11.6 years, frequent nighttime awakening predicted a 33% greater risk of AF (hazard ratio [HR] 1.33; 95% CI 1.17-1.51; P <.001). In patients with polysomnography (N = 1127), every standard deviation percentage decrease in rapid eye movement (REM) sleep was associated with a 18% higher risk of developing AF (HR 1.18; 95% CI 1.00-1.38; P = .047). Among 14,330,651 California residents followed for a median 3.9 years, an insomnia diagnosis predicted a 36% increased risk of new AF (HR 1.36; 95% CI 1.30-1.42; P <.001). CONCLUSION: Sleep disruption consistently predicted AF before and after adjustment for OSA and other potential confounders across several different populations. Sleep quality itself may be important in the pathogenesis of AF, potentially representing a novel target for prevention. The relationship between alcohol consumption and mortality generally exhibits a U-shaped curve. The longevity observed with moderate alcohol consumption may be explained by other confounding factors, and, if such a relationship is present, the mechanism is not well understood. Indeed, the optimal amount of alcohol consumption for health has yet to be determined. Leukocyte telomere length is an emerging quantifiable marker of biological age and health, and a shorter telomere length is a predictor of increased mortality. Because leukocyte telomere length is a quantifiable and objectively measurable biomarker of aging, we sought to identify the amount of alcohol consumption associated with the longest telomere length and least telomere length attrition. Among over 2,000 participants from two distinct cohort studies, we found no pattern of alcohol consumption that was associated with longer telomere length or less telomere length attrition over time. Binge drinking may reduce telomere length. Using telomere length as a marker of age and health, these data fail to demonstrate any benefits of alcohol consumption, even when consumed in moderation. Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirty-five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10 ) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified. Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes. Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk. Background Blacks harbor more cardiovascular risk factors than whites, but experience less atrial fibrillation ( AF ). Conversely, whites may have a lower risk of heart failure ( CHF ). N-terminal pro-B-type natriuretic peptide ( NT -pro BNP) levels are higher in whites, predict incident AF , and have diuretic effects in the setting of increased ventricular diastolic pressures, potentially providing a unifying explanation for these racial differences. Methods and Results We used data from the CHS (Cardiovascular Health Study) to determine the degree to which baseline NT -pro BNP levels mediate the relationships between race and incident AF and CHF by comparing beta estimates between models with and without NT -pro BNP . The ARIC (Atherosclerosis Risk in Communities) study was used to assess reproducibility. Among 4731 CHS (770 black) and 12 418 ARIC (3091 black) participants, there were 1277 and 1253 incident AF events, respectively. Whites had higher baseline NT -pro BNP ( CHS : 40% higher than blacks; 95% CI , 29-53; ARIC : 39% higher; 95% CI , 33-46) and had a greater risk of incident AF compared with blacks ( CHS : adjusted hazard ratio, 1.60; 95% CI , 1.31-1.93; ARIC : hazard ratio, 1.93; 95% CI , 1.57-2.27). NT -pro BNP levels explained a significant proportion of the racial difference in AF risk ( CHS : 36.2%; 95% CI , 23.2-69.2%; ARIC : 24.6%; 95% CI , 14.8-39.6%). Contrary to our hypothesis, given an increased risk of CHF among whites in CHS (adjusted hazard ratio, 1.20; 95% CI , 1.05-1.47) and the absence of a significant association between race and CHF in ARIC (adjusted hazard ratio, 1.07; 95% CI , 0.94-1.23), CHF -related mediation analyses were not performed. Conclusions A substantial portion of the relationship between race and AF was statistically explained by baseline NT -pro BNP levels. No consistent relationship between race and CHF was observed. AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable. BACKGROUND: Ceramides exhibit multiple biological activities that may influence the pathophysiology of heart failure. These activities may be influenced by the saturated fatty acid carried by the ceramide (Cer). However, the associations of different circulating Cer species, and their sphingomyelin (SM) precursors, with heart failure have received limited attention. METHODS AND RESULTS: We studied the associations of plasma Cer and SM species with incident heart failure in the Cardiovascular Health Study. We examined 8 species: Cer and SM with palmitic acid (Cer-16 and SM-16), species with arachidic acid (Cer-20 and SM-20), species with behenic acid (Cer-22 and SM-22), and species with lignoceric acid (Cer-24 and SM-24). During a median follow-up of 9.4 years, we identified 1179 cases of incident heart failure among 4249 study participants. In Cox regression analyses adjusted for risk factors, higher levels