03165nas a2200409 4500008004100000022001400041245018100055210006900236260001300305300001200318490000700330520198400337653000902321653002202330653001902352653002802371653002102399653001902420653001502439653001602454653001502470653001102485653002602496653002402522653002402546653001702570100001502587700001702602700001302619700001502632700001502647700001302662700001102675700001602686700001702702856003602719 1995 eng d a1079-564200aFibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly. Results from The Cardiovascular Health Study.0 aFibrinogen and factor VIII but not factor VII are associated wit c1995 Sep a1269-790 v153 a
No studies have examined the associations of coagulation factor levels with measures of subclinical cardiovascular disease (CVD) in the elderly. The Cardiovascular Health Study (CHS) is a prospective, population-based cohort study of CVD in persons older than 65 years. At the baseline examination, we measured fibrinogen, factor VII, and factor VIII levels in 5024 of the 5201 participants of the CHS and examined the associations of these coagulation factors with measures of subclinical CVD in a cross-sectional analysis. Subclinical CVD measures were based on electrocardiography, carotid ultrasonography, echocardiography, and ankle-arm blood pressure measurements (AAI). For analyses, we used the full cohort as well as two mutually exclusive subgroups: those with prevalent clinical CVD at baseline and those without. Fibrinogen and to a lesser extent factor VIII showed positive associations with a variety of subclinical CVD measures. In age-adjusted analyses, fibrinogen and factor VIII were significantly associated with 8 of 10 measures. In multivariate analyses, fibrinogen was significantly associated with carotid artery stenosis, internal (but not common) carotid artery wall thickness, and AAI. Factor VIII was associated with abnormal wall motion and AAI in the full cohort only. Factor VII was not consistently associated with subclinical disease measures. In bivariate analyses that included data from all three groups, there were 5 positive subclinical disease associations and 5 negative associations for factor VII. In multivariate analyses, there were no significant associations between factor VII and subclinical CVD in the full cohort or in either subgroup. We conclude that in these cross-sectional analyses, fibrinogen and to a lesser extent factor VIII are associated with subclinical CVD in the elderly, even in those without symptoms or a history of clinical CVD. Factor VII, however, was not associated with subclinical CVD in the elderly.
10aAged10aAged, 80 and over10aBlood Pressure10aCardiovascular Diseases10aCarotid Stenosis10aCohort Studies10aFactor VII10aFactor VIII10aFibrinogen10aHumans10aMultivariate Analysis10aProspective Studies10aRegression Analysis10aRisk Factors1 aTracy, R P1 aBovill, E, G1 aYanez, D1 aPsaty, B M1 aFried, L P1 aHeiss, G1 aLee, M1 aPolak, J, F1 aSavage, P, J uhttps://chs-nhlbi.org/node/141601777nas a2200361 4500008004100000022001400041245013300055210006900188260001300257300001000270490000700280520082700287653001001114653001601124653000901140653001301149653001301162653001101175653001101186653000901197653001601206653001301222653001701235653001501252100001501267700002001282700001501302700001501317700001601332700001601348700001501364856003601379 1998 eng d a0340-624500aFactor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study.0 aFactor V Leiden is not a risk factor for arterial vascular disea c1998 May a912-50 v793 aCoagulation factor V Leiden is a risk marker for venous thrombosis. For arterial thrombosis no large study to date has included population-based elderly patients. The Cardiovascular Health Study is a longitudinal study of 5,201 men and women over age 65. With 3.4-year follow-up, we studied 373 incident cases of myocardial infarction (MI), angina, stroke. or transient ischemic attack (TIA), and 482 controls. The odds ratios for each event with heterozygous factor V Leiden were: MI, 0.46 (95% CI 0.17 to 1.25); angina, 1.0 (95% CI 0.45 to 2.23); stroke, 0.77 (95% CI 0.35 to 1.70): TIA, 1.33 (95% CI 0.5 to 3.55); any outcome, 0.83 (95% CI 0.48 to 1.44). Adjustment for cardiovascular risk factors did not change relationships. In older adults factor V Leiden is not a risk factor for future arterial thrombosis.
10aAdult10aAge Factors10aAged10aArteries10aFactor V10aFemale10aHumans10aMale10aMiddle Aged10aMutation10aRisk Factors10aThrombosis1 aCushman, M1 aRosendaal, F, R1 aPsaty, B M1 aCook, E, F1 aValliere, J1 aKuller, L H1 aTracy, R P uhttps://chs-nhlbi.org/node/150801825nas a2200217 4500008004100000022001400041245010300055210006900158260001300227300001000240490000600250520119600256100002001452700001401472700001701486700001901503700001701522700001901539700001401558856003501572 1998 eng d a1751-715X00aFactors Associated With Hospital Utilization in the Elderly: From the Cardiovascular Health Study.0 aFactors Associated With Hospital Utilization in the Elderly From c1998 May a27-350 v73 aOBJECTIVE: Analyze clinical, accepted biochemical, physiologic, and socioeconomic risk factors and correlate them with hospital utilization in an elderly population. DESIGN: Prospective, observational study in a defined, randomly recruited population. PARTICIPANTS: 5201 Medicare participants enrolled in the Cardiovascular Health Study (CHS). METHODS: Medicare recipients were randomly assigned to participate in an observational study. Baseline data were compared to hospital admissions and days of hospitalization over four years. DATA ANALYSIS: Data were grouped by type of risk factor and analyzed by Tobit analysis and logistic regression. RESULTS: Baseline variables associated with hospital use (p is less than 0.0001) were history of CHF, stroke, angina, hypertension, ln (timed walk), ln (blocks walked/week), age, gender, and clinic site. Factors not entering the model (p is greater than 0.05) were income, education, smoking, diabetes, weight, dietary fat, marital status, depression, and measures of mental function. CONCLUSIONS: In the elderly, existing health status is the major determinant of hospitalization and overwhelms many classic "risk factors" for morbidity.
1 aRobbins, J., A.1 aYanez, D.1 aPowe, N., R.1 aSavage, P., J.1 aIves, D., G.1 aGardin, J., M.1 aLyles, M. uhttps://chs-nhlbi.org/node/65002817nas a2200397 4500008004100000022001400041245011500055210006900170260001300239300001000252490000700262520171300269653001601982653000901998653002002007653001502027653001102042653004302053653001702096653001702113653002202130653001702152653001102169653000902180653002602189653003802215653001702253100001502270700001902285700001602304700001502320700001502335700001902350700001502369856003502384 1999 eng d a1079-564200aFibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study.0 aFibrinolytic activation markers predict myocardial infarction in c1999 Mar a493-80 v193 aCoagulation factor levels predict arterial thrombosis in epidemiological studies, but studies of older persons are needed. We studied 3 plasma antigenic markers of fibrinolysis, viz, plasminogen activator inhibitor-1 (PAI-1), fibrin fragment D-dimer, and plasmin-antiplasmin complex (PAP) for the prediction of arterial thrombosis in healthy elderly persons over age 65. The study was a nested case-control study in the Cardiovascular Health Study cohort of 5201 men and women >/=65 years of age who were enrolled from 1989 to 1990. Cases were 146 participants without baseline clinical vascular disease who developed myocardial infarction, angina, or coronary death during a follow-up of 2.4 years. Controls remained free of cardiovascular events and were matched 1:1 to cases with respect to sex, duration of follow-up, and baseline subclinical vascular disease status. With increasing quartile of D-dimer and PAP levels but not of PAI-1, there was an independent increased risk of myocardial infarction or coronary death, but not of angina. The relative risk for D-dimer above versus below the median value (>/=120 microg/L) was 2.5 (95% confidence interval, 1.1 to 5.9) and for PAP above the median (>/=5.25 nmol/L), 3.1 (1.3 to 7.7). Risks were independent of C-reactive protein and fibrinogen concentrations. There were no differences in risk by sex or presence of baseline subclinical disease. D-dimer and PAP, but not PAI-1, predicted future myocardial infarction in men and women over age 65. Relationships were independent of other risk factors, including inflammation markers. Results indicate a major role for these markers in identifying a high risk of arterial disease in this age group.
10aAge Factors10aAged10aAngina Pectoris10aBiomarkers10aFemale10aFibrin Fibrinogen Degradation Products10aFibrinolysin10aFibrinolysis10aFollow-Up Studies10aHeart Arrest10aHumans10aMale10aMyocardial Infarction10aPlasminogen Activator Inhibitor 110aRisk Factors1 aCushman, M1 aLemaitre, R, N1 aKuller, L H1 aPsaty, B M1 aMacy, E, M1 aSharrett, A, R1 aTracy, R P uhttps://chs-nhlbi.org/node/58403278nas a2200517 4500008004100000022001400041245007600055210006900131260001300200300001100213490000700224520194300231653000902174653002202183653001002205653002802215653001902243653000902262653001302271653001102284653001802295653001102313653001402324653001502338653002502353653003102378653000902409653001402418653001602432653002102448653001702469653002102486653002602507653001802533653001802551100001602569700001702585700001502602700001502617700001502632700001402647700001202661700001502673710003702688856003502725 2001 eng d a0002-861400aFactors associated with healthy aging: the cardiovascular health study.0 aFactors associated with healthy aging the cardiovascular health c2001 Mar a254-620 v493 aOBJECTIVES: To identify factors associated with remaining healthy in older adults.
DESIGN: Longitudinal cohort study.
SETTING: Data were collected at the four Cardiovascular Health Study field centers.
PARTICIPANTS: 5,888 participants age 65 years and older in the Cardiovascular Health Study.
MEASUREMENTS: Presence of chronic disease was assessed at baseline and over a maximum 7-year follow-up period. Participants who were free of chronic disease (no cardiovascular disease (CVD), chronic obstructive pulmonary disease, or self-reported cancer, except nonmelanoma skin cancer) at the baseline examination were then monitored for the onset of incident cancer, cardiovascular disease, and fatal outcomes.
RESULTS: A high proportion of these older adults was healthy at the initial examination and remained healthy over the follow-up period. Numerous behavioral factors were associated with continued health, including physical activity, refraining from cigarette smoking, wine consumption (women), higher educational status, and lower waist circumference. A number of CVD risk factors and subclinical disease measures were associated with continued health, including higher high-density lipoprotein (HDL) cholesterol, lack of diabetes, thinner common carotid intimal nmedial thickness, lower blood pressure, lower C-reactive protein, and higher ankle-arm blood pressure ratio. Among the behavioral factors, exercise, not smoking, and not taking aspirin remained significant predictors of health even after controlling for CVD risk factors and subclinical disease in older adults.
CONCLUSIONS: These data suggest that a number of modifiable behavioral factors (physical activity, smoking, and obesity) and cardiovascular risk factors (diabetes, HDL cholesterol, and blood pressure) are associated with maintenance of good health in older adults.
10aAged10aAged, 80 and over10aAging10aCardiovascular Diseases10aCohort Studies10aDiet10aExercise10aFemale10aHealth Status10aHumans10aIncidence10aLife Style10aLongitudinal Studies10aLung Diseases, Obstructive10aMale10aNeoplasms10aProbability10aReference Values10aRisk Factors10aSex Distribution10aSocioeconomic Factors10aSurvival Rate10aUnited States1 aBurke, G, L1 aArnold, A, M1 aBild, D, E1 aCushman, M1 aFried, L P1 aNewman, A1 aNunn, C1 aRobbins, J1 aCHS Collaborative Research Group uhttps://chs-nhlbi.org/node/64604256nas a2200469 4500008004100000022001400041245005500055210005300110260001300163300001200176490000700188520307600195653000903271653002203280653001903302653002103321653001203342653001103354653001803365653001103383653001403394653000903408653002003417653001403437653001503451653002103466653001803487653001603505100001503521700001703536700001503553700001703568700001403585700001803599700001403617700001303631700001403644700001303658700001903671710006103690856003503751 2001 eng d a1079-500600aFrailty in older adults: evidence for a phenotype.0 aFrailty in older adults evidence for a phenotype c2001 Mar aM146-560 v563 aBACKGROUND: Frailty is considered highly prevalent in old age and to confer high risk for falls, disability, hospitalization, and mortality. Frailty has been considered synonymous with disability, comorbidity, and other characteristics, but it is recognized that it may have a biologic basis and be a distinct clinical syndrome. A standardized definition has not yet been established.
METHODS: To develop and operationalize a phenotype of frailty in older adults and assess concurrent and predictive validity, the study used data from the Cardiovascular Health Study. Participants were 5,317 men and women 65 years and older (4,735 from an original cohort recruited in 1989-90 and 582 from an African American cohort recruited in 1992-93). Both cohorts received almost identical baseline evaluations and 7 and 4 years of follow-up, respectively, with annual examinations and surveillance for outcomes including incident disease, hospitalization, falls, disability, and mortality.
RESULTS: Frailty was defined as a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 lbs in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. The overall prevalence of frailty in this community-dwelling population was 6.9%; it increased with age and was greater in women than men. Four-year incidence was 7.2%. Frailty was associated with being African American, having lower education and income, poorer health, and having higher rates of comorbid chronic diseases and disability. There was overlap, but not concordance, in the cooccurrence of frailty, comorbidity, and disability. This frailty phenotype was independently predictive (over 3 years) of incident falls, worsening mobility or ADL disability, hospitalization, and death, with hazard ratios ranging from 1.82 to 4.46, unadjusted, and 1.29-2.24, adjusted for a number of health, disease, and social characteristics predictive of 5-year mortality. Intermediate frailty status, as indicated by the presence of one or two criteria, showed intermediate risk of these outcomes as well as increased risk of becoming frail over 3-4 years of follow-up (odds ratios for incident frailty = 4.51 unadjusted and 2.63 adjusted for covariates, compared to those with no frailty criteria at baseline).
CONCLUSIONS: This study provides a potential standardized definition for frailty in community-dwelling older adults and offers concurrent and predictive validity for the definition. It also finds that there is an intermediate stage identifying those at high risk of frailty. Finally, it provides evidence that frailty is not synonymous with either comorbidity or disability, but comorbidity is an etiologic risk factor for, and disability is an outcome of, frailty. This provides a potential basis for clinical assessment for those who are frail or at risk, and for future research to develop interventions for frailty based on a standardized ascertainment of frailty.
10aAged10aAged, 80 and over10aCohort Studies10aDisabled Persons10aFatigue10aFemale10aFrail Elderly10aHumans10aIncidence10aMale10aMuscle Weakness10aPhenotype10aPrevalence10aSex Distribution10aUnited States10aWeight Loss1 aFried, L P1 aTangen, C, M1 aWalston, J1 aNewman, A, B1 aHirsch, C1 aGottdiener, J1 aSeeman, T1 aTracy, R1 aKop, W, J1 aBurke, G1 aMcBurnie, M, A1 aCardiovascular Health Study Collaborative Research Group uhttps://chs-nhlbi.org/node/63902445nas a2200349 4500008004100000022001400041245010300055210006900158260001600227300001100243490000700254520148900261653000901750653002201759653002901781653001101810653001101821653002501832653000901857653003001866653001101896653002201907653001801929100002001947700001501967700001901982700001502001700001502016700001202031700001702043856003502060 2001 eng d a0028-387800aFrequency and predictors of stroke death in 5,888 participants in the Cardiovascular Health Study.0 aFrequency and predictors of stroke death in 5888 participants in c2001 Feb 13 a368-750 v563 aBACKGROUND: Few population-based studies have examined in detail issues of stroke-related deaths in elderly people.
METHODS: Participants in the Cardiovascular Health Study (CHS) are 65 years of age or older, have had extensive baseline evaluations, and have been followed-up for fatal and nonfatal cardiovascular and cerebrovascular disease outcomes. Investigators adjudicated these outcomes and classified strokes by types and subtypes.
RESULTS: Over 7 years, 1,310 (22.2%) of 5,888 participants died, and 455 (7.7%) experienced incident stroke. For the 5,888, stroke mortality was 3.2 per 1,000 person-years. For the 455, it was 36.1 per 1,000 person-years, with the most lethal type being hemorrhagic and the ischemic subtype being cardioembolic. After controlling for age and stroke type, the only other independent predictor of death after any stroke was poor performance on a timed walk measured before the incident stroke. Considering only ischemic stroke, the independent predictors of death were African American race and poor performance on timed walk.
CONCLUSION: In CHS, death attributable to stroke is common. As in other studies, the most lethal stroke type was hemorrhagic, and ischemic stroke subtype, cardioembolic. Slow walking, possibly a measure of frailty, was associated with an increased risk of death of stroke. Finally, African Americans faced a greater risk of death than others after an ischemic stroke.
10aAged10aAged, 80 and over10aClinical Trials as Topic10aFemale10aHumans10aLongitudinal Studies10aMale10aPredictive Value of Tests10aStroke10aSurvival Analysis10aUnited States1 aLongstreth, W T1 aBernick, C1 aFitzpatrick, A1 aCushman, M1 aKnepper, L1 aLima, J1 aFurberg, C D uhttps://chs-nhlbi.org/node/62903016nas 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/67503092nas a2200409 4500008004100000022001400041245015800055210006900213260001600282300001200298490000800310520185700318653000902175653002202184653003202206653002802238653001902266653002702285653002202312653001102334653001802345653002502363653001102388653001702399653002502416653000902441100002002450700002402470700001702494700002202511700001902533700002202552700002102574700002002595710003202615856003502647 2002 eng d a0003-992600aFrailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.0 aFrailty and activation of the inflammation and coagulation syste c2002 Nov 11 a2333-410 v1623 aBACKGROUND: The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity, and its frequent coexistence with illness.
