02765nas 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 a
BACKGROUND: 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/71602750nas 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/68402781nas 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/70602062nas 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/79303809nas a2200433 4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520259500256653002202851653001602873653000902889653002202898653001802920653002802938653001902966653004002985653001203025653001103037653001103048653001403059653000903073653002303082653001703105653001603122100002403138700001603162700002303178700002303201700002603224700002403250700002203274700002103296700002303317856003503340 2006 eng d a0002-861400aMetabolic syndrome and cardiovascular disease in older people: The cardiovascular health study.0 aMetabolic syndrome and cardiovascular disease in older people Th c2006 Sep a1317-240 v543 aOBJECTIVES: To assess the prospective association between metabolic syndrome (MetS) and cardiovascular disease (CVD) in older people and to evaluate the effect of lowering the threshold for impaired fasting glucose (IFG) on the prevalence of IFG and MetS and the risk of CVD.
DESIGN: Prospective cohort study.
SETTING: Four field centers in U.S. communities.
PARTICIPANTS: Three thousand five hundred eighty-five subjects in the Cardiovascular Health Study free of diabetes mellitus and CVD at baseline (mean age 72, 62% female, 14% black).
MEASUREMENTS: Baseline measures of MetS components and adjudicated incident CVD events. MetS (2001) was defined first using the original criteria from the Third Adult Treatment Panel Report of the National Cholesterol Education Program (> or =3 of the following: large waist circumference (women >88 cm, men >102 cm), elevated triglycerides (> or =1.70 mmol/L), low high-density lipoprotein cholesterol (men <1.04 mmol/L, women <1.30 mmol/L), elevated fasting glucose (6.1-6.9 mmol/L), and high blood pressure (> or =130/85 mmHg or self-reported use of medications for hypertension). Subjects were also classified according to the revised definition of the MetS (2005) that applies the lower threshold for fasting glucose (5.6-6.9 mmol/L).
RESULTS: During follow-up (median 11 years), 818 coronary heart disease (CHD), 401 stroke, and 554 congestive heart failure (CHF) events occurred. Age- and race-adjusted hazard ratios (HRs) for CHD, stroke, and CHF were 1.30 (95% confidence interval (CI) = 1.07-1.57), 0.94 (95% CI = 0.73-1.21), and 1.40 (95% CI = 1.12-1.76) for women and 1.35 (95% CI = 1.10-1.66), 1.51 (95% CI = 1.08-2.12), and 1.47 (95% CI = 1.14-1.90) for men, respectively. Overall, women and men with MetS (2005) were 20% to 30% more likely to experience any CVD event than subjects without MetS (2005). Using the lower cut-point for IFG resulted in a near tripling in IFG prevalence (16% to 46%) and an additional 9% classified with MetS (2005) but HRs similar to those estimated from the original MetS (2001) criteria. High blood pressure was the component most strongly associated with incident CHD.
CONCLUSION: Results from this study of an elderly, population-based cohort provide support for earlier investigations in primarily middle-aged populations that link the presence of MetS with the development of CVD and further underscore the importance of recognizing and treating its individual components, particularly high blood pressure.
10aAfrican Americans10aAge Factors10aAged10aAged, 80 and over10aBlood Glucose10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aFasting10aFemale10aHumans10aIncidence10aMale10aMetabolic Syndrome10aRisk Factors10aSex Factors1 aMcNeill, Ann, Marie1 aKatz, Ronit1 aGirman, Cynthia, J1 aRosamond, Wayne, D1 aWagenknecht, Lynne, E1 aBarzilay, Joshua, I1 aTracy, Russell, P1 aSavage, Peter, J1 aJackson, Sharon, A uhttps://chs-nhlbi.org/node/91802663nas 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/94202680nas a2200421 4500008004100000022001400041245007700055210006900132260001300201300001200214490000700226520153900233653002201772653002101794653002401815653002101839653001101860653002201871653001101893653001701904653001401921653000901935653001601944653002601960653003001986653001502016653002402031653001702055653001102072653001802083100002302101700002102124700002002145700001702165700002302182700001802205856003502223 2007 eng d a1524-462800aRisk factors for intracerebral hemorrhage in a pooled prospective study.0 aRisk factors for intracerebral hemorrhage in a pooled prospectiv c2007 Oct a2718-250 v383 aBACKGROUND AND PURPOSE: Few prospective studies have reported risk factors for intracerebral hemorrhage (ICH), and results are inconsistent. We studied risk factors for ICH in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS).