of Cer-16 and SM-16 were associated with higher risk of incident heart failure (hazard ratio for one SD increase:1.25 [95% CI, 1.16-1.36] and 1.28 [1.18-1.40], respectively). In contrast, higher levels of Cer-22 were associated with lower risk of heart failure in multivariable analyses further adjusted for Cer-16 (hazard ratio, 0.85 [0.78-0.92]); and higher levels of SM-20, SM-22 and SM-24 were associated with lower risk of heart failure in analyses further adjusted for SM-16 (hazard ratios, 0.83 [0.77-0.90], 0.81 [0.75-0.88], and 0.83 [0.77-0.90], respectively). No statistically significant interactions with age, sex, black race, body mass index, or baseline coronary heart disease were detected. Similar associations were observed for heart failure with preserved (n=529) or reduced (n=348) ejection fraction. CONCLUSIONS: This study shows associations of higher plasma levels of Cer-16 and SM-16 with increased risk of heart failure and higher levels of Cer-22, SM-20, SM-22, and SM-24 with decreased risk of heart failure. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00005133. AIMS: Premature atrial contractions (PACs) are known to trigger and predict atrial fibrillation (AF). We sought to identify the determinants of PACs and the degree to which PACs mediate the effects of established risk factors for AF. METHODS AND RESULTS: Predictors of baseline PAC frequency were examined using a Holter Study among 1392 participants in the Cardiovascular Health Study, a community-based cohort of individuals aged ≥65 years. Participants were then followed for their first diagnosis of AF. Independent predictors of PACs were identified, and the extent to which PACs might mediate the relationship between those predictors and AF was determined. The median hourly frequency of PACs was 2.7 (interquartile range 0.8-12.1). After multivariable adjustment, increasing age, increasing height, decreasing body mass index, and a history of myocardial infarction were each associated with more PACs. Regarding modifiable predictors, participants using beta-blockers had 21% less [95% confidence interval (95% CI) 9-30%, P = 0.001] and those performing at least moderate intensity exercise vs. lower intensity exercisers had 10% less (95% CI 1-18%, P = 0.03) PACs. Higher PAC frequency explained 34% (95% CI 22-57%, P < 0.0001) of the relationship between increasing age and AF risk and 27% (95% CI 10-75%, P = 0.004) of the relationship between taller height and AF risk. CONCLUSION: Enhancing physical activity and use of beta-blockers may represent fruitful strategies to mitigate PAC frequency. A substantial proportion of the excess risk of AF due to increasing age and taller height may be explained by an increase in PAC frequency. BACKGROUND: Rare coding mutations underlying deficiencies of antithrombin and proteins C and S contribute to familial venous thromboembolism (VTE). It is uncertain whether rare variants play a role in the etiology of VTE in the general population. OBJECTIVES: We conducted a deep whole-exome sequencing (WES) study to investigate the associations between rare coding variants and the risk of VTE in two population-based prospective cohorts. PATIENTS/METHODS: Whole-exome sequencing was performed in the Longitudinal Investigation of Thromboembolism Etiology (LITE), which combines the Atherosclerosis Risk in Communities (ARIC) study (316 incident VTE events among 3159 African Americans [AAs] and 458 incident VTEs among 7772 European Americans [EAs]) and the Cardiovascular Healthy Study (CHS; 60 incident VTEs among 1751 EAs). We performed gene-based tests of rare variants (allele frequency < 1%, exome-wide significance P < 1.47 × 10 ) separately in each study and ancestry group, and meta-analyzed the results for the EAs in ARIC and CHS. RESULTS: In the meta-analysis of EAs, we identified one gene, PROC, in which the burden of rare, coding variants was significantly associated with increased risk of VTE (HR = 5.42 [3.11, 9.42] for carriers versus non-carriers, P = 2.27 × 10 ). In ARIC EAs, carriers of the PROC rare variants had on average 0.75 standard deviation (SD) lower concentrations of plasma protein C and 0.28 SD higher D-dimer (P < .05) than non-carriers. Adjustment for low protein C status did not eliminate the association of PROC burden with VTE. In AAs, rare coding PROC variants were not associated with VTE. CONCLUSIONS: Rare coding variants in PROC contribute to increased VTE risk in EAs in this general population sample. BACKGROUND: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear. METHODS: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF. RESULTS: Of 4341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over a median follow-up of 10 years, 497 (11.4%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (heart rate [HR], 1.80; 95% CI, 1.31-2.45; P < 0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain. CONCLUSION: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that LA mechanical dysfunction precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF. FUNDING: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants KL2TR001424, R01HL107577, U01HL080295, and U01HL130114 from the NIH's National Center for Advancing Translational Sciences, and National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. OBJECTIVE: To investigate the relationship between high FVIII clotting activity (FVIII:C), MRI-defined white matter hyperintensities (WMH) and cognitive function over time. METHODS: Data from the population-based Cardiovascular Health Study (n = 5,888, aged ≥65) were used. FVIII:C was measured in blood samples taken at baseline. WMH burden was assessed on two cranial MRI scans taken roughly 5 years apart. Cognitive function was assessed annually using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST). We used ordinal logistic regression models adjusted for demographic and cardiovascular factors in cross-sectional and longitudinal WMH analyses, and adjusted linear regression and linear mixed models in the analyses of cognitive function. RESULTS: After adjustment for confounding, higher levels of FVIII:C were not strongly associated with the burden of WMH on the initial MRI scan (OR>p75 = 1.20, 95% CI 0.99-1.45; N = 2,735) nor with WMH burden worsening over time (OR>p75 = 1.18, 95% CI 0.87-1.59; N = 1,527). High FVIII:C showed no strong association with cognitive scores cross-sectionally (3MSE>p75 β = -0.06, 95%CI -0.45 to 0.32, N = 4,005; DSST>p75 β = -0.69, 95%CI -1.52 to 0.13, N = 3,954) or over time (3MSE>p75 β = -0.07,95% CI -0.58 to 0.44, N = 2,764; DSST>p75 β = -0.22, 95% CI -0.97 to 0.53, N = 2,306) after confounding adjustment. INTERPRETATION: The results from this cohort study of older adult participants indicate no strong relationships between higher FVIII:C levels and WMH burden or cognitive function in cross-sectional and longitudinal analyses. Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues. The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. Background Ceramides exhibit multiple biological activities that may influence the pathophysiological characteristics of atrial fibrillation (AF). Whether the length of the saturated fatty acid carried by the ceramide or their sphingomyelin precursors are associated with AF risk is not known. Methods and Results Among 4206 CHS (Cardiovascular Health Study) participants (mean age, 76 years; 40% men) who were free of prevalent AF at baseline, we identified 1198 incident AF cases over a median 8.7 years of follow-up. We examined 8 sphingolipid species: ceramide and sphingomyelin species with palmitic acid and species with very-long-chain saturated fatty acids: arachidic; behenic; and lignoceric. In adjusted Cox regression analyses, ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk (ie, per 2-fold higher ceramide with behenic acid hazard ratio, 0.71; 95% CI, 0.59-0.86; sphingomyelin with behenic acid hazard ratio, 0.60; 95% CI, 0.46-0.77). In contrast, ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (ceramide with palmitic acid hazard ratio, 1.31; 95% CI, 1.03-1.66; sphingomyelin with palmitic acid hazard ratio, 1.73; 95% CI, 1.18-2.55). Associations were attenuated with adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), but did not differ significantly by age, sex, race, body mass index, or history of coronary heart disease. Conclusions Our findings suggest that several ceramide and sphingomyelin species are associated with incident AF, and that these associations differ on the basis of the fatty acid. Ceramides and sphingomyelins with palmitic acid were associated with increased AF risk, whereas ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk. Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN ( = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN ( = 1.82 × 10) among older participants (≥65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity ( = 5.6 × 10), hypertension ( = 2.8 × 10), diabetes ( = 3.6 × 10), and hyperlipidemia ( = 6.3 × 10). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases. BACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF. METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF. RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; <0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF. CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time. OBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Expansion of fat depots is associated with increased circulating total non-esterified fatty acids (NEFAs), elevated levels of which are associated with incident AF. We undertook comprehensive serum measurement of individual NEFA to identify specific associations with new-onset AF late in life. METHODS: The present study focused on participants with available serum and free of AF selected from the Cardiovascular Health Study, a community-based longitudinal investigation of older US adults. Thirty-five individual NEFAs were measured by gas chromatography. Cox regression was used to evaluate the association of individual NEFAs with incident AF. RESULTS: The study sample included 1872 participants (age 77.7±4.4). During median follow-up of 11.3 years, 715 cases of incident AF occurred. After concurrent adjustment