OBJECTIVE: To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus.
METHODS: Participants were 4735 community-dwelling adults 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures.
RESULTS: Of 4735 Cardiovascular Health Study participants, 299 (6.3%) were identified as frail, 2147 (45.3%) as intermediate, and 2289 (48.3%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13 790 +/- 4480 vs 11 860 +/- 3460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1033 vs 224 +/- 258 ng/mL) (P< or =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex, and race.
CONCLUSIONS: These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.
10aAged10aAged, 80 and over10aBlood Coagulation Disorders10aCardiovascular Diseases10aCohort Studies10aDiabetes Complications10aDiabetes Mellitus10aFemale10aFrail Elderly10aGeriatric Assessment10aHumans10aInflammation10aLongitudinal Studies10aMale1 aWalston, Jeremy1 aMcBurnie, Mary, Ann1 aNewman, Anne1 aTracy, Russell, P1 aKop, Willem, J1 aHirsch, Calvin, H1 aGottdiener, John1 aFried, Linda, P1 aCardiovascular Health Study uhttps://chs-nhlbi.org/node/70902781nas 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/70602931nas a2200469 4500008004100000022001400041245005800055210005700113260001600170300001100186490000800197520172200205653000901927653001201936653002401948653002301972653001901995653001202014653000902026653001702035653002502052653001402077653001102091653002202102653001102124653001402135653001802149653003202167653002402199653000902223653001202232653000902244100002502253700002002278700001802298700002402316700002202340700001902362700002102381700002402402856003502426 2004 eng d a1524-453900aFish intake and risk of incident atrial fibrillation.0 aFish intake and risk of incident atrial fibrillation c2004 Jul 27 a368-730 v1103 aBACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is particularly common in the elderly. Although effects of fish intake, including potential antiarrhythmic effects, may favorably influence risk of AF, relationships between fish intake and AF incidence have not been evaluated.
METHODS AND RESULTS: In a prospective, population-based cohort of 4815 adults > or =age 65 years, usual dietary intake was assessed at baseline in 1989 and 1990. Consumption of tuna and other broiled or baked fish correlated with plasma phospholipid long-chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches (fish burgers) did not. AF incidence was prospectively ascertained on the basis of hospital discharge records and annual electrocardiograms. During 12 years' follow-up, 980 cases of incident AF were diagnosed. In multivariate analyses, consumption of tuna or other broiled or baked fish was inversely associated with incidence of AF, with 28% lower risk with intake 1 to 4 times per week (HR=0.72, 95% CI=0.58 to 0.91, P=0.005), and 31% lower risk with intake > or =5 times per week (HR=0.69, 95% CI=0.52 to 0.91, P=0.008), compared with <1 time per month (P trend=0.004). Results were not materially different after adjustment for preceding myocardial infarction or congestive heart failure. In similar analyses, fried fish/fish sandwich consumption was not associated with lower risk of AF.
CONCLUSIONS: Among elderly adults, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches, is associated with lower incidence of AF. Fish intake may influence risk of this common cardiac arrhythmia.
10aAged10aAnimals10aAtrial Fibrillation10aCardiotonic Agents10aCohort Studies10aCooking10aDiet10aDietary Fats10aFatty Acids, Omega-310aFish Oils10aFishes10aFollow-Up Studies10aHumans10aIncidence10aMassachusetts10aProportional Hazards Models10aProspective Studies10aRisk10aSeafood10aTuna1 aMozaffarian, Dariush1 aPsaty, Bruce, M1 aRimm, Eric, B1 aLemaitre, Rozenn, N1 aBurke, Gregory, L1 aLyles, Mary, F1 aLefkowitz, David1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/79702819nas a2200409 4500008004100000022001400041245014000055210006900195260001300264300001100277490000800288520165500296653000901951653002801960653001901988653001502007653001102022653001802033653001102051653001402062653002002076653000902096653001502105653001502120653001702135653001602152653004702168653003102215100002002246700001602266700001602282700002102298700002102319700001702340700001702357856003502374 2005 eng d a0002-962900aFactors associated with incidence and persistence of symptoms of disturbed sleep in an elderly cohort: the Cardiovascular Health Study.0 aFactors associated with incidence and persistence of symptoms of c2005 Apr a163-720 v3293 aBACKGROUND: There are limited data pertaining to the factors influencing the incidence and persistence of sleep symptoms in the elderly. The purpose of this study was to determine the incidence and nonremission rates of the following sleep symptoms: trouble falling asleep (TFA), frequent awakenings (FA), and excessive daytime sleepiness (EDS) in the Cardiovascular Health Study (CHS), a prospective multicenter study of cardiovascular disease in a large cohort of elderly adults. Factors influencing these rates were assessed as well.
METHODS: 4467 participants in CHS were surveyed for the presence of TFA, FA, and EDS as well as other health problems at their baseline examination and at a follow-up examination 1 to 4 years later.
RESULTS: Annualized incidence and nonremission rates were the following: TFA (2.8% and 15.4%), FA (12.3% and 22.7%), and EDS (4.4% and 13.4%). Women were more likely to have incident and persistent TFA. Depression was the primary factor predicting the incidence of all three sleep symptoms. However, other health conditions, including respiratory symptoms and cardiovascular disease, and limitation in activities of daily living were important as well. Depression also was the most important factor associated with persistence of these sleep symptoms. The role of other health conditions in determining nonremission was much more limited.
CONCLUSIONS: Incidence of sleep disturbances in the elderly is related to depression, health conditions, and physical functioning. However, persistence of sleep disturbances is best predicted by the presence of depression.
10aAged10aCardiovascular Diseases10aCohort Studies10aDepression10aFemale10aHealth Status10aHumans10aIncidence10aLogistic Models10aMale10aOdds Ratio10aPrevalence10aRisk Factors10aSex Factors10aSleep Initiation and Maintenance Disorders10aSurveys and Questionnaires1 aQuan, Stuart, F1 aKatz, Ronit1 aOlson, Jean1 aBonekat, William1 aEnright, Paul, L1 aYoung, Terry1 aNewman, Anne uhttps://chs-nhlbi.org/node/83303506nas a2200517 4500008004100000022001400041245009400055210006900149260001600218300001000234490000800244520209500252653002102347653000902368653002202377653001202399653001902411653002502430653000902455653002502464653001102489653001402500653001102514653001102525653001402536653000902550653002602559653001602585653003202601653002002633653001202653653003202665653002102697653001102718653003102729653001802760653001802778100002502796700002002821700002402841700002102865700002102886700002202907700002402929856003502953 2005 eng d a0003-992600aFish consumption and stroke risk in elderly individuals: the cardiovascular health study.0 aFish consumption and stroke risk in elderly individuals the card c2005 Jan 24 a200-60 v1653 aBACKGROUND: Associations between fish consumption and stroke risk have been inconsistent, possibly because of the differences in types of fish meals consumed. Additionally, such relationships have not been specifically evaluated in the elderly, in whom disease burden may be high and diet less influential.
METHODS: Among 4775 adults 65 years or older (range, 65-98 years) and free of known cerebrovascular disease at baseline in 1989-1990, usual dietary intake was assessed using a food frequency questionnaire. In a subset, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches (fish burgers), correlated with plasma phospholipid long-chain n-3 fatty acid levels. Incident strokes were prospectively ascertained.
RESULTS: During 12 years of follow-up, participants experienced 626 incident strokes, including 529 ischemic strokes. In multivariate analyses, tuna/other fish consumption was inversely associated with total stroke (P = .04) and ischemic stroke (P = .02), with 27% lower risk of ischemic stroke with an intake of 1 to 4 times per week (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.55-0.98) and 30% lower risk with intake of 5 or more times per week (HR, 0.70; 95% CI, 0.50-0.99) compared with an intake of less than once per month. In contrast, fried fish/fish sandwich consumption was positively associated with total stroke (P = .006) and ischemic stroke (P = .003), with a 44% higher risk of ischemic stroke with consumption of more than once per week (HR, 1.44; 95% CI, 1.12-1.85) compared with consumption of less than once per month. Fish consumption was not associated with hemorrhagic stroke.
CONCLUSIONS: Among elderly individuals, consumption of tuna or other broiled or baked fish is associated with lower risk of ischemic stroke, while intake of fried fish or fish sandwiches is associated with higher risk. These results suggest that fish consumption may influence stroke risk late in life; potential mechanisms and alternate explanations warrant further study.
10aAge Distribution10aAged10aAged, 80 and over10aAnimals10aCohort Studies10aConfidence Intervals10aDiet10aFatty Acids, Omega-310aFemale10aFish Oils10aFishes10aHumans10aIncidence10aMale10aMultivariate Analysis10aProbability10aProportional Hazards Models10aRisk Assessment10aSeafood10aSensitivity and Specificity10aSex Distribution10aStroke10aSurveys and Questionnaires10aSurvival Rate10aUnited States1 aMozaffarian, Dariush1 aLongstreth, W T1 aLemaitre, Rozenn, N1 aManolio, Teri, A1 aKuller, Lewis, H1 aBurke, Gregory, L1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/81802802nas a2200373 4500008004100000022001400041245005200055210005100107260001600158300001200174490000700186520187100193653000902064653001202073653001902085653001202104653000902116653001702125653002602142653001102168653001102179653001802190653001102208653001402219653000902233653001702242653001802259100002502277700002102302700002402323700002202347700002402369856003502393 2005 eng d a0735-109700aFish intake and risk of incident heart failure.0 aFish intake and risk of incident heart failure c2005 Jun 21 a2015-210 v453 aOBJECTIVES: Our aim was to investigate the relation between fish consumption and incidence of congestive heart failure (CHF).
BACKGROUND: The incidence and health burden of CHF are rising, particularly in older persons. Although n-3 fatty acids have effects that could favorably influence risk of CHF, the relation between fish intake and CHF incidence is unknown.
METHODS: Among 4,738 adults age > or =65 years and free of CHF at baseline in 1989-90, usual dietary intake was assessed using a food frequency questionnaire. In a participant subsample, consumption of tuna or other broiled or baked fish, but not fried fish, correlated with plasma phospholipid n-3 fatty acids. Incidence of CHF was prospectively adjudicated.
RESULTS: During 12 years' follow-up, 955 participants developed CHF. In multivariate-adjusted analyses, tuna/other fish consumption was inversely associated with incident CHF, with 20% lower risk with intake 1 to 2 times/week (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.64 to 0.99), 31% lower risk with intake 3 to 4 times/week (HR = 0.69, 95% CI = 0.52 to 0.91), and 32% lower risk with intake > or =5 times/week (HR = 0.68, 95% CI = 0.45 to 1.03), compared with intake <1 time/month (p trend = 0.009). In similar analyses, fried fish consumption was positively associated with incident CHF (p trend = 0.01). Dietary long-chain n-3 fatty acid intake was also inversely associated with CHF (p trend = 0.009), with 37% lower risk in the highest quintile of intake (HR = 0.73, 95% CI = 0.57 to 0.94) compared with the lowest.
CONCLUSIONS: Among older adults, consumption of tuna or other broiled or baked fish, but not fried fish, is associated with lower incidence of CHF. Confirmation in additional studies and evaluation of potential mechanisms is warranted.
10aAged10aAnimals10aCohort Studies10aCooking10aDiet10aDiet Surveys10aDisease-Free Survival10aFemale10aFishes10aHeart Failure10aHumans10aIncidence10aMale10aRisk Factors10aUnited States1 aMozaffarian, Dariush1 aBryson, Chris, L1 aLemaitre, Rozenn, N1 aBurke, Gregory, L1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/84302929nas a2200409 4500008004100000022001400041245011800055210006900173260001300242300001100255490000700266520181100273653000902084653001002093653001502103653001102118653001102129653001402140653003102154653000902185653001302194653001902207653001702226653003202243653002002275653001702295653001102312100001902323700002102342700002002363700001702383700002302400700002202423700001802445700002102463856003502484 2006 eng d a1524-462800aFactors associated with geographic variations in stroke incidence among older populations in four US communities.0 aFactors associated with geographic variations in stroke incidenc c2006 Aug a1980-50 v373 aBACKGROUND AND PURPOSE: In the Cardiovascular Health Study (CHS), we previously observed lower stroke incidence in Allegheny County, PA compared with the other 3 study sites. The purpose of this study was to study possible reasons for the lower stroke incidence in Allegheny County.
METHODS: CHS participants 65 years or older who were stroke-free at baseline (n=5639) were followed between 1989 to 1990 and 2000 for the development of stroke. Risk factors at baseline and their subsequent control were compared among both groups. Site-specific hazard ratios for stroke incidence were calculated using Cox regression models.
RESULTS: The unadjusted hazard ratio for total stroke incidence in Forsyth County, NC; Sacramento County, CA; and Washington County, MD combined compared with Allegheny County, PA was 1.74 (95% CI: 1.42, 2.14). After adjustment for age and other traditional risk factors, there was modest reduction of the excess hazard in non-Allegheny sites compared with Allegheny County (hazard ratio=1.52, 95% CI: 1.17, 1.98). Between baseline and the seventh-year visits, control of hypertension, diabetes, lipids, smoking, atrial fibrillation and transient ischemic attack were similar across sites. White matter grade > or = 3 on the baseline brain MRI was less common in Allegheny County (25.8% versus 36.3%, respectively; P<0.001) and accounted for 25% of the excess hazard in non-Allegheny sites compared with Allegheny County.
CONCLUSIONS: Site differences in stroke risk factors at baseline and subsequent control only partially explain site differences in stroke incidence. White matter grade as a possible integrated measure of exposure and control of risk factors may help in explaining geographic variations in stroke incidence.
10aAged10aBrain10aCalifornia10aFemale10aHumans10aIncidence10aMagnetic Resonance Imaging10aMale10aMaryland10aNorth Carolina10aPennsylvania10aProportional Hazards Models10aRisk Assessment10aRisk Factors10aStroke1 aEl-Saed, Aiman1 aKuller, Lewis, H1 aNewman, Anne, B1 aLopez, Oscar1 aCostantino, Joseph1 aMcTigue, Kathleen1 aCushman, Mary1 aKronmal, Richard uhttps://chs-nhlbi.org/node/90002449nas a2200361 4500008004100000022001400041245011700055210006900172260001300241300001100254490000600265520147100271653001201742653001301754653001501767653001501782653001101797653001301808653001101821653000901832653002601841653002401867653001701891653002001908653002201928100001701950700001501967700001801982700001302000700002402013700001502037856003502052 2007 eng d a1538-793300aFactor VII coagulant activity, factor VII -670A/C and -402G/A polymorphisms, and risk of venous thromboembolism.0 aFactor VII coagulant activity factor VII 670AC and 402GA polymor c2007 Aug a1674-80 v53 aBACKGROUND: Most epidemiological studies have found no association between levels of factor (F) VII:C and venous thromboembolism (VTE). Our Longitudinal Investigation of Thromboembolism Etiology (LITE) had, in contrast, reported an independent, increased risk of VTE after 7.8 years of follow-up for those with high baseline levels of FVII:C.
OBJECTIVE: To confirm whether FVII:C is associated with VTE after 12.6 years of follow-up and to examine whether two FVII gene polymorphisms (-670A/C and -402G/A) are related to VTE occurrence.
METHODS: In 19 091 LITE participants with no prior history of VTE or cancer, we measured FVII:C at baseline and identified 404 new VTEs. We also performed a nested case-control study to relate the polymorphisms to VTE (n = 490 without exclusion for cancer or prior VTE).
RESULTS: FVII:C was not independently associated with VTE occurrence after extended follow-up. Multivariable-adjusted rate ratios for VTE were 1.00, 1.00, 0.94, 1.00, and 1.38 (P-trend = 0.48) for the <25th, 25th-49th, 50th-74th, 75th-94th, and >or=95th percentiles of FVII:C, respectively. The -670C and -402A alleles were in high linkage disequilibrium, and both were associated with greater FVII:C levels. However, neither polymorphism was associated with VTE occurrence.
CONCLUSION: After extended follow-up, LITE offers little evidence that a greater FVII level is a risk factor for VTE.
10aAlleles10aAntigens10aCoagulants10aFactor VII10aFemale10aGenotype10aHumans10aMale10aPolymorphism, Genetic10aProspective Studies10aRisk Factors10aThromboembolism10aVenous Thrombosis1 aFolsom, A, R1 aCushman, M1 aHeckbert, S R1 aOhira, T1 aRasmussen-Torvik, L1 aTsai, M, Y uhttps://chs-nhlbi.org/node/97302479nas a2200397 4500008004100000022001400041245010800055210006900163260001300232300001100245490000700256520136700263653000901630653002201639653002501661653001201686653003001698653001401728653001101742653001101753653002001764653002501784653003101809653000901840653001701849653001801866653001801884100002101902700002601923700001501949700002001964700002101984700002002005700002102025856003502046 2007 eng d a1051-228400aFocal atrophy and cerebrovascular disease increase dementia risk among cognitively normal older adults.0 aFocal atrophy and cerebrovascular disease increase dementia risk c2007 Apr a148-550 v173 aBACKGROUND AND PURPOSE: This study investigated the association of medial temporal lobe (MTL) atrophy and cerebrovascular disease (white matter hyperintensities [WMH], subclinical infarcts) with the risk of developing Alzheimer's disease (AD) among cognitively normal older adults.