METHODS: The ARIC cohort was recruited in 1987 to 1989 and involves 15 792 men and women, aged 45 to 64 years at baseline, sampled from 4 US communities. The CHS cohort was recruited in 1989 to 1993 and involves 5888 men and women, aged 65 or over at baseline, sampled from 4 US communities. Baseline measurements included many potential vascular risk factors. The cohorts were followed for incident stroke events.
RESULTS: Over 263 489 person-years of follow-up, 135 incident ICH events occurred. In a multivariable model, age, African-American ethnicity (versus Whites), and hypertension were positively associated with incident ICH, whereas low-density lipoprotein cholesterol and triglycerides were inversely related to incident ICH. Participants with systolic blood pressure >or=160 mm Hg or diastolic blood pressure >/=110 mm Hg had 5.55 (95% CI 3.07 to 10.0) times the rate of ICH as nonhypertensives. Sex, smoking, alcohol intake, body mass index, waist-to-hip ratio, waist circumference, and diabetes were not related to ICH.
CONCLUSIONS: In this pooled cohort the risk factors for ICH were older age, African-American ethnicity, hypertension, lower LDL-C, and lower triglycerides.
10aAfrican Americans10aAge Distribution10aCerebral Hemorrhage10aCholesterol, LDL10aFemale10aFollow-Up Studies10aHumans10aHypertension10aIncidence10aMale10aMiddle Aged10aMultivariate Analysis10aPredictive Value of Tests10aPrevalence10aProspective Studies10aRisk Factors10aStroke10aTriglycerides1 aSturgeon, Jared, D1 aFolsom, Aaron, R1 aLongstreth, W T1 aShahar, Eyal1 aRosamond, Wayne, D1 aCushman, Mary uhttps://chs-nhlbi.org/node/97702653nas a2200469 4500008004100000022001400041245009400055210006900149260001300218300001200231490000700243520139700250653002101647653000901668653001501677653002301692653002401715653001901739653001601758653001101774653001501785653002201800653001101822653002001833653001901853653000901872653001601881653002601897653001501923653001701938653001101955653001801966653001501984653002601999100002302025700002102048700002002069700001702089700002302106700001802129856003602147 2008 eng d a1524-462800aHemostatic and inflammatory risk factors for intracerebral hemorrhage in a pooled cohort.0 aHemostatic and inflammatory risk factors for intracerebral hemor c2008 Aug a2268-730 v393 aBACKGROUND AND PURPOSE: The purpose of this study was to identify novel risk factors for intracerebral hemorrhagic stroke (ICH).
METHODS: Risk factors were assessed at baseline in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) involving 21,680 adults aged 45 or over. Over 263,489 person-years of follow-up, we identified 135 incident ICH events.
RESULTS: In multivariable models, for each SD higher baseline level of fibrinogen, the relative rate of incident ICH increased 35% (95% CI, 17% to 55%). Fibrinogen was more strongly related to ICH in ARIC than in CHS. In multivariable models, those with von Willebrand factor levels above the median were 1.72 (95% CI, 0.97 to 3.03) times more likely to have an incident ICH as those below the median. Factor VIII was significantly positively related to ICH in ARIC (relative rate per standard deviation of 1.31; 95% CI, 1.07 to 1.62), but not in CHS. There was no relation in multivariable models between lipoprotein (a), Factor VII, white blood cell count, or C-reactive protein and ICH.
CONCLUSIONS: Greater plasma fibrinogen and, to some degree, von Willebrand factor were associated with increased rates of ICH in these prospective studies, whereas Factor VIII was related to ICH in younger ARIC study participants only.
10aAge Distribution10aAged10aBiomarkers10aC-Reactive Protein10aCerebral Hemorrhage10aCohort Studies10aFactor VIII10aFemale10aFibrinogen10aFollow-Up Studies10aHumans10aLeukocyte Count10aLipoprotein(a)10aMale10aMiddle Aged10aMultivariate Analysis10aPrevalence10aRisk Factors10aStroke10aUnited States10aVasculitis10avon Willebrand Factor1 aSturgeon, Jared, D1 aFolsom, Aaron, R1 aLongstreth, W T1 aShahar, Eyal1 aRosamond, Wayne, D1 aCushman, Mary uhttps://chs-nhlbi.org/node/103602289nas 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/104004313nas 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/109204239nas 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/119704080nas a2200757 4500008004100000022001400041245019100055210006900246260001300315300001100328490000600339520181900345653002202164653000902186653002202195653001502217653001902232653004002251653001102291653003402302653001302336653001802349653001102367653001202378653000902390653003802399653002202437653001602459653003602475653001702511100002402528700002102552700002502573700002202598700002002620700001902640700002302659700001902682700002302701700002402724700001802748700002302766700002102789700002602810700002402836700001902860700001802879700002302897700003002920700002102950700002302971700001902994700001703013700002203030700001803052700002803070700002003098700002003118700002403138700002303162700002103185700003003206700002703236700002303263856003603286 2010 eng d a1942-326800aGenomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium.0 aGenomic variation associated with mortality among adults of Euro c2010 Jun a248-550 v33 aBACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF 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: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.
CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.
10aAfrican Americans10aAged10aAged, 80 and over10aChemokines10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart Failure10aHumans10aIntrons10aMale10aMARVEL Domain-Containing Proteins10aMembrane Proteins10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aMorrison, Alanna, C1 aFelix, Janine, F1 aCupples, Adrienne, L1 aGlazer, Nicole, L1 aLoehr, Laura, R1 aDehghan, Abbas1 aDemissie, Serkalem1 aBis, Joshua, C1 aRosamond, Wayne, D1 aAulchenko, Yurii, S1 aWang, Ying, A1 aHaritunians, Talin1 aFolsom, Aaron, R1 aRivadeneira, Fernando1 aBenjamin, Emelia, J1 aLumley, Thomas1 aCouper, David1 aStricker, Bruno, H1 aO'Donnell, Christopher, J1 aRice, Kenneth, M1 aChang, Patricia, P1 aHofman, Albert1 aLevy, Daniel1 aRotter, Jerome, I1 aFox, Ervin, R1 aUitterlinden, André, G1 aWang, Thomas, J1 aPsaty, Bruce, M1 aWillerson, James, T1 aDuijn, Cornelia, M1 aBoerwinkle, Eric1 aWitteman, Jacqueline, C M1 aVasan, Ramachandran, S1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/118702515nas 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/117504219nas 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/622006729nas a2201369 4500008004100000022001400041245006600055210006500121260001500186300001000201490000800211520297400219653001003193653000903203653001603212653002203228653001103250653001103261653002003272653000903292653001603301653001403317653002603331653001703357653001103374110004003385700003003425700002103455700001903476700001903495700002503514700002103539700002303560700001303583700002003596700002103616700002303637700001903660700002103679700002003700700002403720700002303744700002803767700002003795700001603815700002403831700002103855700002003876700002203896700002103918700002003939700002203959700003003981700001804011700002204029700002304051700002904074700002004103700002104123700001504144700002504159700002104184700002304205700002104228700002204249700002504271700001804296700001604314700002304330700002504353700001804378700002004396700001904416700001904435700001704454700001904471700002404490700002304514700002604537700002104563700002204584700001804606700002104624700001904645700002504664700002204689700002204711700002504733700001904758700002104777700002004798700001804818700002204836700002204858700002004880700002004900700002104920700001804941700002404959700001904983700002205002700001905024700002105043700001805064700002505082700002105107700002105128700001605149700003205165700002205197700002305219700002205242700001905264700002305283700001705306856003605323 2015 eng d a1538-359800aAssociation of Cardiometabolic Multimorbidity With Mortality.0 aAssociation of Cardiometabolic Multimorbidity With Mortality c2015 Jul 7 a52-600 v3143 aIMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing.
OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.
DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates.
EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).
MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy.
RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.
CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
10aAdult10aAged10aComorbidity10aDiabetes Mellitus10aFemale10aHumans10aLife Expectancy10aMale10aMiddle Aged10aMortality10aMyocardial Infarction10aRisk Factors10aStroke1 aEmerging Risk Factors Collaboration1 aDi Angelantonio, Emanuele1 aKaptoge, Stephen1 aWormser, David1 aWilleit, Peter1 aButterworth, Adam, S1 aBansal, Narinder1 aO'Keeffe, Linda, M1 aGao, Pei1 aWood, Angela, M1 aBurgess, Stephen1 aFreitag, Daniel, F1 aPennells, Lisa1 aPeters, Sanne, A1 aHart, Carole, L1 aHåheim, Lise, Lund1 aGillum, Richard, F1 aNordestgaard, Børge, G1 aPsaty, Bruce, M1 aYeap, Bu, B1 aKnuiman, Matthew, W1 aNietert, Paul, J1 aKauhanen, Jussi1 aSalonen, Jukka, T1 aKuller, Lewis, H1 aSimons, Leon, A1 aSchouw, Yvonne, T1 aBarrett-Connor, Elizabeth1 aSelmer, Randi1 aCrespo, Carlos, J1 aRodriguez, Beatriz1 aVerschuren, W, M Monique1 aSalomaa, Veikko1 aSvärdsudd, Kurt1 aHarst, Pim1 aBjörkelund, Cecilia1 aWilhelmsen, Lars1 aWallace, Robert, B1 aBrenner, Hermann1 aAmouyel, Philippe1 aBarr, Elizabeth, L M1 aIso, Hiroyasu1 aOnat, Altan1 aTrevisan, Maurizio1 aD'Agostino, Ralph, B1 aCooper, Cyrus1 aKavousi, Maryam1 aWelin, Lennart1 aRoussel, Ronan1 aHu, Frank, B1 aSato, Shinichi1 aDavidson, Karina, W1 aHoward, Barbara, V1 aLeening, Maarten, J G1 aLeening, Maarten1 aRosengren, Annika1 aDörr, Marcus1 aDeeg, Dorly, J H1 aKiechl, Stefan1 aStehouwer, Coen, D A1 aNissinen, Aulikki1 aGiampaoli, Simona1 aDonfrancesco, Chiara1 aKromhout, Daan1 aPrice, Jackie, F1 aPeters, Annette1 aMeade, Tom, W1 aCasiglia, Edoardo1 aLawlor, Debbie, A1 aGallacher, John1 aNagel, Dorothea1 aFranco, Oscar, H1 aAssmann, Gerd1 aDagenais, Gilles, R1 aJukema, Wouter1 aSundström, Johan1 aWoodward, Mark1 aBrunner, Eric, J1 aKhaw, Kay-Tee1 aWareham, Nicholas, J1 aWhitsel, Eric, A1 aNjølstad, Inger1 aHedblad, Bo1 aWassertheil-Smoller, Sylvia1 aEngström, Gunnar1 aRosamond, Wayne, D1 aSelvin, Elizabeth1 aSattar, Naveed1 aThompson, Simon, G1 aDanesh, John uhttps://chs-nhlbi.org/node/681107247nas a2202185 4500008004100000022001400041245013000055210006900185260001500254300000900269490000600278520110800284653002001392653003101412653003501443653002101478653003801499653003401537653001101571653001401582653002801596653003601624653002801660653001701688100002301705700002801728700002201756700001701778700001901795700002401814700002201838700002401860700002301884700001601907700002001923700001901943700002101962700001701983700003002000700001902030700001502049700001902064700003302083700002102116700002002137700002002157700002102177700002502198700002002223700002302243700001802266700001902284700001802303700001902321700002302340700001902363700002202382700001902404700002802423700001702451700002102468700002002489700001902509700002002528700002002548700001602568700002102584700002302605700002302628700002502651700002402676700002002700700002502720700002302745700002002768700001502788700001902803700002002822700001702842700002102859700002002880700002002900700002102920700002602941700001902967700002002986700001903006700002003025700002003045700001903065700002003084700001803104700001903122700002503141700002203166700001603188700002303204700002003227700002003247700002003267700001703287700001803304700002003322700001903342700003103361700001503392700002303407700002203430700002003452700001803472700002103490700002103511700002103532700001803553700001903571700001903590700001903609700002003628700002103648700002603669700001903695700002203714700002203736700002003758700001803778700001703796700001803813700002103831700002103852700001903873700002203892700002303914700002303937700002503960700002203985700001604007700001604023700002104039700002004060700002004080700001704100700002304117700001604140700002204156700002204178700002504200700001504225700001804240700002104258700002304279700001604302700001804318700002004336700001704356700001804373700001904391700002204410700002404432700002004456700002004476700002304496700002304519700002904542700002204571700002004593700002104613700002104634700002204655700002304677700002004700700001904720700002804739700002104767700002204788700002304810700002404833700001704857700002404874700002404898700002804922700001904950700003004969710002604999856003605025 2018 eng d a2041-172300aGWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.0 aGWAS and colocalization analyses implicate carotid intimamedia t c2018 12 03 a51410 v93 aCarotid 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.