of all NEFAs and full adjustment for potential confounders, higher serum concentration of nervonic acid (24:1 n-9), a long-chain monounsaturated fatty acid, was associated with higher risk of AF (HR per SD: 1.18, 95% CI 1.08 to 1.29; p<0.001). Conversely, higher serum concentration of gamma-linolenic acid (GLA) (18:3 n-6), a polyunsaturated n-6 fatty acid, was associated with lower risk of AF (HR per SD: 0.81, 95% CI 0.71 to 0.94; p=0.004). None of the remaining NEFAs was significantly associated with AF. CONCLUSIONS: Among older adults, serum levels of non-esterified nervonic acid were positively associated, while serum levels of non-esterified GLA were inversely associated, with incident AF. If confirmed, these results could offer new strategies for AF prevention and early intervention in this segment of the population at highest risk. BACKGROUND: Hypertension is a major source of cardiovascular morbidity and mortality. Recent evidence from mouse models, genetic, and cross-sectional human studies suggest increased proportions of selected immune cell subsets may be associated with levels of systolic blood pressure (SBP). METHODS: We assayed immune cells from cryopreserved samples collected at the baseline examination (2000-2002) from 1195 participants from the multi-ethnic study of atherosclerosis (MESA). We used linear mixed models, with adjustment for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and cytomegalovirus titers, to estimate the associations between 30 immune cell subsets (4 of which were a priori hypotheses) and repeated measures of SBP (baseline and up to four follow-up measures) over 10 years. The analysis provides estimates of the association with blood pressure level. RESULTS: The mean age of the MESA participants at baseline was 64 ± 10 years and 53% were male. A one standard deviation (1-SD) increment in the proportion of γδ T cells was associated with 2.40 mmHg [95% confidence interval (CI) 1.34-3.42] higher average systolic blood pressure; and for natural killer cells, a 1-SD increment was associated with 1.88 mmHg (95% CI 0.82-2.94) higher average level of systolic blood pressure. A 1-SD increment in classical monocytes (CD14CD16) was associated with 2.01 mmHG (95% CI 0.79-3.24) lower average systolic blood pressure. There were no associations of CD4 T helper cell subsets with average systolic blood pressure. CONCLUSION: These findings suggest that the innate immune system plays a role in levels of SBP whereas there were no associations with adaptive immune cells. The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%. Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms. Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease. BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments. OBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Fasting and postload levels of glucose and non-esterified fatty acids (NEFAs) reflect different facets of metabolic regulation. We sought to study their respective contributions to AF risk concurrently. METHODS: We assessed levels of fasting and postload glucose and NEFA in the Cardiovascular Health Study to identify associations with AF incidence and, secondarily, with ECG parameters of AF risk available at baseline. Linear and Cox regressions were performed. RESULTS: The study included 1876 participants (age 77.7±4.4). During the median follow-up of 11.4 years, 717 cases of incident AF occurred. After adjustment for potential confounders, postload glucose showed an association with incident AF (HR per SD increment of postload glucose=1.11, 95% CI 1.02 to 1.21, p=0.017). Both glucose measures, but not NEFA, were positively associated with higher P wave terminal force in V1 (PTFV1); the association remained significant only for postload glucose when the two measures were entered together (β per SD increment=138 μV·ms, 95% CI 15 to 260, p=0.028). Exploratory analyses showed significant interaction by sex for fasting NEFA (p=0.044) and postload glucose (p=0.015) relative to AF, with relationships stronger in women. For postload glucose, the association with incident AF was observed among women but not among men. CONCLUSIONS: Among older adults, postload glucose was positively associated with incident AF, with consistent findings for PTFV1. In exploratory analyses, the relationship with AF appeared specific to women. These findings require further study but suggest that interventions to address postprandial dysglycaemia late in life might reduce AF. Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity. Premature atrial contractions (PACs) are frequently observed on electrocardiograms and are associated with increased risks of atrial fibrillation (AF), stroke, and mortality. In this study, we aimed to identify genetic susceptibility loci for PAC frequency. We performed a genome-wide association study meta-analysis with PAC frequency obtained from ambulatory cardiac monitoring in 4,831 individuals of European ancestry. We identified a genome-wide significant locus at the gene. The lead variant, rs7373862, located in an intron of , was associated with an increase of 0.12 [95% CI 0.08-0.16] standard deviations of the normalized PAC frequency per risk allele. Among genetic variants previously associated with AF, there was a significant enrichment in concordance of effect for PAC frequency (n = 73/106, p = 5.1 × 10). However, several AF risk loci, including , were not associated with PAC frequency. These findings suggest the existence of both shared and distinct genetic mechanisms for PAC frequency and AF. Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population. We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/ = 1.4 ms, 95% CI 1.3 -1.5; p-value=1.1×10). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk. BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology. METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations. CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults. Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking. Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI ≥ 30 kg/m), and extreme obesity (BMI ≥ 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49%, and 2.97% and 3.68%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations. The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits. Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation. Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis. BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer's disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults. METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality. RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition. DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community. BACKGROUND AND OBJECTIVES: There are disparities in the prevalence of obesity by race, and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and whether the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared with normal weight and that the effect of obesity on cognitive decline is more pronounced in Black adults compared with their White counterparts. METHODS: We pooled data from 28,867 participants free of stroke and dementia (mean, SD: age 61 [10.7] years at the first cognitive assessment, 55% female, 24% Black, and 29% obese) from 6 cohorts. The primary outcome was the annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, SD 10) at a participant's first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the 6 cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15). RESULTS: Obese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, -0.36 [95% CI, -0.46 to -0.17]; < 0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, -0.19 [95% CI, -0.39 to 0.002]; = 0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95% CI, -0.009 to 0.03]; = 0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95% CI, 0.01 to 0.05]; < 0.001). There was no evidence that race modified the association between body mass index and global cognitive decline ( = 0.34). DISCUSSION: These results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG. The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction. Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences. BACKGROUND: Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS). METHODS: Eligible CHS participants were free of prevalent stroke and underwent quantification of 1298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992-1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-standard deviation increase in the log-2 transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and non-cardioembolic IS as well as proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation. RESULTS: Of 2983 eligible participants, the mean age was 74.3 (± 4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal pro-brain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23-1.53, P=2.08x10) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16-1.45, P=4.55x10) were independently associated with IS risk. These two associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident non-cardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction. CONCLUSIONS: In a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and non-cardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction. INTRODUCTION: Most current clinical risk prediction scores for cardiovascular disease prevention use a composite outcome. Risk prediction scores for specific cardiovascular events could identify people who are at higher risk for some events than others informing personalized care and trial recruitment. We sought to predict risk for multiple different events, describe how those risks differ, and examine if these differences could improve treatment priorities. METHODS: We used participant-level data from five cohort studies. We included participants between 40 and 79 years old who had no history of myocardial infarction (MI), stroke, or heart failure (HF). We made separate models to predict 10-year rates of first atherosclerotic cardiovascular disease (ASCVD), first fatal or nonfatal MI, first fatal or nonfatal stroke, new-onset HF, fatal ASCVD, fatal MI, fatal stroke, and all-cause mortality using established ASCVD risk