METHODS: Risk of developing AD was examined for 155 cognitively normal older adults (77.4 years, 60% women, 81% white). The MTL volumes and the presence of WMH and of subclinical infarcts were determined from brain magnetic resonance imaging (MRI) at the beginning of the study. Follow-up cognitive evaluations (average 4.3 years) identified those who developed AD.
RESULTS: The presence of either MTL atrophy or subclinical infarcts was independently and significantly associated with a greater risk to develop AD (OR [95% CI]: 4.4 [1.5, 12.3] and 2.7 [1.0, 7.1], respectively). In addition, those participants with both MTL atrophy and at least one brain infarct had a 7-fold increase in the risk of developing AD (OR [95% CI]: 7.0 [1.5, 33.1]), compared to those who had neither of these conditions.
CONCLUSIONS: In cognitively normal older adults, markers of neurodegeneration (as reflected by MTL atrophy) and of cerebrovascular disease (as reflected by infarcts on MRI) independently contribute to the risk to develop AD.
10aAged10aAlzheimer Disease10aAnalysis of Variance10aAtrophy10aCerebrovascular Disorders10aCognition10aFemale10aHumans10aLogistic Models10aLongitudinal Studies10aMagnetic Resonance Imaging10aMale10aRisk Factors10aTemporal Lobe10aUnited States1 aRosano, Caterina1 aAizenstein, Howard, J1 aWu, Minjie1 aNewman, Anne, B1 aBecker, James, T1 aLopez, Oscar, L1 aKuller, Lewis, H uhttps://chs-nhlbi.org/node/96002475nas 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/94203455nas a2200421 4500008004100000022001400041245010600055210006900161260001300230300001200243490000700255520228800262653000902550653001802559653002002577653001902597653002802616653003002644653001202674653001102686653001102697653000902708653001602717653001502733653001102748653001902759653002002778653002102798653002902819100002602848700002102874700001702895700002402912700002102936700001702957700002302974856003602997 2008 eng d a0161-810500aFasting glycemia in sleep disordered breathing: lowering the threshold on oxyhemoglobin desaturation.0 aFasting glycemia in sleep disordered breathing lowering the thre c2008 Jul a1018-240 v313 aSTUDY OBJECTIVES: Commonly used definitions of sleep-disordered breathing (SDB) are based on identifying discrete events of breathing abnormalities during sleep that are accompanied by an oxyhemoglobin desaturation (delta SaO2) of at least 4%. However, it is not known whether disordered breathing events with oxyhemoglobin desaturation less than 4% are associated with clinical sequelae such as abnormalities in fasting glycemia.
DESIGN: Cross-sectional study.
SUBJECTS AND SETTING: Participants from the Sleep Heart Health Study (SHHS) with a fasting glucose measurement made within a year of the baseline polysomnogram.
MEASUREMENTS AND RESULTS: SDB severity was defined using the apnea-hypopnea index (AHI) and the hypopnea index (HI) by counting events with different levels of oxyhemoglobin desaturation (0.0%-1.9%, 2.0%-2.9%, 3.0%-3.9%, > or = 4.0%). Fasting glucose levels were used to classify individuals into normal (<100 mg/dL), impaired (100-125 mg/dL), and diabetic (> or = 126 mg/dL) groups. Ordinal logistic regression was used to determine the adjusted relative odds of an abnormal glucose value across quartiles of the hypopnea index, independent of factors such as age, body mass index, waist circumference, and usual sleep duration. The prevalence of impaired and diabetic fasting glucose in the analytical sample was 32.9% and 5.8%, respectively. The covariate-adjusted relative odds of impaired or diabetic fasting glucose in the highest versus the lowest AHI quartile was 1.35 (95% CI: 1.04-1.76) for events with a delta SaO2 > or = 4.0%, 1.72 (95% CI: 1.20-2.48) for events with a delta SaO2 between 3.0%-3.9%, 1.41 (95% CI: 1.07-1.86) for events with a delta SaO2 between 2.0%-2.9%, and 1.07 (95% CI: 0.84-1.37) for events with a delta SaO2 between 0.0%-1.9%. The corresponding odds ratios for the HI were 1.47 (95% CI: 1.13-1.92), 2.25 (95% CI: 1.59-3.19), 1.44 (95% CI: 1.09-1.90), and 1.15 (95% CI: 0.90-1.47), respectively.
CONCLUSIONS: The results of this study indicate that SDB events accompanied by oxyhemoglobin desaturation of between 2% to 4% are associated with fasting hyperglycemia. These findings suggest that milder degrees of SDB may predispose to adverse metabolic outcomes.
10aAged10aBlood Glucose10aBody Mass Index10aCohort Studies10aCross-Sectional Studies10aDiabetes Mellitus, Type 210aFasting10aFemale10aHumans10aMale10aMiddle Aged10aOdds Ratio10aOxygen10aOxyhemoglobins10aPolysomnography10aReference Values10aSleep Apnea, Obstructive1 aStamatakis, Katherine1 aSanders, Mark, H1 aCaffo, Brian1 aResnick, Helaine, E1 aGottlieb, Dan, J1 aMehra, Reena1 aPunjabi, Naresh, M uhttps://chs-nhlbi.org/node/104302595nas a2200373 4500008004100000022001400041245008900055210006900144260001600213300001100229490000700240520161900247653000901866653001201875653001001887653002101897653001201918653002801930653000901958653001101967653001801978653001101996653001102007653003102018653000902049653002402058653000902082100001902091700002002110700002002130700001602150700001902166856003602185 2008 eng d a1526-632X00aFish consumption and risk of subclinical brain abnormalities on MRI in older adults.0 aFish consumption and risk of subclinical brain abnormalities on c2008 Aug 05 a439-460 v713 aOBJECTIVE: To investigate the association between fish consumption and subclinical brain abnormalities.
METHODS: In the population-based Cardiovascular Health Study, 3,660 participants age > or =65 underwent an MRI scan in 1992-1994. Five years later, 2,313 were scanned. Neuroradiologists assessed MRI scans in a standardized and blinded manner. Food frequency questionnaires were used to assess dietary intakes. Participants with known cerebrovascular disease were excluded from the analyses.
RESULTS: After adjustment for multiple risk factors, the risk of having one or more prevalent subclinical infarcts was lower among those consuming tuna/other fish > or =3 times/week, compared to <1/month (relative risk 0.74, 95% CI = 0.54-1.01, p = 0.06, p trend = 0.03). Tuna/other fish consumption was also associated with trends toward lower incidence of subclinical infarcts. Additionally, tuna/other fish intake was associated with better white matter grade, but not with sulcal and ventricular grades, markers of brain atrophy. No significant associations were found between fried fish consumption and any subclinical brain abnormalities.
CONCLUSIONS: Among older adults, modest consumption of tuna/other fish, but not fried fish, was associated with lower prevalence of subclinical infarcts and white matter abnormalities on MRI examinations. Our results add to prior evidence that suggest that dietary intake of fish with higher eicosapentaenoic acid and docosahexaenoic acid content, and not fried fish intake, may have clinically important health benefits.
10aAged10aAnimals10aBrain10aBrain Infarction10aCooking10aCross-Sectional Studies10aDiet10aFemale10aFish Products10aFishes10aHumans10aMagnetic Resonance Imaging10aMale10aProspective Studies10aRisk1 aVirtanen, J, K1 aSiscovick, D, S1 aLongstreth, W T1 aKuller, L H1 aMozaffarian, D uhttps://chs-nhlbi.org/node/104602812nas a2200349 4500008004100000022001400041245012200055210006900177260001300246300001100259490000700270520183800277653000902115653002202124653001202146653001702158653000902175653001102184653001102195653001802206653001102224653000902235653001702244653003102261100002302292700002502315700002002340700002402360700001802384700002402402856003602426 2010 eng d a1523-468100aFish consumption, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study.0 aFish consumption bone mineral density and risk of hip fracture a c2010 Sep a1972-90 v253 aMarine n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may be beneficial for bone health, but few studies have investigated the association with fish consumption. Our aim was to study associations of fish and EPA + DHA consumption with bone mineral density (BMD) and hip fracture risk and determine whether high linoleic acid (LA) intake, the major dietary n-6 PUFA, modifies the associations. The study population consisted of 5045 participants aged 65 years and older from the Cardiovascular Health Study. Data on BMD were available for 1305 participants. Food-frequency questionnaire was used to assess dietary intake, and hip fracture incidence was assessed prospectively by review of hospitalization records. After multivariable adjustment, femoral neck BMD was 0.01 g/cm(2) lower in the highest versus lowest tuna/other-fish intake category (p = .05 for trend). EPA + DHA intake (higher versus lower median of 0.32 g/day) was associated with lower femoral neck BMD (0.66 versus 0.71 g/cm(2), p < .001) among those with LA intake greater than the median 12.1 g/day (p = .03 for interaction). No significant associations were found with total-hip BMD. During mean follow-up of 11.1 years, 505 hip fractures occurred. Fish or EPA + DHA consumption was not significantly associated with fracture incidence [hazard ratio (HR) for extreme categories: HR = 1.23, 95% confidence interval (CI) 0.83-1.84 for tuna/other fish; HR = 1.16, 95% CI 0.91-1.49 for fried fish; and HR = 0.98, 95% CI 0.71-1.36 for EPA + DHA]. High LA intake did not modify these associations. In this large prospective cohort of older adults, fish consumption was associated with very small differences in BMD and had no association with hip fracture risk.
10aAged10aAged, 80 and over10aAnimals10aBone Density10aDiet10aFemale10aFishes10aHip Fractures10aHumans10aMale10aRisk Factors10aSurveys and Questionnaires1 aVirtanen, Jyrki, K1 aMozaffarian, Dariush1 aCauley, Jane, A1 aMukamal, Kenneth, J1 aRobbins, John1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/121103431nas a2200433 4500008004100000022001400041245011000055210006900165260001300234300001100247490000700258520225200265653000902517653002602526653000902552653001702561653001702578653001102595653001802606653001102624653001102635653001802646653001402664653000902678653001802687653001502705653002402720653003102744653002202775100001802797700001902815700002402834700001802858700001702876700001902893700002402912700002502936856003602961 2010 eng d a1938-320700aFood sources of individual plasma phospholipid trans fatty acid isomers: the Cardiovascular Health Study.0 aFood sources of individual plasma phospholipid trans fatty acid c2010 Apr a883-930 v913 aBACKGROUND: The overall consumption of trans fatty acids (TFAs) increases the risk of coronary artery disease. However, multiple TFA isomers exist, each with potentially different health effects. Different food sources of these specific TFA isomers are not well established.
OBJECTIVE: Our objective was to determine the major independent food sources of specific TFA isomers.
DESIGN: We investigated relations of major potential food sources of TFAs, as assessed by serial food-frequency questionnaires, with 10 plasma phospholipid TFA isomers [5 trans (t-) 18:1, 3 t-18:2, and 2 t-16:1] in 3330 older adults in the Cardiovascular Health Study, a community-based multicenter cohort. Stepwise regression was used to identify independent major food sources of individual plasma phospholipid TFA isomers, which were adjusted for demographic, lifestyle, and dietary factors.
RESULTS: All 5 t-18:1 isomers were similarly associated with foods commonly made with partially hydrogenated vegetable oils (PHVOs), including biscuits (0.51 higher SD of total 18:1 fatty acid concentrations per serving/d, P < 0.01), chips and/or popcorn (0.33 higher SD per serving/d, P = 0.02), margarine (0.32 higher SD per serving/d, P < 0.001), fried foods (0.32 higher SD per serving/d, P = 0.04), and bakery foods (0.23 higher SD per serving/d, P = 0.02). Each of the t-18:2 isomers were associated only with bakery foods (0.50 higher SD of total 18:2 fatty acid concentrations per serving/d, P < 0.001). Ruminant foods were major correlates of t-16:1n-7, including red meats (0.72 higher SD per serving/d, P < 0.001), butter (0.43 higher SD per serving/d, P < 0.001), and higher-fat dairy (0.37 higher SD per serving/d, P < 0.001). In contrast, t-16:1n-9 were derived mainly from margarine (0.31 higher SD per serving/d, P < 0.001).
CONCLUSIONS: t-18:1 Isomers are similarly derived from multiple PHVO-containing foods. In contrast, t-18:2 and t-16:1n-9 isomers are derived from more-specific types of PHVO-containing foods. Ruminant foods are major sources of t-16:1n-7. Different TFA isomers and dietary sources should be considered when investigating health effects and interventions to lower TFAs.
10aAged10aCardiovascular System10aDiet10aDiet Surveys10aDietary Fats10aFemale10aFood Analysis10aHealth10aHumans10aHydrogenation10aIsomerism10aMale10aPhospholipids10aPlant Oils10aRegression Analysis10aSurveys and Questionnaires10aTrans Fatty Acids1 aMicha, Renata1 aKing, Irena, B1 aLemaitre, Rozenn, N1 aRimm, Eric, B1 aSacks, Frank1 aSong, Xiaoling1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/117205209nas 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/124303239nas a2200577 4500008004100000022001400041245008800055210006900143260001600212300001200228490000700240520165400247653001501901653001001916653000901926653001001935653002101945653001901966653001801985653001102003653002402014653003402038653001102072653000902083653001602092653003602108653001602144100002602160700002302186700002002209700002302229700001702252700002002269700001902289700002302308700001602331700002202347700001802369700001902387700001902406700001602425700002102441700001502462700002102477700002302498700001702521700002302538700002202561710004202583856003602625 2010 eng d a1460-208300aFucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease.0 aFucosyltransferase 2 FUT2 nonsecretor status is associated with c2010 Sep 01 a3468-760 v193 aGenetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.
10aAdolescent10aAdult10aAged10aChild10aChild, Preschool10aCohort Studies10aCrohn Disease10aFemale10aFucosyltransferases10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aYoung Adult1 aMcGovern, Dermot, P B1 aJones, Michelle, R1 aTaylor, Kent, D1 aMarciante, Kristin1 aYan, Xiaofei1 aDubinsky, Marla1 aIppoliti, Andy1 aVasiliauskas, Eric1 aBerel, Dror1 aDerkowski, Carrie1 aDutridge, Deb1 aFleshner, Phil1 aShih, David, Q1 aMelmed, Gil1 aMengesha, Emebet1 aKing, Lily1 aPressman, Sheila1 aHaritunians, Talin1 aGuo, Xiuqing1 aTargan, Stephan, R1 aRotter, Jerome, I1 aInternational IBD Genetics Consortium uhttps://chs-nhlbi.org/node/120902783nas 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/133903194nas a2200409 4500008004100000022001400041245012000055210006900175260001300244300001000257490000700267520204100274653000902315653002202324653001902346653002102365653002702386653000902413653001602422653001102438653001102449653001602460653000902476653001802485653003202503653002402535653001702559100001802576700002402594700002102618700001902639700001902658700002202677700002402699700002502723856003602748 2011 eng d a1938-320700aFatty acids in the de novo lipogenesis pathway and risk of coronary heart disease: the Cardiovascular Health Study.0 aFatty acids in the de novo lipogenesis pathway and risk of coron c2011 Aug a431-80 v943 aBACKGROUND: De novo lipogenesis (DNL) is an endogenous pathway whereby carbohydrates and proteins are converted to fatty acids. DNL could affect coronary heart disease (CHD) or sudden cardiac arrest (SCA) via generation of specific fatty acids. Whether these fatty acids are prospectively associated with SCA or other CHD events is unknown.
OBJECTIVE: The objective was to investigate the relations of 4 fatty acids in the DNL pathway-palmitic acid (16:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and cis-vaccenic acid (18:1n-7)-with incident CHD, including fatal CHD, nonfatal myocardial infarction (NFMI), and SCA.
DESIGN: A community-based prospective study was conducted in 2890 men and women aged ≥65 y, who were free of known CHD at baseline and who were followed from 1992 to 2006. Cardiovascular disease risk factors and plasma phospholipid fatty acids were measured at baseline by using standardized methods. Incident CHD was ascertained prospectively and was centrally adjudicated by using medical records. Risk was assessed by using multivariable-adjusted Cox proportional hazards.
RESULTS: During 29,835 person-years of follow-up, 631 CHD and 71 SCA events occurred. Both 18:1n-7 and 16:1n-9 were associated with a higher risk of SCA [multivariable-adjusted hazard ratio (95% CI) for the interquintile range: 7.63 (2.58, 22.6) for 18:1n-7 and 2.30 (1.16, 4.55) for 16:1n-9] but not of total CHD, fatal CHD, or NFMI. In secondary analyses censored to mid-follow-up (7 y) to minimize the effects of changes in concentrations over time, 16:1n-9 was also associated with a significantly higher risk of total CHD (2.11; 1.76, 2.54), including a higher risk of CHD death, NFMI, and SCA; 16:0 and 16:1n-7 were not associated with clinical CHD outcomes.
CONCLUSION: Higher plasma phospholipid 18:1n-7 and 16:1n-9 concentrations were prospectively associated with an elevated risk of SCA but not of other CHD events, except in secondary analyses.