10aADAMTS9 Protein10aAmino Acid Oxidoreductases10aCarotid Intima-Media Thickness10aCoronary Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLod Score10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors1 aFranceschini, Nora1 aGiambartolomei, Claudia1 ade Vries, Paul, S1 aFinan, Chris1 aBis, Joshua, C1 aHuntley, Rachael, P1 aLovering, Ruth, C1 aTajuddin, Salman, M1 aWinkler, Thomas, W1 aGraff, Misa1 aKavousi, Maryam1 aDale, Caroline1 aSmith, Albert, V1 aHofer, Edith1 avan Leeuwen, Elisabeth, M1 aNolte, Ilja, M1 aLu, Lingyi1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aPitkänen, Niina1 aFranzén, Oscar1 aJoshi, Peter, K1 aNoordam, Raymond1 aMarioni, Riccardo, E1 aHwang, Shih-Jen1 aMusani, Solomon, K1 aSchminke, Ulf1 aPalmas, Walter1 aIsaacs, Aaron1 aCorrea, Adolfo1 aZonderman, Alan, B1 aHofman, Albert1 aTeumer, Alexander1 aCox, Amanda, J1 aUitterlinden, André, G1 aWong, Andrew1 aSmit, Andries, J1 aNewman, Anne, B1 aBritton, Annie1 aRuusalepp, Arno1 aSennblad, Bengt1 aHedblad, Bo1 aPasaniuc, Bogdan1 aPenninx, Brenda, W1 aLangefeld, Carl, D1 aWassel, Christina, L1 aTzourio, Christophe1 aFava, Cristiano1 aBaldassarre, Damiano1 aO'Leary, Daniel, H1 aTeupser, Daniel1 aKuh, Diana1 aTremoli, Elena1 aMannarino, Elmo1 aGrossi, Enzo1 aBoerwinkle, Eric1 aSchadt, Eric, E1 aIngelsson, Erik1 aVeglia, Fabrizio1 aRivadeneira, Fernando1 aBeutner, Frank1 aChauhan, Ganesh1 aHeiss, Gerardo1 aSnieder, Harold1 aCampbell, Harry1 aVölzke, Henry1 aMarkus, Hugh, S1 aDeary, Ian, J1 aJukema, Wouter1 ade Graaf, Jacqueline1 aPrice, Jacqueline1 aPott, Janne1 aHopewell, Jemma, C1 aLiang, Jingjing1 aThiery, Joachim1 aEngmann, Jorgen1 aGertow, Karl1 aRice, Kenneth1 aTaylor, Kent, D1 aDhana, Klodian1 aKiemeney, Lambertus, A L M1 aLind, Lars1 aRaffield, Laura, M1 aLauner, Lenore, J1 aHoldt, Lesca, M1 aDörr, Marcus1 aDichgans, Martin1 aTraylor, Matthew1 aSitzer, Matthias1 aKumari, Meena1 aKivimaki, Mika1 aNalls, Mike, A1 aMelander, Olle1 aRaitakari, Olli1 aFranco, Oscar, H1 aRueda-Ochoa, Oscar, L1 aRoussos, Panos1 aWhincup, Peter, H1 aAmouyel, Philippe1 aGiral, Philippe1 aAnugu, Pramod1 aWong, Quenna1 aMalik, Rainer1 aRauramaa, Rainer1 aBurkhardt, Ralph1 aHardy, Rebecca1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aMorris, Richard, W1 aStrawbridge, Rona, J1 aWannamethee, Goya1 aHägg, Sara1 aShah, Sonia1 aMcLachlan, Stela1 aTrompet, Stella1 aSeshadri, Sudha1 aKurl, Sudhir1 aHeckbert, Susan, R1 aRing, Susan1 aHarris, Tamara, B1 aLehtimäki, Terho1 aGalesloot, Tessel, E1 aShah, Tina1 ade Faire, Ulf1 aPlagnol, Vincent1 aRosamond, Wayne, D1 aPost, Wendy1 aZhu, Xiaofeng1 aZhang, Xiaoling1 aGuo, Xiuqing1 aSaba, Yasaman1 aDehghan, Abbas1 aSeldenrijk, Adrie1 aMorrison, Alanna, C1 aHamsten, Anders1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLawlor, Deborah, A1 aMook-Kanamori, Dennis, O1 aBowden, Donald, W1 aSchmidt, Helena1 aWilson, James, F1 aWilson, James, G1 aRotter, Jerome, I1 aWardlaw, Joanna, M1 aDeanfield, John1 aHalcox, Julian1 aLyytikäinen, Leo-Pekka1 aLoeffler, Markus1 aEvans, Michele, K1 aDebette, Stephanie1 aHumphries, Steve, E1 aVölker, Uwe1 aGudnason, Vilmundur1 aHingorani, Aroon, D1 aBjörkegren, Johan, L M1 aCasas, Juan, P1 aO'Donnell, Christopher, J1 aMEGASTROKE Consortium uhttps://chs-nhlbi.org/node/7913