factors. To limit overfitting, we used elastic net regularization with alpha = 0.75. We assessed the models for calibration, discrimination, and for correlations between predicted risks for different events. We also estimated the potential impact of varying treatment based on patients who are high risk for some ASCVD events, but not others. RESULTS: Our study included 24,505 people; 55.6% were women, and 20.7% were non-Hispanic Black. Our models had C-statistics between 0.75 for MI and 0.85 for HF, good calibration, and minimal overfitting. The models were least similar for fatal stroke and all MI (0.58). In 1,840 participants whose risk of MI but not stroke or all-cause mortality was in the top quartile, we estimate one blood pressure-lowering medication would have a 2.4% chance of preventing any ASCVD event per 10 years. A moderate-strength statin would have a 2.1% chance. In 1,039 participants who had top quartile risk of stroke but not MI or mortality, a blood pressure-lowering medication would have a 2.5% chance of preventing an event, but a moderate-strength statin, 1.6%. CONCLUSION: We developed risk scores for eight key clinical events and found that cardiovascular risk varies somewhat for different clinical events. Future work could determine if tailoring decisions by risk of separate events can improve care. BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD. METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D. RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( <5.0×10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, =3.6×10 , rs11444867 (intergenic variant near ) with HR 1.89, 95% CI 1.52 - 2.35, =9.9×10 , and rs335407 (intergenic variant between and ) HR 1.25, 95% CI 1.16 - 1.35, =1.5×10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase ( =1.0×10 ). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D. CLINICAL PERSPECTIVE: We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD. Background Risk for venous thromboembolism has a strong genetic component. Whole genome sequencingfrom the Trans-Omics for Precision Medicine program allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods The 3793 cases and 7834 controls (11.6% of cases were Black, Hispanic/Latino, or Asian American) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only (odds ratio, 6.2 for carriers of rare variants; =7.4×10) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at (odds ratio, 3.8; =1.6×10), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: became significant (minimum =1.8×10 with the secondary filter), while did not (minimum =4.4×10 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, , became significant (=4.4×10 using all missense variants with minor allele frequency <0.0005). Conclusions Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel locus and to identify additional rare variation associated with venous thromboembolism. Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 × 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine. BACKGROUND: The size/magnitude of cognitive changes after incident heart failure (HF) are unclear. We assessed whether incident HF is associated with changes in cognitive function after accounting for pre-HF cognitive trajectories and known determinants of cognition. METHODS: This pooled cohort study included adults without HF, stroke, or dementia from six US population-based cohort studies from 1971-2019: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study. Linear mixed-effects models estimated changes in cognition at the time of HF (change in the intercept) and the rate of cognitive change over the years after HF (change in the slope), controlling for pre-HF cognitive trajectories and participant factors. Change in global cognition was the primary outcome. Change in executive function and memory were secondary outcomes. Cognitive outcomes were standardized to a -score metric (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. RESULTS: The study included 29,614 adults (mean [SD] age was 61.1 [10.5] years, 55% female, 70.3% White, 22.2% Black 7.5% Hispanic). During a median follow-up of 6.6 (Q1-Q3: 5-19.8) years, 1,407 (4.7%) adults developed incident HF. Incident HF was associated with an acute decrease in global cognition (-1.08 points; 95% CI -1.36, -0.80) and executive function (-0.65 points; 95% CI -0.96, -0.34) but not memory (-0.51 points; 95% CI -1.37, 0.35) at the time of the event. Greater acute decreases in global cognition after HF were seen in those with older age, female sex and White race. Individuals with incident HF, compared to HF-free individuals, demonstrated faster declines in global cognition (-0.15 points per year; 95% CI, -0.21, -0.09) and executive function (-0.16 points per year; 95% CI -0.23, -0.09) but not memory ( -0.11 points per year; 95% CI -0.26, 0.04) compared with pre-HF slopes. CONCLUSIONS: In this pooled cohort study, incident HF was associated with an acute decrease in global cognition and executive function at the time of the event and faster declines in global cognition and executive function over the following years.