10aAged10aAged, 80 and over10aCohort Studies10aCoronary Disease10aDeath, Sudden, Cardiac10aDiet10aFatty Acids10aFemale10aHumans10aLipogenesis10aMale10aPhospholipids10aProportional Hazards Models10aProspective Studies10aRisk Factors1 aH Y Wu, Jason1 aLemaitre, Rozenn, N1 aImamura, Fumiaki1 aKing, Irena, B1 aSong, Xiaoling1 aSpiegelman, Donna1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/129903302nas a2200397 4500008004100000022001400041245015200055210006900207260001600276300001000292490000700302520213300309653000902442653002202451653001502473653001102488653003002499653001802529653001102547653002602558653000902584653001402593653003302607653001802640100001902658700001602677700002502693700002002718700002102738700002402759700001702783700002402800700002002824700002402844856003602868 2012 eng d a1558-359700aFibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study).0 aFibroblast growth factor23 and death heart failure and cardiovas c2012 Jul 17 a200-70 v603 aOBJECTIVES: This study sought to determine the association of fibroblast growth factor (FGF)-23 with death, heart failure (HF), and cardiovascular disease (CVD) in the general population, as well as the influence of chronic kidney disease (CKD) in this setting.
BACKGROUND: FGF-23 increases renal phosphorus excretion and inhibits vitamin D activation. In end-stage renal disease, high FGF-23 levels are associated with mortality. The association of FGF-23 with death, HF, and CVD in the general population, and the influence of CKD in this setting, are unknown.
METHODS: Plasma FGF-23 was measured in 3,107 community-living persons ≥ 65 years of age in 1996 and 1997, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF-23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status.
RESULTS: Both lower estimated glomerular filtration rate and higher urine albumin to creatinine ratios were associated with high FGF-23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF-23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (p interactions all <0.006). In the CKD group (n = 1,128), the highest FGF-23 quartile had adjusted hazards ratios (HR) of 1.87 (95% confidence interval [CI]: 1.47 to 2.38) for all-cause death, 1.94 (95% CI: 1.32 to 2.83) for incident HF, and 1.49 (95% CI: 1.02 to 2.18) for incident CVD events compared with the lowest quartile. Corresponding HRs in those without CKD (n = 1,979) were 1.29 (95% CI: 1.05 to 1.59), 1.37 (95% CI: 0.99 to 1.89), and 1.07 (95% CI: 0.79 to 1.45).
CONCLUSIONS: FGF-23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD.
10aAged10aAged, 80 and over10aBiomarkers10aFemale10aFibroblast Growth Factors10aHeart Failure10aHumans10aKidney Function Tests10aMale10aMortality10aRenal Insufficiency, Chronic10aUnited States1 aIx, Joachim, H1 aKatz, Ronit1 aKestenbaum, Bryan, R1 ade Boer, Ian, H1 aChonchol, Michel1 aMukamal, Kenneth, J1 aRifkin, Dena1 aSiscovick, David, S1 aSarnak, Mark, J1 aShlipak, Michael, G uhttps://chs-nhlbi.org/node/139203996nas a2200625 4500008004100000022001400041245008800055210006900143260000900212300001300221490000600234520220300240653002202443653000902465653002602474653002402500653004002524653001102564653003802575653003402613653001102647653002702658653000902685653001702694653001602711653003602727653002802763653003402791653001702825653001602842653001802858100002202876700002402898700001902922700001802941700001602959700001902975700001902994700001803013700002503031700002303056700002003079700001703099700002303116700001903139700002103158700002203179700002103201700002403222700002703246700002103273700002103294700001903315856003603334 2012 eng d a1553-740400aFine-mapping and initial characterization of QT interval loci in African Americans.0 aFinemapping and initial characterization of QT interval loci in c2012 ae10028700 v83 aThe QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.
10aAfrican Americans10aAged10aComputational Biology10aElectrocardiography10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMale10aMetagenomics10aMiddle Aged10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRisk Factors10aTachycardia10aUnited States1 aAvery, Christy, L1 aSethupathy, Praveen1 aBuyske, Steven1 aHe, Qianchuan1 aLin, Dan-Yu1 aArking, Dan, E1 aCarty, Cara, L1 aDuggan, David1 aFesinmeyer, Megan, D1 aHindorff, Lucia, A1 aJeff, Janina, M1 aKlein, Liviu1 aPatton, Kristen, K1 aPeters, Ulrike1 aShohet, Ralph, V1 aSotoodehnia, Nona1 aYoung, Alicia, M1 aKooperberg, Charles1 aHaiman, Christopher, A1 aMohlke, Karen, L1 aWhitsel, Eric, A1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/608308598nas a2202365 4500008004100000022001400041245007900055210006900134260001600203300001100219490000800230520193500238653005002173653001602223653002002239653002602259653001102285653002202296653003402318653001102352653000902363653002602372653001402398653003602412653001302448653002302461100001502484700002002499700002202519700002202541700002802563700002302591700001902614700002502633700003202658700001802690700001902708700002602727700003102753700001902784700001802803700002002821700001202841700001702853700002202870700002502892700002002917700002002937700001602957700002002973700001902993700001903012700001803031700002103049700001803070700002603088700001903114700002103133700002003154700002103174700001903195700002103214700002003235700001903255700003503274700002403309700002103333700001803354700001503372700002803387700001903415700003403434700001803468700001803486700002003504700002203524700002103546700002103567700002503588700002903613700002303642700001603665700002003681700002203701700001403723700002303737700001603760700001803776700001903794700002203813700001903835700002103854700002203875700002203897700002003919700002103939700002303960700002003983700002004003700001804023700002104041700002304062700002404085700001904109700001804128700002704146700001804173700001704191700002204208700001904230700001904249700002404268700002604292700002104318700001704339700002004356700001904376700002004395700002004415700002004435700002504455700002004480700002404500700002204524700002004546700001604566700001904582700002104601700001904622700002304641700002304664700002504687700002504712700002404737700002304761700002504784700002104809700002104830700002104851700002404872700002104896700002204917700002404939700002804963700001704991700002305008700001905031700001805050700002105068700003005089700002605119700002205145700002405167700002005191700002705211700001905238700002305257700002005280700002105300700002005321700002405341700001505365700002005380700001805400700001905418700002805437700002505465700002805490700002605518700002505544700002705569700002305596700002505619700002405644700001905668700002205687700001805709700002005727700001905747700002205766700002205788700002105810700002105831700002405852700002005876700002505896700002405921700002205945700002305967700002105990700002006011700002006031700002806051700002106079700002506100700002406125700002406149700002306173856003606196 2012 eng d a1476-468700aFTO genotype is associated with phenotypic variability of body mass index.0 aFTO genotype is associated with phenotypic variability of body m c2012 Oct 11 a267-720 v4903 aThere is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aBody Height10aBody Mass Index10aCo-Repressor Proteins10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aProteins10aRepressor Proteins1 aYang, Jian1 aLoos, Ruth, J F1 aPowell, Joseph, E1 aMedland, Sarah, E1 aSpeliotes, Elizabeth, K1 aChasman, Daniel, I1 aRose, Lynda, M1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aMägi, Reedik1 aWaite, Lindsay1 aSmith, Albert, Vernon1 aYerges-Armstrong, Laura, M1 aMonda, Keri, L1 aHadley, David1 aMahajan, Anubha1 aLi, Guo1 aKapur, Karen1 aVitart, Veronique1 aHuffman, Jennifer, E1 aWang, Sophie, R1 aPalmer, Cameron1 aEsko, Tõnu1 aFischer, Krista1 aZhao, Jing Hua1 aDemirkan, Ayse1 aIsaacs, Aaron1 aFeitosa, Mary, F1 aLuan, Jian'an1 aHeard-Costa, Nancy, L1 aWhite, Charles1 aJackson, Anne, U1 aPreuss, Michael1 aZiegler, Andreas1 aEriksson, Joel1 aKutalik, Zoltán1 aFrau, Francesca1 aNolte, Ilja, M1 avan Vliet-Ostaptchouk, Jana, V1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aVerweij, Niek1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aEstrada, Karol1 aBragg-Gresham, Jennifer, Lynn1 aSanna, Serena1 aSidore, Carlo1 aTyrer, Jonathan1 aTeumer, Alexander1 aProkopenko, Inga1 aMangino, Massimo1 aLindgren, Cecilia, M1 aAssimes, Themistocles, L1 aShuldiner, Alan, R1 aHui, Jennie1 aBeilby, John, P1 aMcArdle, Wendy, L1 aHall, Per1 aHaritunians, Talin1 aZgaga, Lina1 aKolcic, Ivana1 aPolasek, Ozren1 aZemunik, Tatijana1 aOostra, Ben, A1 aJunttila, Juhani1 aGrönberg, Henrik1 aSchreiber, Stefan1 aPeters, Annette1 aHicks, Andrew, A1 aStephens, Jonathan1 aFoad, Nicola, S1 aLaitinen, Jaana1 aPouta, Anneli1 aKaakinen, Marika1 aWillemsen, Gonneke1 aVink, Jacqueline, M1 aWild, Sarah, H1 aNavis, Gerjan1 aAsselbergs, Folkert, W1 aHomuth, Georg1 aJohn, Ulrich1 aIribarren, Carlos1 aHarris, Tamara1 aLauner, Lenore1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBoerwinkle, Eric1 aCadby, Gemma1 aPalmer, Lyle, J1 aJames, Alan, L1 aMusk, Arthur, W1 aIngelsson, Erik1 aPsaty, Bruce, M1 aBeckmann, Jacques, S1 aWaeber, Gérard1 aVollenweider, Peter1 aHayward, Caroline1 aWright, Alan, F1 aRudan, Igor1 aGroop, Leif, C1 aMetspalu, Andres1 aKhaw, Kay, Tee1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aProvince, Michael, A1 aWareham, Nicholas, J1 aTardif, Jean-Claude1 aHuikuri, Heikki, V1 aCupples, Adrienne, L1 aAtwood, Larry, D1 aFox, Caroline, S1 aBoehnke, Michael1 aCollins, Francis, S1 aMohlke, Karen, L1 aErdmann, Jeanette1 aSchunkert, Heribert1 aHengstenberg, Christian1 aStark, Klaus1 aLorentzon, Mattias1 aOhlsson, Claes1 aCusi, Daniele1 aStaessen, Jan, A1 avan der Klauw, Melanie, M1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aJolley, Jennifer, D1 aRipatti, Samuli1 aJarvelin, Marjo-Riitta1 aGeus, Eco, J C1 aBoomsma, Dorret, I1 aPenninx, Brenda1 aWilson, James, F1 aCampbell, Harry1 aChanock, Stephen, J1 aHarst, Pim1 aHamsten, Anders1 aWatkins, Hugh1 aHofman, Albert1 aWitteman, Jacqueline, C1 aZillikens, Carola, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aZillikens, Carola, M1 aKiemeney, Lambertus, A1 aVermeulen, Sita, H1 aAbecasis, Goncalo, R1 aSchlessinger, David1 aSchipf, Sabine1 aStumvoll, Michael1 aTönjes, Anke1 aSpector, Tim, D1 aNorth, Kari, E1 aLettre, Guillaume1 aMcCarthy, Mark, I1 aBerndt, Sonja, I1 aHeath, Andrew, C1 aMadden, Pamela, A F1 aNyholt, Dale, R1 aMontgomery, Grant, W1 aMartin, Nicholas, G1 aMcKnight, Barbara1 aStrachan, David, P1 aHill, William, G1 aSnieder, Harold1 aRidker, Paul, M1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N1 aGoddard, Michael, E1 aVisscher, Peter, M uhttps://chs-nhlbi.org/node/617502728nas a2200457 4500008004100000022001400041245009400055210006900149260001300218300001000231490000700241520142400248653000901672653002201681653002001703653001901723653003201742653001101774653002201785653003101807653001801838653001101856653000901867653003201876653002401908653001701932653001801949653003101967100001801998700002002016700001902036700001902055700002002074700002402094700002202118700002502140700002402165700002402189700002102213856003602234 2013 eng d a1879-084400aFatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study.0 aFatty acidbinding protein 4 and incident heart failure the Cardi c2013 Apr a394-90 v153 aAIM: To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure.
METHODS AND RESULTS: In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95% confidence interval (CI) 1.25-1.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95% CI 1.01-1.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion.
CONCLUSION: An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors.
10aAged10aAged, 80 and over10aBody Mass Index10aCohort Studies10aFatty Acid-Binding Proteins10aFemale10aFollow-Up Studies10aGlomerular Filtration Rate10aHeart Failure10aHumans10aMale10aProportional Hazards Models10aProspective Studies10aRisk Factors10aUnited States10aVentricular Function, Left1 aDjoussé, Luc1 aBartz, Traci, M1 aIx, Joachim, H1 aKochar, Jinesh1 aKizer, Jorge, R1 aGottdiener, John, S1 aTracy, Russell, P1 aMozaffarian, Dariush1 aSiscovick, David, S1 aMukamal, Kenneth, J1 aZieman, Susan, J uhttps://chs-nhlbi.org/node/156502824nas a2200397 4500008004100000022001400041245011600055210006900171260001300240300001100253490000700264520170200271653000901973653002201982653002802004653003002032653001102062653001202073653001102085653001402096653002502110653000902135653001702144100002202161700002002183700002402203700001802227700002002245700002202265700002102287700001802308700002402326700002102350700001902371856003602390 2013 eng d a1935-554800aFetuin-A, type 2 diabetes, and risk of cardiovascular disease in older adults: the cardiovascular health study.0 aFetuinA type 2 diabetes and risk of cardiovascular disease in ol c2013 May a1222-80 v363 aOBJECTIVE: Fetuin-A, a hepatic secretory protein that simultaneously inhibits arterial calcification and insulin action, is associated with type 2 diabetes, but its association with cardiovascular disease (CVD) is uncertain. Preliminary studies suggest that the association of fetuin-A with CVD might differ among individuals with or without type 2 diabetes.
RESEARCH DESIGN AND METHODS: This was a prospective study of 3,810 community-living individuals older than 65 years (511 with type 2 diabetes) and free of CVD in 1992 when fetuin-A levels were measured. Participants were followed-up for incident CVD through June 2008.
RESULTS: Mean age was 75 years, and 61% were women; 1,456 participants had an incident CVD event (248 among individuals with type 2 diabetes). The association of fetuin-A with CVD was modified by type 2 diabetes (P interaction = 0.02). Higher fetuin-A was associated with lower CVD risk among persons without type 2 diabetes [hazard ratio per SD 0.1 g/L higher fetuin-A, 0.93 (95% CI, 0.88-0.99)], whereas a trend in the opposite direction was observed among individuals with type 2 diabetes, although it was not statistically significant [1.07 (0.93-1.22)]. Among individuals without type 2 diabetes, similar effect modification was observed by obesity and insulin resistance. Consistently, higher fetuin-A was associated with lower CVD risk only in the subgroups without obesity or with HOMA-IR below the median [0.91 (0.85-0.97) and 0.87 (0.79-0.95), respectively].
CONCLUSIONS: The association of fetuin-A with risk of CVD differs among elderly individuals with and without insulin resistance or type 2 diabetes.
10aAged10aAged, 80 and over10aCardiovascular Diseases10aDiabetes Mellitus, Type 210aFemale10aFetuins10aHumans10aIncidence10aLongitudinal Studies10aMale10aRisk Factors1 aJensen, Majken, K1 aBartz, Traci, M1 aMukamal, Kenneth, J1 aDjoussé, Luc1 aKizer, Jorge, R1 aTracy, Russell, P1 aZieman, Susan, J1 aRimm, Eric, B1 aSiscovick, David, S1 aShlipak, Michael1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/155203280nas a2200469 4500008004100000022001400041245013300055210006900188260001300257300001200270490000700282520195800289653000902247653002202256653001702278653001102295653003002306653001802336653001102354653002502365653000902390653001602399653002402415653000902439653002102448100002102469700002102490700002102511700001802532700002002550700002002570700002202590700001602612700001902628700001802647700002202665700002402687700002002711700002402731700001902755856003602774 2013 eng d a1945-719700aFibroblast growth factor 23, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study.0 aFibroblast growth factor 23 bone mineral density and risk of hip c2013 Aug a3323-310 v983 aCONTEXT: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that also inhibits calcitriol synthesis.
OBJECTIVE: Our objective was to evaluate the relationships of plasma FGF23 concentrations with bone mineral density (BMD) and hip fracture in community-dwelling older adults.
DESIGN AND SETTING: Linear regression and Cox proportional hazard models were used to examine the associations of plasma FGF23 concentrations with BMD and incident hip fracture, respectively. Analyses were also stratified by chronic kidney disease.
PARTICIPANTS: Participants included 2008 women and 1329 men ≥65 years from the 1996 to 1997 Cardiovascular Health Study visit.
MAIN OUTCOME MEASURES: Dual x-ray absorptiometry measured total hip (TH) and lumbar spine (LS) BMD in 1291 participants. Hip fracture incidence was assessed prospectively through June 30, 2008 by hospitalization records in all participants.
RESULTS: Women had higher plasma FGF23 concentrations than men (75 [56-107] vs 66 [interquartile range = 52-92] relative units/mL; P < .001). After adjustment, higher FGF23 concentrations were associated with greater total hip and lumbar spine BMD in men only (β per doubling of FGF23 = 0.02, with 95% confidence interval [CI] = 0.001-0.04 g/cm(2), and 0.03 with 95% CI = 0.01-0.06 g/cm(2)). During 9.6 ± 5.1-11.0 years of follow-up, 328 hip fractures occurred. Higher FGF23 concentrations were not associated with hip fracture risk in women or men (adjusted hazard ratio = 0.95, with 95% CI = 0.78-1.15, and 1.09 with 95% CI = 0.82-1.46 per doubling of FGF23). Results did not differ by chronic kidney disease status (P > .4 for interactions).
CONCLUSIONS: In this large prospective cohort of community-dwelling older adults, higher FGF23 concentrations were weakly associated with greater lumbar spine and total hip BMD but not with hip fracture risk.
10aAged10aAged, 80 and over10aBone Density10aFemale10aFibroblast Growth Factors10aHip Fractures10aHumans10aLongitudinal Studies10aMale10aMiddle Aged10aProspective Studies10aRisk10aSpinal Fractures1 aJovanovich, Anna1 aBůzková, Petra1 aChonchol, Michel1 aRobbins, John1 aFink, Howard, A1 ade Boer, Ian, H1 aKestenbaum, Bryan1 aKatz, Ronit1 aCarbone, Laura1 aLee, Jennifer1 aLaughlin, Gail, A1 aMukamal, Kenneth, J1 aFried, Linda, F1 aShlipak, Michael, G1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/599602980nas a2200409 4500008004100000022001400041245012500055210006900180260001300249300001000262490000800272520179200280653000902072653001102081653003002092653002102122653001102143653003402154653002502188653000902213653003302222653001702255653002002272100002102292700001902313700002102332700001602353700001602369700002202385700002002407700001702427700002402444700002402468700002102492700002102513856003602534 2013 eng d a1879-148400aFibroblast growth factor 23, left ventricular mass, and left ventricular hypertrophy in community-dwelling older adults.0 aFibroblast growth factor 23 left ventricular mass and left ventr c2013 Nov a114-90 v2313 aOBJECTIVES: In chronic kidney disease (CKD), high FGF23 concentrations are associated with left ventricular hypertrophy (LVH), cardiovascular events, and death. The associations of FGF23 with left ventricular mass (LVM) and LVH in the general population and the influence of CKD remains uncertain.
METHODS: C-terminal plasma FGF23 concentrations were measured, and LVM and LVH evaluated by echocardiogram among 2255 individuals ≥65 years in the Cardiovascular Health Study. Linear regression analysis adjusting for demographics, cardiovascular, and kidney related risk factors examined the associations of FGF23 concentrations with LVM. Analyses were stratified by CKD status and adjusted linear and logistic regression analysis explored the associations of FGF23 with LVM and LVH.
RESULTS: Among the entire cohort, higher FGF23 concentrations were associated with greater LVM in adjusted analyses (β = 6.71 [95% CI 4.35-9.01] g per doubling of FGF23). 32% (n = 624) had CKD (eGFR <60 mL/min/1.73 m(2) and/or urine albumin-to-creatinine ratio >30 mg/g). Associations were stronger among participants with CKD (p interaction = 0.006): LVM β = 9.71 [95% CI 5.86-13.56] g per doubling of FGF23 compared to those without CKD (β = 3.44 [95% CI 0.77, 6.11] g per doubling of FGF23). While there was no significant interaction between FGF23 and CKD for LVH (p interaction = 0.25), the OR (1.46 95% CI [1.20-1.77]) in the CKD group was statistically significant and of larger magnitude than the OR for in the no CKD group (1.12 [95% CI 0.97-1.48]).
CONCLUSION: In a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD.
10aAged10aFemale10aFibroblast Growth Factors10aHeart Ventricles10aHumans10aHypertrophy, Left Ventricular10aLongitudinal Studies10aMale10aRenal Insufficiency, Chronic10aRisk Factors10aUltrasonography1 aJovanovich, Anna1 aIx, Joachim, H1 aGottdiener, John1 aMcFann, Kim1 aKatz, Ronit1 aKestenbaum, Bryan1 ade Boer, Ian, H1 aSarnak, Mark1 aShlipak, Michael, G1 aMukamal, Kenneth, J1 aSiscovick, David1 aChonchol, Michel uhttps://chs-nhlbi.org/node/737904096nas a2200901 4500008004100000022001400041245007000055210006900125260001500194300001100209490000700220520164400227653001001871653002201881653000901903653002201912653002001934653001101954653001701965653003801982653001802020653003402038653001302072653001102085653002702096653000902123653001602132653001202148653003602160653001602196100001502212700002502227700001502252700002302267700001902290700001902309700002802328700002102356700002102377700002002398700001702418700002102435700002102456700002502477700002002502700001702522700001602539700002002555700002502575700002102600700001602621700002102637700001602658700001902674700001802693700001902711700001702730700002602747700002002773700002202793700002102815700002002836700002402856700001502880700002002895700001602915700003002931700002202961700002102983700002403004700002003028700002303048700002203071700002703093700001903120700001903139856003603158 2013 eng d a1537-660500aFine Mapping and Identification of BMI Loci in African Americans.0 aFine Mapping and Identification of BMI Loci in African Americans c2013 Oct 3 a661-710 v933 aGenome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.
10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aBody Mass Index10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aLinkage Disequilibrium10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aYoung Adult1 aGong, Jian1 aSchumacher, Fredrick1 aLim, Unhee1 aHindorff, Lucia, A1 aHaessler, Jeff1 aBuyske, Steven1 aCarlson, Christopher, S1 aRosse, Stephanie1 aBůzková, Petra1 aFornage, Myriam1 aGross, Myron1 aPankratz, Nathan1 aPankow, James, S1 aSchreiner, Pamela, J1 aCooper, Richard1 aEhret, Georg1 aGu, Charles1 aHouston, Denise1 aIrvin, Marguerite, R1 aJackson, Rebecca1 aKuller, Lew1 aHenderson, Brian1 aCheng, Iona1 aWilkens, Lynne1 aLeppert, Mark1 aLewis, Cora, E1 aLi, Rongling1 aNguyen, Khanh-Dung, H1 aGoodloe, Robert1 aFarber-Eger, Eric1 aBoston, Jonathan1 aDilks, Holli, H1 aRitchie, Marylyn, D1 aFowke, Jay1 aPooler, Loreall1 aGraff, Misa1 aFernandez-Rhodes, Lindsay1 aCochrane, Barbara1 aBoerwinkle, Eric1 aKooperberg, Charles1 aMatise, Tara, C1 aLe Marchand, Loïc1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aNorth, Kari, E1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/662602957nas a2200373 4500008004100000022001400041245013400055210006900189260001300258300000900271490000800280520182700288653000902115653002502124653002802149653002802177653003002205653001102235653001402246653003202260653001702292100002502309700001902334700001602353700002402369700002502393700002002418700002402438700001902462700002202481700002402503700002002527856003602547 2014 eng d a1879-148400aFibroblast growth factor 23, the ankle-brachial index, and incident peripheral artery disease in the Cardiovascular Health Study.0 aFibroblast growth factor 23 the anklebrachial index and incident c2014 Mar a91-60 v2333 aBACKGROUND: Fibroblast growth factor 23 (FGF23) has emerged as a novel risk factor for mortality and cardiovascular events. Its association with the ankle-brachial index (ABI) and clinical peripheral artery disease (PAD) is less known.
METHODS: Using data (N = 3143) from the Cardiovascular Health Study (CHS), a cohort of community dwelling adults >65 years of age, we analyzed the cross-sectional association of FGF23 with ABI and its association with incident clinical PAD events during 9.8 years of follow up using multinomial logistic regression and Cox proportional hazards models respectively.
RESULTS: The prevalence of cardiovascular disease (CVD) and traditional risk factors like diabetes, coronary artery disease, and heart failure increased across higher quartiles of FGF23. Compared to those with ABI of 1.1-1.4, FGF23 per doubling at baseline was associated with prevalent PAD (ABI < 0.9) although this association was attenuated after adjusting for CVD risk factors, and kidney function (OR 0.91, 95% CI 0.76-1.08). FGF23 was not associated with high ABI (>1.4) (OR 1.06, 95% CI 0.75-1.51). Higher FGF23 was associated with incidence of PAD events in unadjusted, demographic adjusted, and CVD risk factor adjusted models (HR 2.26, 95% CI 1.28-3.98; highest versus lowest quartile). The addition of estimated glomerular filtration and urine albumin to creatinine ratio to the model however, attenuated these findings (HR 1.46, 95% CI, 0.79-2.70).
CONCLUSIONS: In community dwelling older adults, FGF23 was not associated with baseline low or high ABI or incident PAD events after adjusting for confounding variables. These results suggest that FGF23 may primarily be associated with adverse cardiovascular outcomes through non atherosclerotic mechanisms.
10aAged10aAnkle Brachial Index10aCardiovascular Diseases10aCross-Sectional Studies10aFibroblast Growth Factors10aHumans10aIncidence10aPeripheral Arterial Disease10aRisk Factors1 aGarimella, Pranav, S1 aIx, Joachim, H1 aKatz, Ronit1 aChonchol, Michel, B1 aKestenbaum, Bryan, R1 ade Boer, Ian, H1 aSiscovick, David, S1 aShastri, Shani1 aHiramoto, Jade, S1 aShlipak, Michael, G1 aSarnak, Mark, J uhttps://chs-nhlbi.org/node/623903407nas 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/639903491nas a2200493 4500008004100000022001400041245012600055210006900181260001300250300001100263490000600274520211000280653002402390653001602414653000902430653002202439653001602461653001502477653001502492653001502507653001102522653003002533653003102563653002002594653001102614653002302625653001102648653002502659653000902684653001402693653003202707653002402739653001702763653001702780100002302797700001602820700001902836700002002855700002402875700002102899700002102920700002002941856003602961 2014 eng d a1555-905X00aFibroblast growth factor-23 and the long-term risk of hospital-associated AKI among community-dwelling older individuals.0 aFibroblast growth factor23 and the longterm risk of hospitalasso c2014 Feb a239-460 v93 aBACKGROUND AND OBJECTIVES: AKI occurs frequently in older persons. Elevated circulating fibroblast growth factor-23 (FGF-23), a known marker of impaired mineral metabolism, may also reflect tubular dysfunction and risk of AKI. This study evaluated FGF-23 as well as traditional markers of kidney disease, namely urine albumin-to-creatinine ratio (UACR) and creatinine-cystatin C estimated GFR (eGFRCrCyC), as risk factors for AKI in elderly individuals.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma FGF-23, UACR, and eGFRCrCyC were measured in 3241 community-dwelling elderly individuals in the Cardiovascular Health Study. Hospitalization for AKI was defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Associations of each biomarker with AKI were evaluated using Cox proportional hazards models adjusted for demographics, cardiovascular risk factors, and biomarkers of kidney function.
RESULTS: The mean participant age was 78 years; 60% of participants were women and 16% were African American. The median (interquartile range) values of biomarkers were as follows: FGF-23, 70 RU/ml (53, 99); UACR, 8.88 mg/g (4.71, 20.47); and eGFRCrCyC, 71 ml/min per 1.73 m(2) (59, 83). Hospitalized AKI occurred in 119 participants over 10.0 years of median follow-up. In fully adjusted analyses, compared with the lowest quartiles, the highest quartiles of FGF-23 (≥100 RU/ml) and UACR (≥20.9 mg/g) were associated with AKI (FGF-23: hazard ratio [HR], 1.99; 95% confidence interval [95% CI], 1.04 to 3.80; and UACR: HR, 3.35; 95% CI, 1.83 to 6.13). Compared with the highest quartile, the lowest quartile of eGFRCrCyC (<57 ml/min per 1.73 m(2)) was associated with AKI with an HR of 2.15 (95% CI, 1.21 to 3.82).
CONCLUSIONS: FGF-23 adjusted for albuminuria, cardiovascular disease risk factors, and baseline eGFR is independently associated with a higher risk of AKI hospitalizations in community-dwelling elderly individuals. Further studies to understand the nature of this association are warranted.
10aAcute Kidney Injury10aAge Factors10aAged10aAged, 80 and over10aAlbuminuria10aBiomarkers10aCreatinine10aCystatin C10aFemale10aFibroblast Growth Factors10aGlomerular Filtration Rate10aHospitalization10aHumans10aIndependent Living10aKidney10aLongitudinal Studies10aMale10aPrognosis10aProportional Hazards Models10aProspective Studies10aRisk Factors10aTime Factors1 aBrown, Jeremiah, R1 aKatz, Ronit1 aIx, Joachim, H1 ade Boer, Ian, H1 aSiscovick, David, S1 aGrams, Morgan, E1 aShlipak, Michael1 aSarnak, Mark, J uhttps://chs-nhlbi.org/node/630803351nas a2200577 4500008004100000022001400041245011800055210006900173260001300242300001000255490000600265520177300271653001602044653000902060653002202069653001002091653001502101653002302116653002802139653001102167653001302178653001802191653001102209653001402220653000902234653002602243653002202269653001602291653001402307653002402321653002002345653001702365653001102382653001702393653003602410653001802446100001802464700002202482700001802504700001902522700001802541700002802559700002402587700001902611700002002630700001802650700002302668700002202691700002402713856003602737 2014 eng d a1941-308400aFibrosis-related biomarkers and incident cardiovascular disease in older adults: the cardiovascular health study.0 aFibrosisrelated biomarkers and incident cardiovascular disease i c2014 Aug a583-90 v73 aBACKGROUND: Fibrotic changes in the heart and arteries have been implicated in a diverse range of cardiovascular diseases (CVD), but whether circulating biomarkers that reflect fibrosis are associated with CVD is unknown.
METHODS AND RESULTS: We determined the associations of 2 biomarkers of fibrosis, transforming growth factor- β (TGF-β), and procollagen type III N-terminal propeptide (PIIINP), with incident heart failure, myocardial infarction, and stroke among community-living older adults in the Cardiovascular Health Study. We measured circulating TGF-β (n=1371) and PIIINP (n=2568) from plasma samples collected in 1996 and ascertained events through 2010. Given TGF-β's pleiotropic effects on inflammation and fibrogenesis, we investigated potential effect modification by C-reactive protein in secondary analyses. After adjustment for sociodemographic, clinical, and biochemical risk factors, PIIINP was associated with total CVD (hazard ratio [HR] per SD=1.07; 95% confidence interval [CI], 1.01-1.14) and heart failure (HR per SD=1.08; CI, 1.01-1.16) but not myocardial infarction or stroke. TGF-β was not associated with any CVD outcomes in the full cohort but was associated with total CVD (HR per SD=1.16; CI, 1.02-1.31), heart failure (HR per SD=1.16; CI, 1.01-1.34), and stroke (HR per SD=1.20; CI, 1.01-1.42) among individuals with C-reactive protein above the median, 2.3 mg/L (P interaction <0.05).
CONCLUSIONS: Our findings provide large-scale, prospective evidence that circulating biomarkers of fibrosis, measured in community-living individuals late in life, are associated with CVD. Further research on whether TGF-β has a stronger fibrogenic effect in the setting of inflammation is warranted.
10aAge Factors10aAged10aAged, 80 and over10aAging10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aFemale10aFibrosis10aHeart Failure10aHumans10aIncidence10aMale10aMyocardial Infarction10aPeptide Fragments10aProcollagen10aPrognosis10aProspective Studies10aRisk Assessment10aRisk Factors10aStroke10aTime Factors10aTransforming Growth Factor beta10aUnited States1 aAgarwal, Isha1 aGlazer, Nicole, L1 aBarasch, Eddy1 aBiggs, Mary, L1 aDjoussé, Luc1 aFitzpatrick, Annette, L1 aGottdiener, John, S1 aIx, Joachim, H1 aKizer, Jorge, R1 aRimm, Eric, B1 aSicovick, David, S1 aTracy, Russell, P1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/654102905nas a2200505 4500008004100000022001400041245011300055210006900168260001600237300001100253490000800264520146700272653000901739653002201748653001501770653001901785653001101804653001301815653002201828653001101850653002501861653000901886653002601895653002201921653001601943653003201959653002401991653001702015653003602032100001802068700002202086700001802108700001902126700001802145700002802163700002402191700001902215700002002234700001802254700002402272700002202296700002102318700002402339856003602363 2014 eng d a1476-625600aFibrosis-related biomarkers and risk of total and cause-specific mortality: the cardiovascular health study.0 aFibrosisrelated biomarkers and risk of total and causespecific m c2014 Jun 01 a1331-90 v1793 aFibrosis has been implicated in diverse diseases of the liver, kidney, lungs, and heart, but its importance as a risk factor for mortality remains unconfirmed. We determined the prospective associations of 2 complementary biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with total and cause-specific mortality risks among community-living older adults in the Cardiovascular Health Study (1996-2010). We measured circulating TGF-β and PIIINP levels in plasma samples collected in 1996 and ascertained the number of deaths through 2010. Both TGF-β and PIIINP were associated with elevated risks of total and pulmonary mortality after adjustment for sociodemographic, clinical, and biochemical risk factors. For total mortality, the hazard ratios per doubling of TGF-β and PIIINP were 1.09 (95% confidence interval (CI): 1.01, 1.17; P = 0.02) and 1.14 (CI: 1.03, 1.27; P = 0.01), respectively. The corresponding hazard ratios for pulmonary mortality were 1.27 (CI: 1.01, 1.60; P = 0.04) for TGF-β and 1.52 (CI: 1.11, 2.10; P = 0.01) for PIIINP. Associations of TGF-β and PIIINP with total and pulmonary mortality were strongest among individuals with higher C-reactive protein concentrations (P for interaction < 0.05). Our findings provide some of the first large-scale prospective evidence that circulating biomarkers of fibrosis measured late in life are associated with death.
10aAged10aAged, 80 and over10aBiomarkers10aCause of Death10aFemale10aFibrosis10aFollow-Up Studies10aHumans10aLikelihood Functions10aMale10aMultivariate Analysis10aPeptide Fragments10aProcollagen10aProportional Hazards Models10aProspective Studies10aRisk Factors10aTransforming Growth Factor beta1 aAgarwal, Isha1 aGlazer, Nicole, L1 aBarasch, Eddy1 aBiggs, Mary, L1 aDjoussé, Luc1 aFitzpatrick, Annette, L1 aGottdiener, John, S1 aIx, Joachim, H1 aKizer, Jorge, R1 aRimm, Eric, B1 aSiscovick, David, S1 aTracy, Russell, P1 aZieman, Susan, J1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/633606392nas a2201669 4500008004100000022001400041245009700055210006900152260001600221300001200237490000700249520182200256653001002078653002202088653000902110653001202119653003702131653002002168653002602188653001702214653002102231653001802252653004002270653001102310653001902321653001102340653000902351653001602360653001202376653003602388653001302424100001402437700002802451700002002479700002002499700002002519700001902539700002102558700001902579700002002598700001802618700002302636700001802659700001802677700001602695700002402711700001202735700003202747700002302779700001502802700001902817700002002836700001902856700002502875700001702900700002302917700002202940700002302962700002202985700001503007700002503022700002703047700002003074700002203094700002403116700001203140700002103152700002103173700002103194700002503215700001903240700002003259700001903279700002603298700002103324700001703345700002403362700001703386700002303403700002103426700001603447700001803463700002503481700002003506700002003526700002103546700001903567700002303586700001903609700002403628700002303652700002203675700001803697700001803715700002303733700001703756700001203773700001703785700002003802700001703822700001903839700002503858700001603883700001903899700002003918700002003938700002303958700002203981700002804003700002504031700002104056700001604077700001804093700002404111700001504135700002904150700002404179700002504203700003004228700001504258700002004273700001704293700001804310700002204328700002004350700002304370700002104393700002104414700002004435700002504455700002004480700002504500700001404525700002304539700002004562700002904582700001704611700002004628700002704648700001104675856003604686 2014 eng d a1460-208300aFTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.0 aFTO genetic variants dietary intake and body mass index insights c2014 Dec 20 a6961-720 v233 aFTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
10aAdult10aAfrican Americans10aAged10aAlleles10aAsian Continental Ancestry Group10aBody Mass Index10aDietary Carbohydrates10aDietary Fats10aDietary Proteins10aEnergy Intake10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aHumans10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aProteins1 aQi, Qibin1 aKilpeläinen, Tuomas, O1 aDowner, Mary, K1 aTanaka, Toshiko1 aSmith, Caren, E1 aSluijs, Ivonne1 aSonestedt, Emily1 aChu, Audrey, Y1 aRenstrom, Frida1 aLin, Xiaochen1 aÄngquist, Lars, H1 aHuang, Jinyan1 aLiu, Zhonghua1 aLi, Yanping1 aAli, Muhammad, Asif1 aXu, Min1 aAhluwalia, Tarunveer, Singh1 aBoer, Jolanda, M A1 aChen, Peng1 aDaimon, Makoto1 aEriksson, Johan1 aPerola, Markus1 aFriedlander, Yechiel1 aGao, Yu-Tang1 aHeppe, Denise, H M1 aHolloway, John, W1 aHouston, Denise, K1 aKanoni, Stavroula1 aKim, Yu-Mi1 aLaaksonen, Maarit, A1 aJääskeläinen, Tiina1 aLee, Nanette, R1 aLehtimäki, Terho1 aLemaitre, Rozenn, N1 aLu, Wei1 aLuben, Robert, N1 aManichaikul, Ani1 aMännistö, Satu1 aMarques-Vidal, Pedro1 aMonda, Keri, L1 aNgwa, Julius, S1 aPerusse, Louis1 avan Rooij, Frank, J A1 aXiang, Yong-Bing1 aWen, Wanqing1 aWojczynski, Mary, K1 aZhu, Jingwen1 aBorecki, Ingrid, B1 aBouchard, Claude1 aCai, Qiuyin1 aCooper, Cyrus1 aDedoussis, George, V1 aDeloukas, Panos1 aFerrucci, Luigi1 aForouhi, Nita, G1 aHansen, Torben1 aChristiansen, Lene1 aHofman, Albert1 aJohansson, Ingegerd1 aJørgensen, Torben1 aKarasawa, Shigeru1 aKhaw, Kay-Tee1 aKim, Mi-Kyung1 aKristiansson, Kati1 aLi, Huaixing1 aLin, Xu1 aLiu, Yongmei1 aLohman, Kurt, K1 aLong, Jirong1 aMikkilä, Vera1 aMozaffarian, Dariush1 aNorth, Kari1 aPedersen, Oluf1 aRaitakari, Olli1 aRissanen, Harri1 aTuomilehto, Jaakko1 aSchouw, Yvonne, T1 aUitterlinden, André, G1 aZillikens, Carola, M1 aFranco, Oscar, H1 aTai, Shyong1 aShu, Xiao, Ou1 aSiscovick, David, S1 aToft, Ulla1 aVerschuren, W, M Monique1 aVollenweider, Peter1 aWareham, Nicholas, J1 aWitteman, Jacqueline, C M1 aZheng, Wei1 aRidker, Paul, M1 aKang, Jae, H1 aLiang, Liming1 aJensen, Majken, K1 aCurhan, Gary, C1 aPasquale, Louis, R1 aHunter, David, J1 aMohlke, Karen, L1 aUusitupa, Matti1 aCupples, Adrienne, L1 aRankinen, Tuomo1 aOrho-Melander, Marju1 aWang, Tao1 aChasman, Daniel, I1 aFranks, Paul, W1 aSørensen, Thorkild, I A1 aHu, Frank, B1 aLoos, Ruth, J F1 aNettleton, Jennifer, A1 aQi, Lu uhttps://chs-nhlbi.org/node/693803694nas a2200529 4500008004100000022001400041245015700055210006900212260001300281300001000294490000800304520211100312653000902423653002202432653002802454653003502482653002102517653001102538653002202549653001302571653001902584653001102603653002302614653002502637653000902662653003702671653003602708653002402744653001702768653002702785100002202812700001902834700002002853700001802873700002002891700002202911700001902933700002102952700002002973700001802993700002403011700003003035700001703065700002403082700002203106856003603128 2015 eng d a1879-148400aFetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies.0 aFetuinA and risk of coronary heart disease A Mendelian randomiza c2015 Nov a44-520 v2433 aBACKGROUND AND AIMS: Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification).
METHODS: Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993.
RESULTS: Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele (P < 0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95% CI: 1.00-1.26) for rs2248690 and 1.02 (0.91-1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70-1.00) for rs2248690 and 0.97 (95% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048).
CONCLUSION: Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.
10aAged10aAged, 80 and over10aalpha-2-HS-Glycoprotein10aCarotid Intima-Media Thickness10aCoronary Vessels10aFemale10aGenetic Variation10aGenotype10aHeart Diseases10aHumans10aInsulin Resistance10aLongitudinal Studies10aMale10aMendelian Randomization Analysis10aPolymorphism, Single Nucleotide10aProspective Studies10aRisk Factors10aVascular Calcification1 aLaugsand, Lars, E1 aIx, Joachim, H1 aBartz, Traci, M1 aDjoussé, Luc1 aKizer, Jorge, R1 aTracy, Russell, P1 aDehghan, Abbas1 aRexrode, Kathryn1 aLopez, Oscar, L1 aRimm, Eric, B1 aSiscovick, David, S1 aO'Donnell, Christopher, J1 aNewman, Anne1 aMukamal, Kenneth, J1 aJensen, Majken, K uhttps://chs-nhlbi.org/node/685303793nas a2200493 4500008004100000022001400041245010900055210006900164260001300233300000900246490000700255520239600262653000902658653002202667653001502689653001602704653002702720653002402747653001102771653003002782653002202812653001702834653001902851653001102870653002602881653000902907653002402916653003302940653001702973653003102990653001803021100001503039700001603054700002003070700002203090700002203112700002403134700002103158700002003179700002103199700002403220700001903244856003603263 2015 eng d a1523-683800aFibroblast growth factor 23 and sudden versus non-sudden cardiac death: the Cardiovascular Health Study.0 aFibroblast growth factor 23 and sudden versus nonsudden cardiac c2015 Jul a40-60 v663 aBACKGROUND: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Because individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 level is a stronger risk factor for SCD versus non-SCD.
STUDY DESIGN: Cohort study.
SETTING & PARTICIPANTS: 3,244 participants 65 years or older in the community-based Cardiovascular Health Study.
PREDICTOR: Plasma FGF-23 concentrations.
OUTCOMES: We assessed SCD and non-SCD in these analyses. SCD was adjudicated rigorously and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in the emergency department.
MEASUREMENTS: We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbid conditions, and kidney function. We also tested whether associations differed by CKD status.
RESULTS: During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbid conditions, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95% CI, 1.06-1.30). However, elevated FGF-23 concentrations were not associated independently with SCD (HR [per doubling], 1.07; 95% CI, 0.85-1.35). In stratified analysis by CKD status (36.5% of cohort), doubling of FGF-23 concentrations was associated independently with non-SCD (adjusted HR, 1.26; 95% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 level and SCD in the CKD subgroup; however, it was not significant (HR, 1.20; 95% CI, 0.89-1.62).
LIMITATIONS: Limited power to detect moderate-sized effects between FGF-23 level and SCD in both the primary and stratified analyses.
CONCLUSIONS: In this population-based study, FGF-23 level elevations were associated independently with non-SCD. Among individuals with CKD, the associations between FGF-23 level and SCD and non-SCD were similar.
10aAged10aAged, 80 and over10aBiomarkers10aComorbidity10aDeath, Sudden, Cardiac10aElectrocardiography10aFemale10aFibroblast Growth Factors10aFollow-Up Studies10aHeart Arrest10aHeart Diseases10aHumans10aKaplan-Meier Estimate10aMale10aProspective Studies10aRenal Insufficiency, Chronic10aRisk Factors10aSympathetic Nervous System10aUnited States1 aDeo, Rajat1 aKatz, Ronit1 ade Boer, Ian, H1 aSotoodehnia, Nona1 aKestenbaum, Bryan1 aMukamal, Kenneth, J1 aChonchol, Michel1 aSarnak, Mark, J1 aSiscovick, David1 aShlipak, Michael, G1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/666203583nas a2200589 4500008004100000022001400041245010100055210006900156260001300225300001100238490000800249520192100257653000902178653002502187653001502212653002002227653002802247653003502275653002802310653001102338653001302349653001102362653001402373653000902387653002202396653003202418653003002450653001602480653001402496653002402510653002102534653001702555653003602572653001802608653001702626100001802643700001802661700002202679700001802701700001802719700002802737700002402765700001902789700002302808700002002831700001802851700002402869700002202893700001802915700002402933856003602957 2015 eng d a1879-148400aFibrosis-related biomarkers and large and small vessel disease: the Cardiovascular Health Study.0 aFibrosisrelated biomarkers and large and small vessel disease th c2015 Apr a539-460 v2393 aOBJECTIVE: Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels.
METHODS: We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima-media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-β and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996 and 1998.
RESULTS: After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-β was associated with incident PAD (hazard ratio [HR] = 1.36 per doubling of TGF-β, 95% confidence interval [CI] = 1.04, 1.78) and retinal venular diameter (1.63 μm per doubling of TGF-β, CI = 0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102 mm per doubling of PIIINP, CI = 0.029, 0.174) and impaired brachial artery reactivity (-0.20% change per doubling of PIIINP, CI = -0.39, -0.02). Neither TGF-β nor PIIINP were associated with retinal arteriolar diameter or retinopathy.
CONCLUSIONS: Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults.
10aAged10aAnkle Brachial Index10aBiomarkers10aBrachial Artery10aCarotid Artery Diseases10aCarotid Intima-Media Thickness10aCross-Sectional Studies10aFemale10aFibrosis10aHumans10aIncidence10aMale10aPeptide Fragments10aPeripheral Arterial Disease10aPredictive Value of Tests10aProcollagen10aPrognosis10aProspective Studies10aRetinal Diseases10aRisk Factors10aTransforming Growth Factor beta10aUnited States10aVasodilation1 aAgarwal, Isha1 aArnold, Alice1 aGlazer, Nicole, L1 aBarasch, Eddy1 aDjoussé, Luc1 aFitzpatrick, Annette, L1 aGottdiener, John, S1 aIx, Joachim, H1 aJensen, Richard, A1 aKizer, Jorge, R1 aRimm, Eric, B1 aSiscovick, David, S1 aTracy, Russell, P1 aWong, Tien, Y1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/666503388nas a2200457 4500008004100000022001400041245012000055210006900175260001300244300001000257490000700267520205200274653000902326653001802335653001502353653002802368653002802396653003802424653001102462653003002473653001802503653003102521653001102552653002302563653002502586653000902611653001402620653001702634653003102651100001802682700001902700700002402719700002002743700002002763700002502783700002102808700002502829700002002854700002002874856003602894 2016 eng d a1532-541500aFibroblast Growth Factor-23 and Frailty in Elderly Community-Dwelling Individuals: The Cardiovascular Health Study.0 aFibroblast Growth Factor23 and Frailty in Elderly CommunityDwell c2016 Feb a270-60 v643 aOBJECTIVES: To evaluate whether fibroblast growth factor 23 (FGF-23) is related to frailty and to characterize the nature of their joint association with mortality.
DESIGN: Cross-sectional analysis for frailty and longitudinal cohort analysis for mortality.
SETTING: Cardiovascular Health Study.
PARTICIPANTS: Community-dwelling individuals (N = 2,977; mean age 77.9 ± 4.7, 40% male, 83% white).
MEASUREMENTS: The predictor was serum FGF-23 concentration (C-terminal enzyme-linked immunosorbent assay), and the outcomes were frailty status (determined according to frailty phenotype criteria of weight loss, weakness, exhaustion, slowness, and low physical activity) and mortality. Multinomial logistic regression was used to assess the cross-sectional association between FGF-23 and frailty and prefrailty, adjusting for demographic characteristics, cardiovascular disease and risk factors, and kidney markers. Proportional hazards Cox proportional hazards regression was used to assess the association between FGF-23, frailty, and all-cause mortality.
RESULTS: Mean estimated glomerular filtration rate (eGFR) was 64 ± 17 mL/min per 1.73 m(2) . Median FGF-23 was 70.3 RU/mL (interquartile range 53.4-99.2); 52% were prefrail, and 13% were frail. After multivariate adjustment, each doubling in FGF-23 concentration was associated with 38% (95% confidence interval (CI) = 17-62%) higher odds of frailty than of nonfrailty and 16% (95% CI = 3-30%) higher odds of prefrailty. FGF-23 (hazard ratio (HR) = 1.16, 95% CI = 1.10-1.23) and frailty (HR = 1.82, 95% CI = 1.57-2.12) were independently associated with mortality, but neither association was meaningfully attenuated when adjusted for the other.
CONCLUSION: In a large cohort of older adults, higher FGF-23 was independently associated with prevalent frailty and prefrailty. FGF-23 and frailty were independent and additive risk factors for mortality. FGF-23 may be a marker for functional outcomes.
10aAged10aAnthropometry10aBiomarkers10aCardiovascular Diseases10aCross-Sectional Studies10aEnzyme-Linked Immunosorbent Assay10aFemale10aFibroblast Growth Factors10aFrail Elderly10aGlomerular Filtration Rate10aHumans10aIndependent Living10aLongitudinal Studies10aMale10aPhenotype10aRisk Factors10aSurveys and Questionnaires1 aBeben, Tomasz1 aIx, Joachim, H1 aShlipak, Michael, G1 aSarnak, Mark, J1 aFried, Linda, F1 aHoofnagle, Andrew, N1 aChonchol, Michel1 aKestenbaum, Bryan, R1 ade Boer, Ian, H1 aRifkin, Dena, E uhttps://chs-nhlbi.org/node/699002719nas a2200241 4500008004100000022001400041245007500055210006900130260001300199300001100212490000700223520205900230100001902289700001802308700001602326700001602342700001302358700001502371700002002386700001702406700001802423856003602441 2016 eng d a1433-296500aFibrosis markers, hip fracture risk, and bone density in older adults.0 aFibrosis markers hip fracture risk and bone density in older adu c2016 Feb a815-200 v273 aUNLABELLED: We examined whether blood levels of two markers of fibrosis (transforming growth factor beta one (TGF-β1) and procollagen type III N-terminal propeptide (PIIINP)) are related to hip fracture risk and to bone mineral density (BMD). TGF-β1 levels were associated with lower hip fracture risk in women and with lower BMD in men. PIIINP levels were not associated with either outcome.
INTRODUCTION: TGF-β1 serves several roles in bone formation and resorption. A consequence of TGF-β1 activation is the production of PIIINP, a marker of collagen III deposition. Here, we explore whether these two biomarkers are related to incident hip fracture and bone mineral density (BMD) and whether their associations are modified by systemic inflammation, as measured by C-reactive protein (CRP) levels.
METHODS: Participants were from the Cardiovascular Health Study (mean age 78 years; mean follow-up 8.3 years). We included 1681 persons with measured levels of TGF-β1 (149 hip fractures) and 3226 persons with measured levels of PIIINP (310 hip fractures).
RESULTS: Among women, higher TGF-β1 levels were associated with lower hip fracture risk (HR, per doubling, 0.78 [95 % CI 0.61, 0.91]). Among men, TGF-β1 levels were associated with hip fracture risk in a non-linear manner, but among those with elevated CRP levels, doubling was associated with increased risk of fracture (HR 2.22 [1.20, 4.08]) (p = 0.02, interaction between low and high CRP and TGF-β1 on fracture risk). TGF-β1 levels had no significant association with total hip or total body BMD in women but were significantly associated with lower BMD in men. There were no associations of PIIINP levels with hip fracture risk or BMD in men or women.
CONCLUSIONS: TGF-β1 levels appear to be associated with bone-related phenotypes in a sex-specific manner. The reasons for these differences between men and women regarding TGF-β1 levels and hip fracture risk and bone density require further investigation.
1 aBarzilay, J, I1 aBůžková, P1 aKizer, J, R1 aDjoussé, L1 aIx, J, H1 aFink, H, A1 aSiscovick, D, S1 aCauley, J, A1 aMukamal, K, J uhttps://chs-nhlbi.org/node/680604382nas 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/725902992nas a2200397 4500008004100000022001400041245008300055210006900138260001300207300001400220490000700234520188600241653003102127653000902158653002202167653001902189653001902208653001102227653002202238653001802260653001102278653000902289653002502298653001702323653001102340653001802351100003202369700002702401700002102428700001902449700002902468700001802497700002002515700002302535856003602558 2017 eng d a1524-462800aFactors Associated With Ischemic Stroke Survival and Recovery in Older Adults.0 aFactors Associated With Ischemic Stroke Survival and Recovery in c2017 Jul a1818-18260 v483 aBACKGROUND AND PURPOSE: Little is known about factors that predispose older adults to poor recovery after a stroke. In this study, we sought to evaluate prestroke measures of frailty and related factors as markers of vulnerability to poor outcomes after ischemic stroke.
METHODS: In participants aged 65 to 99 years with incident ischemic strokes from the Cardiovascular Health Study, we evaluated the association of several risk factors (frailty, frailty components, C-reactive protein, interleukin-6, and cystatin C) assessed before stroke with stroke outcomes of survival, cognitive decline (≥5 points on Modified Mini-Mental State Examination), and activities of daily living decline (increase in limitations).
RESULTS: Among 717 participants with incident ischemic stroke with survival data, slow walking speed, low grip strength, and cystatin C were independently associated with shorter survival. Among participants <80 years of age, frailty and interleukin-6 were also associated with shorter survival. Among 509 participants with recovery data, slow walking speed, and low grip strength were associated with both cognitive and activities of daily living decline poststroke. C-reactive protein and interleukin-6 were associated with poststroke cognitive decline among men only. Frailty status was associated with activities of daily living decline among women only.
CONCLUSIONS: Markers of physical function-walking speed and grip strength-were consistently associated with survival and recovery after ischemic stroke. Inflammation, kidney function, and frailty also seemed to be determinants of survival and recovery after an ischemic stroke. These markers of vulnerability may identify targets for differing pre and poststroke medical management and rehabilitation among older adults at risk of poor stroke outcomes.
10aActivities of Daily Living10aAged10aAged, 80 and over10aBrain Ischemia10aCohort Studies10aFemale10aFollow-Up Studies10aFrail Elderly10aHumans10aMale10aRecovery of Function10aRisk Factors10aStroke10aSurvival Rate1 aWinovich, Divya, Thekkethal1 aLongstreth, William, T1 aArnold, Alice, M1 aVaradhan, Ravi1 aHazzouri, Adina, Zeki Al1 aCushman, Mary1 aNewman, Anne, B1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/749302608nas a2200241 4500008004100000022001400041245009900055210006900154260001300223300001400236490000700250520187800257100002202135700002002157700002202177700002002199700002202219700002402241700002502265700001902290700002102309856003602330 2017 eng d a1533-345000aFibroblast Growth Factor 23 and the Risk of Infection-Related Hospitalization in Older Adults.0 aFibroblast Growth Factor 23 and the Risk of InfectionRelated Hos c2017 Apr a1239-12460 v283 aWithin monocytes, 1,25-dihydroxyvitamin D [1,25(OH)2D] is important for production of cathelicidins, which in turn, are critical for antibacterial action. Fibroblast growth factor 23 (FGF23) decreases 1,25(OH)2D production and thus, could increase infection risk. We examined this possibility in 3141 community-dwelling adults ages ≥65 years old at baseline in the Cardiovascular Health Study using Cox proportional hazards models to examine the association between FGF23 concentrations and first infection-related hospitalizations and determine whether associations differed by the presence of CKD (eGFR<60 ml/min per 1.73 m(2) [n=832] or urine albumin-to-creatinine ratio >30 mg/g [n=577]). Mean±SD age of participants was 78±5 years old, 60% of participants were women, and the median plasma FGF23 concentration was 70 (interquartile range, 53-99) relative units per milliliter. In fully adjusted models, higher FGF23 concentrations associated with higher risk of first infection-related hospitalization (hazard ratio [HR], 1.11; 95% confidence interval [95% CI], 1.03 to 1.20 per doubling of FGF23) during a median follow-up of 8.6 years. In participants with or without CKD (defined by eGFR), FGF23 concentration associated with first infection-related hospitalization with HRs of 1.24 (95% CI, 1.08 to 1.42) and 1.06 (95% CI, 0.97 to 1.17) per doubling of FGF23, respectively (P=0.13 for interaction). Associations did not differ between groups when stratified by urine albumin-to-creatinine ratio. In sensitivity analyses, the addition of serum calcium, phosphorus, 25-hydroxyvitamin D, intact parathyroid hormone, and 24,25-dihydroxyvitamin D did not meaningfully change the estimates. In conclusion, in community-dwelling older adults, higher plasma FGF23 concentrations independently associated with the risk of first infection-related hospitalization.
1 aNowak, Kristen, L1 aBartz, Traci, M1 aDalrymple, Lorien1 ade Boer, Ian, H1 aKestenbaum, Bryan1 aShlipak, Michael, G1 aGarimella, Pranav, S1 aIx, Joachim, H1 aChonchol, Michel uhttps://chs-nhlbi.org/node/735402980nas a2200433 4500008004100000022001400041245009400055210006900149260001600218300001400234490000800248520176800256653001402024653000902038653002202047653002802069653001102097653003002108653003102138653001102169653001102180653000902191653001602200653001302216653003302229653001702262100001802279700002002297700002102317700002202338700002002360700003002380700002002410700001902430700002202449700002102471700001802492856003602510 2017 eng d a1945-719700aFibroblast Growth Factor 23, Mineral Metabolism, and Adiposity in Normal Kidney Function.0 aFibroblast Growth Factor 23 Mineral Metabolism and Adiposity in c2017 Apr 01 a1387-13950 v1023 aContext: Obesity is associated with poor bone mineralization and quality. Fibroblast growth factor 23 (FGF23) plays an important role in skeletal physiology.
Objective: To test hypothesis that greater adiposity results in higher FGF23 levels among individuals with normal estimated glomerular filtration rate (eGFR).
Design, Setting, Participants: Cross-sectional analyses among participants with eGFR ≥60 mL/min/1.73m2. We assessed the association between crude [body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR); n = 5610] and refined (abdominal adipose tissue area by computed tomography; n = 1313) measures of adiposity and FGF23 using multivariable linear regression.
Main Outcome Measure: Serum FGF23.
Results: FGF23 was higher across BMI categories (BMI <25: 37.7; BMI 25 to 29.99: 38.7; BMI 30 to 39.99: 39.8; BMI ≥40: 40.9 pg/mL, unadjusted P trend < 0.0001). The association between BMI and FGF23 was independent of known confounders of FGF23 (adjusted β = +7.2% higher FGF23 per 10 kg/m2; P < 0.0001). Similar results were observed using WC and WHR. Abdominal adipose tissue area was also independently associated with higher FGF23 (P < 0.01). Notably, the positive associations between FGF23 and adiposity were observed despite the fact that eGFR did not decline and serum phosphate levels did not increase with adiposity.
Conclusion: In a large cohort with normal kidney function, adiposity was associated with higher FGF23 levels independent of known confounders, including eGFR and phosphate. Further studies are needed to evaluate the causes of higher FGF23 in settings of greater adiposity and the potential impact on skeletal health.
10aAdiposity10aAged10aAged, 80 and over10aCross-Sectional Studies10aFemale10aFibroblast Growth Factors10aGlomerular Filtration Rate10aHumans10aKidney10aMale10aMiddle Aged10aMinerals10aRenal Insufficiency, Chronic10aRisk Factors1 aZaheer, Sarah1 ade Boer, Ian, H1 aAllison, Matthew1 aBrown, Jenifer, M1 aPsaty, Bruce, M1 aRobinson-Cohen, Cassianne1 aMichos, Erin, D1 aIx, Joachim, H1 aKestenbaum, Bryan1 aSiscovick, David1 aVaidya, Anand uhttps://chs-nhlbi.org/node/760104297nas 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/755703442nas a2200469 4500008004100000022001400041245018400055210006900239260001300308300001200321490000700333520199400340100002202334700002502356700002402381700002502405700002002430700001702450700002402467700002002491700002602511700001302537700002302550700002002573700002702593700001902620700002202639700001902661700002102680700002302701700002002724700002102744700002202765700001702787700002102804700001902825700002702844700002202871700002402893700001902917856003602936 2017 eng d a1556-387100aFine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations.0 aFine mapping of QT interval regions in global populations refine c2017 Apr a572-5800 v143 aBACKGROUND: The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance.
OBJECTIVE: To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry.
METHODS: Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans-ethnic meta-analysis.
RESULTS: The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76%) were significantly (P-value≤9.1×10(-5)) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs.
CONCLUSION: Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist.
1 aAvery, Christy, L1 aWassel, Christina, L1 aRichard, Melissa, A1 aHighland, Heather, M1 aBien, Stephanie1 aZubair, Niha1 aSoliman, Elsayed, Z1 aFornage, Myriam1 aBielinski, Suzette, J1 aTao, Ran1 aSeyerle, Amanda, A1 aShah, Sanjiv, J1 aLloyd-Jones, Donald, M1 aBuyske, Steven1 aRotter, Jerome, I1 aPost, Wendy, S1 aRich, Stephen, S1 aHindorff, Lucia, A1 aJeff, Janina, M1 aShohet, Ralph, V1 aSotoodehnia, Nona1 aLin, Dan, Yu1 aWhitsel, Eric, A1 aPeters, Ulrike1 aHaiman, Christopher, A1 aCrawford, Dana, C1 aKooperberg, Charles1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/746302189nas a2200181 4500008004100000022001400041245014000055210006900195260001600264520159400280100001501874700001601889700001401905700001601919700001801935700001801953856003601971 2018 eng d a1590-372900aFasting and post-glucose load measures of insulin resistance and risk of incident atrial fibrillation: The Cardiovascular Health Study.0 aFasting and postglucose load measures of insulin resistance and c2018 Mar 023 aBACKGROUND AND AIMS: Existing literature in individuals without diabetes has not demonstrated a relationship between IR and incident AF; however, data are limited and only fasting glucose measures of IR were assessed. We evaluated the relationship of both fasting and post-glucose load IR measures with the development of atrial fibrillation in nondiabetic older adults.
METHODS AND RESULTS: Among Cardiovascular Health Study participants, a population-based cohort of 5888 adults aged 65 years or older enrolled in two waves (1989-1990 and 1992-1993), those without prevalent AF or diabetes and with IR measures at baseline were followed for the development of AF, identified by follow-up visit electrocardiograms, hospital discharge diagnosis coding, or Medicare claims data, through 2014. Fasting IR was determined by the homeostatic model of insulin resistance (HOMA-IR) and post-glucose load IR was determined by the Gutt index. Cox proportional hazards models were used to determine the association of IR with risk of AF. Analyses included 3601 participants (41% men) with a mean age of 73 years. Over a median follow-up of 12.3 years, 1443 (40%) developed AF. After multivariate adjustment, neither HOMA-IR nor the Gutt index was associated with risk of developing AF [hazard ratios (95% confidence intervals): 0.96 (0.90, 1.03) for 1-SD increase in HOMA-IR and 1.03 (0.97, 1.10) for 1-SD decrease in the Gutt index].
CONCLUSIONS: We found no evidence of an association between either fasting or post-glucose load IR measures and incident AF.
1 aGarg, P, K1 aBiggs, M, L1 aKaplan, R1 aKizer, J, R1 aHeckbert, S R1 aMukamal, K, J uhttps://chs-nhlbi.org/node/766602617nas a2200301 4500008004100000022001400041245008000055210006900135260001200204300001200216490000700228520176700235653001502002653002302017653003202040653002002072653001302092653001102105653002702116653002402143653001702167100001902184700002002203700001702223700002102240700001802261856003602279 2018 eng d a1098-227200aFastSKAT: Sequence kernel association tests for very large sets of markers.0 aFastSKAT Sequence kernel association tests for very large sets o c2018 09 a516-5270 v423 aThe sequence kernel association test (SKAT) is widely used to test for associations between a phenotype and a set of genetic variants that are usually rare. Evaluating tail probabilities or quantiles of the null distribution for SKAT requires computing the eigenvalues of a matrix related to the genotype covariance between markers. Extracting the full set of eigenvalues of this matrix (an
BACKGROUND: We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D).
METHODS AND FINDINGS: Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist.
CONCLUSIONS: In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.
10aAged10aAustralia10aBiomarkers10aDairy Products10aDiabetes Mellitus, Type 210aDietary Fats10aEurope10aFatty Acids10aFatty Acids, Monounsaturated10aFemale10aHumans10aIncidence10aMale10aMiddle Aged10aProspective Studies10aSex Factors10aTaiwan10aUnited States1 aImamura, Fumiaki1 aFretts, Amanda1 aMarklund, Matti1 aKorat, Andres, V Ardisson1 aYang, Wei-Sin1 aLankinen, Maria1 aQureshi, Waqas1 aHelmer, Catherine1 aChen, Tzu-An1 aWong, Kerry1 aBassett, Julie, K1 aMurphy, Rachel1 aTintle, Nathan1 aYu, Chaoyu, Ian1 aBrouwer, Ingeborg, A1 aChien, Kuo-Liong1 aFrazier-Wood, Alexis, C1 aDel Gobbo, Liana, C1 aDjoussé, Luc1 aGeleijnse, Johanna, M1 aGiles, Graham, G1 ade Goede, Janette1 aGudnason, Vilmundur1 aHarris, William, S1 aHodge, Allison1 aHu, Frank1 aKoulman, Albert1 aLaakso, Markku1 aLind, Lars1 aLin, Hung-Ju1 aMcKnight, Barbara1 aRajaobelina, Kalina1 aRiserus, Ulf1 aRobinson, Jennifer, G1 aSamieri, Cecilia1 aSiscovick, David, S1 aSoedamah-Muthu, Sabita, S1 aSotoodehnia, Nona1 aSun, Qi1 aTsai, Michael, Y1 aUusitupa, Matti1 aWagenknecht, Lynne, E1 aWareham, Nick, J1 aWu, Jason, HY1 aMicha, Renata1 aForouhi, Nita, G1 aLemaitre, Rozenn, N1 aMozaffarian, Dariush1 aInterAct Consortium1 aFatty Acids and Outcomes Research Consortium (FORCE) uhttps://chs-nhlbi.org/node/804102360nas a2200229 4500008004100000022001400041245010200055210006900157260001600226300001200242490000600254520167100260100002001931700001901951700001901970700002001989700001902009700002402028700001802052700002402070856003602094 2020 eng d a2047-998000aFatty Acid Binding Protein-4 and Risk of Cardiovascular Disease: The Cardiovascular Health Study.0 aFatty Acid Binding Protein4 and Risk of Cardiovascular Disease T c2020 Apr 07 ae0140700 v93 aBackground FABP-4 (fatty acid binding protein-4) is a lipid chaperone in adipocytes and has been associated with prognosis in selected clinical populations. We investigated the associations between circulating FABP-4, risk of incident cardiovascular disease (CVD), and risk of CVD mortality among older adults with and without established CVD. Methods and Results In the Cardiovascular Health Study, we measured FABP4 levels in stored specimens from the 1992-993 visit and followed participants for incident CVD if they were free of prevalent CVD at baseline and for CVD mortality through June 2015. We used Cox regression to estimate hazard ratios for incident CVD and CVD mortality per doubling in serum FABP-4 adjusted for age, sex, race, field center, waist circumference, blood pressure, lipids, fasting glucose, and C-reactive protein. Among 4026 participants free of CVD and 681 with prevalent CVD, we documented 1878 cases of incident CVD and 331 CVD deaths, respectively. In adjusted analyses, FABP-4 was modestly associated with risk of incident CVD (mean, 34.24; SD, 18.90; HR, 1.10 per doubling in FABP-4, 95% CI, 1.00-1.21). In contrast, FABP-4 was more clearly associated with risk of CVD mortality among participants without (HR hazard ratio 1.24, 95% CI, 1.10-1.40) or with prevalent CVD (HR hazard ratio 1.57, 95% CI, 1.24-1.98). These associations were not significantly modified by sex, age, and waist circumference. Conclusions Serum FABP-4 is modestly associated with risk of incident CVD even after adjustment for standard risk factors, but more strongly associated with CVD mortality among older adults with and without established CVD.
1 aEgbuche, Obiora1 aBiggs, Mary, L1 aIx, Joachim, H1 aKizer, Jorge, R1 aLyles, Mary, F1 aSiscovick, David, S1 aDjoussé, Luc1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/836904202nas a2200745 4500008004100000245013400041210006900175260000700244300001300251490000700264520222500271100001602496700001902512700001702531700002602548700001702574700001702591700001602608700001502624700001702639700002102656700001302677700002002690700001502710700001502725700001502740700002002755700001802775700001702793700001702810700002202827700001602849700002202865700001802887700001702905700001702922700001902939700001402958700001102972700001602983700001502999700001303014700001603027700001703043700002003060700001603080700002103096700001603117700001303133700002203146700002703168700002003195700001203215700001703227700002203244700001703266700002403283700002003307700001803327700001403345700002103359700002003380700002003400856003603420 2020 eng d00a{Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies0 aFatty acids in the de novo lipogenesis pathway and incidence of c06 ae10031020 v173 aDe novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D).\ Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors.\ Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.1 aImamura, F.1 aFretts, A., M.1 aMarklund, M.1 aKorat, A., V. Ardisso1 aYang, W., S.1 aLankinen, M.1 aQureshi, W.1 aHelmer, C.1 aChen, T., A.1 aVirtanen, J., K.1 aWong, K.1 aBassett, J., K.1 aMurphy, R.1 aTintle, N.1 aYu, C., I.1 aBrouwer, I., A.1 aChien, K., L.1 aChen, Y., Y.1 aWood, A., C.1 aDel Gobbo, L., C.1 aDjousse, L.1 aGeleijnse, J., M.1 aGiles, G., G.1 ade Goede, J.1 aGudnason, V.1 aHarris, W., S.1 aHodge, A.1 aHu, F.1 aKoulman, A.1 aLaakso, M.1 aLind, L.1 aLin, H., J.1 aMcKnight, B.1 aRajaobelina, K.1 aRiserus, U.1 aRobinson, J., G.1 aSamieri, C.1 aSenn, M.1 aSiscovick, D., S.1 aSoedamah-Muthu, S., S.1 aSotoodehnia, N.1 aSun, Q.1 aTsai, M., Y.1 aTuomainen, T., P.1 aUusitupa, M.1 aWagenknecht, L., E.1 aWareham, N., J.1 aWu, J., H. Y.1 aMicha, R.1 aLemaitre, R., N.1 aMozaffarian, D.1 aForouhi, N., G. uhttps://chs-nhlbi.org/node/845502481nas a2200169 4500008004100000022001400041245010400055210006900159260001300228300001200241490000700253520194500260100002702205700002302232700002002255856003602275 2020 eng d a1943-365400aFEV as a Standalone Spirometric Predictor and the Attributable Fraction for Death in Older Persons.0 aFEV as a Standalone Spirometric Predictor and the Attributable F c2020 Feb a217-2260 v653 aBACKGROUND: Commonly used thresholds for staging FEV have not been evaluated as standalone spirometric predictors of death in older persons. Specifically, the proportion of deaths attributed to a reduced FEV, when staged by commonly used thresholds in L, percent of predicted (% pred), and Z scores, has not been previously reported.
METHODS: In 4,232 white persons ≥ 65 y old, sampled from the Cardiovascular Health Study, FEV was stratified as stage 1 (FEV ≥ 2.00 L, ≥80% pred, and Z score ≥-1.64), stage 2 (FEV 1.50-1.99 L, 50-79%pred, and Z score -2.55 to -1.63), and stage 3 (FEV < 1.50 L, < 50% pred, and Z score < -2.55). Notably, a Z score threshold of -1.64 defines normal-for-age lung function as the lower limit of normal (ie, 5th percentile of distribution), and accounts for differences in age, sex, height, and ethnicity. Next, adjusted odds ratios and average attributable fractions for 10-y all-cause mortality were calculated, comparing FEV stages 2 and 3 against stage 1, expressed in L, % pred, and Z scores. The average attributable fraction estimates the proportion of deaths attributed to a predictor by combining the prevalence of the predictor with the relative risk of death conferred by that predictor.
RESULTS: FEV stage 2 and 3 in L, % pred, and Z scores yielded similar adjusted odds ratios of death: 1.40-1.51 for stage 2 and 2.35-2.66 for stage 3. Conversely, FEV stages 2 and 3 in L, % pred, and Z scores differed in prevalence: 12.8-28.6% for stage 2 and 6.4-17.5% for stage 3, and also differed in the adjusted average attributable fraction for death: 3.2-6.4% for stage 2 and 4.5-9.1% for stage 3.
CONCLUSIONS: In older persons, the proportion of deaths attributed to a reduced FEV is best stratified by Z score staging thresholds because these yield a similar relative risk of death but a more age- and sex-appropriate prevalence of FEV stage.
1 aFragoso, Carlos, A Vaz1 aVan Ness, Peter, H1 aMcAvay, Gail, J uhttps://chs-nhlbi.org/node/829103927nas a2200709 4500008004100000022001400041245011200055210006900167260001600236520183400252100002102086700001302107700001702120700002902137700002002166700003002186700002202216700002502238700001702263700001302280700002002293700002202313700002302335700002202358700001802380700002302398700002402421700002902445700002702474700002102501700002902522700001902551700002102570700002302591700002102614700002302635700002802658700001802686700001902704700001902723700002102742700002002763700001802783700002502801700001902826700003202845700002902877700002002906700002102926700002302947700001902970700001802989700002203007700002203029700002403051700002103075700002403096700002003120700001803140700002303158856003603181 2021 eng d a1538-783600aFGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.0 aFGL1 as a modulator of plasma Ddimer levels Exomewide marker ana c2021 Apr 203 aBACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.
OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.
METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.
RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.
CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.
1 aThibord, Florian1 aSong, Ci1 aPattee, Jack1 aRodriguez, Benjamin, A T1 aChen, Ming-Huei1 aO'Donnell, Christopher, J1 aKleber, Marcus, E1 aDelgado, Graciela, E1 aGuo, Xiuqing1 aYao, Jie1 aTaylor, Kent, D1 aOzel, Ayse, Bilge1 aBrody, Jennifer, A1 aMcKnight, Barbara1 aGyorgy, Beata1 aSimonsick, Eleanor1 aLeonard, Hampton, L1 aCarrasquilla, Germán, D1 aGuindo-Martinez, Marta1 aSilveira, Angela1 aTemprano-Sagrera, Gerard1 aYanek, Lisa, R1 aBecker, Diane, M1 aMathias, Rasika, A1 aBecker, Lewis, C1 aRaffield, Laura, M1 aKilpeläinen, Tuomas, O1 aGrarup, Niels1 aPedersen, Oluf1 aHansen, Torben1 aLinneberg, Allan1 aHamsten, Anders1 aWatkins, Hugh1 aSabater-Lleal, Maria1 aNalls, Mike, A1 aTrégouët, David-Alexandre1 aMorange, Pierre-Emmanuel1 aPsaty, Bruce, M1 aTracy, Russel, P1 aSmith, Nicholas, L1 aDesch, Karl, C1 aCushman, Mary1 aRotter, Jerome, I1 ade Vries, Paul, S1 aPankratz, Nathan, D1 aFolsom, Aaron, R1 aMorrison, Alanna, C1 aMärz, Winfried1 aTang, Weihong1 aJohnson, Andrew, D uhttps://chs-nhlbi.org/node/879102585nas a2200217 4500008004100000022001400041245012500055210006900180260001600249520188200265100001902147700002102166700002102187700001902208700002202227700002402249700001802273700002002291700002002311856003602331 2022 eng d a1758-535X00aFasting and Post-Load Glucose and Non-Esterified Fatty Acids and Risk of Heart Failure and its Subtypes in Older Adults.0 aFasting and PostLoad Glucose and NonEsterified Fatty Acids and R c2022 Nov 143 aBACKGROUND: Glucose and non-esterified fatty acids (NEFA) are myocardial fuels whose fasting and post-prandial levels are under different homeostatic regulation. The relationships of fasting and post-load glucose and NEFA with incident heart failure (HF) remain incompletely defined.
METHODS: Serum glucose and NEFA were measured during fasting and 2 hours post oral glucose tolerance test, performed in Cardiovascular Health Study participants not receiving hypoglycemic medication. Participants with prevalent HF or lacking relevant data were excluded. Outcomes were incident HF (primary), and HF with preserved (HFpEF) and reduced (HFrEF) ejection fraction (secondary).
RESULTS: Among 2238 participants (age 78±4) with median follow-up of 9.9 years, there were 737 HF events. After adjustment for demographic and lifestyle factors, both fasting (HR=1.11 per SD [95% CI=1.01-1.23], p=0.040) and post-load (HR=1.14 per SD [1.05-1.24], p=0.002) glucose were significantly associated with incident HF. No association was seen for fasting or post-load NEFA. Upon mutual adjustment, only post-load glucose (HR=1.11 [1.003-1.22], p=0.044), but not fasting glucose (HR=1.06 [0.94-1.20], p=0.340), remained associated with HF. Further adjustment for cardiovascular disease and other risk factors in the causal pathway did not affect the association for post-load glucose, but eliminated that for fasting glucose. Associations for fasting and post-load glucose appeared stronger with higher adiposity, and were observed specifically for HFrEF, but not HFpEF.
CONCLUSIONS: Fasting and post-load glucose, but not NEFA, were associated with incident HF. The association was especially robust for post-load glucose, suggesting that pathways involved in post-prandial dysglycemia could offer new targets for HF prevention late in life.
1 aOesterle, Adam1 aBůzková, Petra1 aPellegrini, Cara1 aHirsch, Calvin1 aTracy, Russell, P1 aSiscovick, David, S1 aDjoussé, Luc1 aMukamal, Ken, J1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/925702666nas a2200385 4500008004100000022001400041245009400055210006900149260001600218300001400234490000800248520159500256653000901851653001801860653003001878653001201908653003101920653001101951653001201962653001101974653001201985653002301997653000902020653002402029100002302053700001902076700001902095700002202114700002202136700002402158700001802182700002402200700002002224856003602244 2022 eng d a1476-625600aFasting and Postload Nonesterified Fatty Acids and Glucose Dysregulation in Older Adults.0 aFasting and Postload Nonesterified Fatty Acids and Glucose Dysre c2022 Jun 27 a1235-12470 v1913 aTo evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989-1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996-1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio = 1.18, 95% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio = 1.12, 95% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders.
10aAged10aBlood Glucose10aDiabetes Mellitus, Type 210aFasting10aFatty Acids, Nonesterified10aFemale10aGlucose10aHumans10aInsulin10aInsulin Resistance10aMale10aProspective Studies1 aShitole, Sanyog, G1 aBiggs, Mary, L1 aIx, Joachim, H1 aFretts, Amanda, M1 aTracy, Russell, P1 aSiscovick, David, S1 aDjoussé, Luc1 aMukamal, Kenneth, J1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/929502314nas a2200181 4500008004100000022001400041245016400055210006900219260001600288520166700304100001901971700002401990700002002014700001702034700002402051700002102075856003602096 2022 eng d a1590-372900aFishing for health: Neighborhood variation in fish intake, fish quality and association with stroke risk among older adults in the Cardiovascular Health Study.0 aFishing for health Neighborhood variation in fish intake fish qu c2022 Mar 123 aBACKGROUND AND AIMS: Fish consumption has been associated with better health outcomes. Dietary patterns may vary substantially by neighborhood of residence. However, it is unclear if the benefits of a healthy diet are equivalent in different communities. This study examines associations of fish consumption with stroke incidence and stroke risk factors, and whether these differ by neighborhood socioeconomic status (NSES).
METHODS AND RESULTS: We studied 4007 participants in the Cardiovascular Health Study who were 65 years or older and recruited between 1989 and 1990 from 4 US communities. Outcomes included fish consumption type (bakes/broiled vs. fried) and frequency, stroke incidence, and stroke risk factors. Multilevel regressions models were used to estimate fish consumption associations with clinical outcomes. Lower NSES was associated with higher consumption of fried fish (aOR = 1.47, 95% CI: 1.10-1.98) and lower consumption of non-fried fish (0.64, 0.47-0.86). Frequent fried fish (11.9 vs. 9.2 person-years for at least once weekly vs. less than once a month, respectively) and less frequent non-fried fish (17.7 vs. 9.6 person-years for less than once a month vs. at least once weekly, respectively) were independently associated with an increased risk of stroke (p-values < 0.05). However, among those with similar levels of healthy fish consumption, residents with low NSES had less benefit on stroke risk reduction, compared with high NSES.
CONCLUSION: Fish consumption type and frequency both impact stroke risk. Benefits of healthy fish consumption differ by neighborhood socioeconomic status.
1 aLiang, Li-Jung1 aCasillas, Alejandra1 aLongstreth, W T1 aPhanVo, Lynn1 aVassar, Stefanie, D1 aBrown, Arleen, F uhttps://chs-nhlbi.org/node/902404304nas a2201045 4500008004100000022001400041245011400055210006900169260001300238300001400251490000700265520128500272653002201557653001101579653003401590653001101624653001401635653002801649100001401677700001401691700001701705700002201722700003201744700002401776700001801800700001501818700001401833700001401847700001601861700002101877700001801898700002401916700001901940700002501959700001901984700002102003700002202024700002302046700001902069700002402088700001902112700002502131700002202156700002202178700002802200700002302228700002302251700002502274700001702299700002102316700002402337700001902361700002102380700002002401700002102421700002202442700002002464700002302484700002002507700002502527700002202552700002402574700001702598700002602615700002602641700002402667700002002691700002302711700001902734700002502753700003402778700002102812700002102833700002302854700002002877700002202897700002702919700002102946700002102967700001902988700001403007700002203021700002303043700002303066700002003089700001603109710006503125710003203190856003603222 2022 eng d a1548-710500aA framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies.0 aframework for detecting noncoding rarevariant associations of la c2022 Dec a1599-16110 v193 aLarge-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.
10aGenetic Variation10aGenome10aGenome-Wide Association Study10aHumans10aPhenotype10aWhole Genome Sequencing1 aLi, Zilin1 aLi, Xihao1 aZhou, Hufeng1 aGaynor, Sheila, M1 aSelvaraj, Margaret, Sunitha1 aArapoglou, Theodore1 aQuick, Corbin1 aLiu, Yaowu1 aChen, Han1 aSun, Ryan1 aDey, Rounak1 aArnett, Donna, K1 aAuer, Paul, L1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlackwell, Thomas, W1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aBrody, Jennifer, A1 aCade, Brian, E1 aConomos, Matthew, P1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 ade Vries, Paul, S1 aDuggirala, Ravindranath1 aFranceschini, Nora1 aFreedman, Barry, I1 aGöring, Harald, H H1 aGuo, Xiuqing1 aKalyani, Rita, R1 aKooperberg, Charles1 aKral, Brian, G1 aLange, Leslie, A1 aLin, Bridget, M1 aManichaikul, Ani1 aManning, Alisa, K1 aMartin, Lisa, W1 aMathias, Rasika, A1 aMeigs, James, B1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aNaseri, Take1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aRedline, Susan1 aReiner, Alexander, P1 aReupena, Muagututi'a, Sefuiva1 aRice, Kenneth, M1 aRich, Stephen, S1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aTaub, Margaret, A1 aVasan, Ramachandran, S1 aWeeks, Daniel, E1 aWilson, James, G1 aYanek, Lisa, R1 aZhao, Wei1 aRotter, Jerome, I1 aWiller, Cristen, J1 aNatarajan, Pradeep1 aPeloso, Gina, M1 aLin, Xihong1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/925304551nas a2200505 4500008004100000022001400041245010500055210006900160260001600229520307000245100002203315700001803337700002103355700001803376700002803394700002203422700002203444700001903466700002203485700002103507700002003528700001803548700002503566700002203591700002003613700001803633700001803651700002103669700002003690700002403710700002003734700001903754700002403773700002003797700002203817700002103839700002103860700001903881700002403900700002503924700002103949700002303970700001603993856003604009 2023 eng d a1539-370400aFactors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.0 aFactors Associated With Circulating Sex Hormones in Men Individu c2023 Aug 293 aBACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements.
PURPOSE: To clarify factors associated with variations in sex hormone concentrations.
DATA SOURCES: Systematic literature searches (to July 2019).
STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry.
DATA EXTRACTION: Individual participant data (IPD) (9 studies; = 21 074) and aggregate data (2 studies; = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted.
DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years.
LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data.
CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer.
PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).
1 aMarriott, Ross, J1 aMurray, Kevin1 aAdams, Robert, J1 aAntonio, Leen1 aBallantyne, Christie, M1 aBauer, Douglas, C1 aBhasin, Shalender1 aBiggs, Mary, L1 aCawthon, Peggy, M1 aCouper, David, J1 aDobs, Adrian, S1 aFlicker, Leon1 aHandelsman, David, J1 aHankey, Graeme, J1 aHannemann, Anke1 aHaring, Robin1 aHsu, Benjumin1 aKarlsson, Magnus1 aMartin, Sean, A1 aMatsumoto, Alvin, M1 aMellström, Dan1 aOhlsson, Claes1 aO'Neill, Terence, W1 aOrwoll, Eric, S1 aQuartagno, Matteo1 aShores, Molly, M1 aSteveling, Antje1 aTivesten, Åsa1 aTravison, Thomas, G1 aVanderschueren, Dirk1 aWittert, Gary, A1 aWu, Frederick, C W1 aYeap, Bu, B uhttps://chs-nhlbi.org/node/948704426nas a2200493 4500008004100000022001400041245010800055210006900163260001600232520296700248100001603215700002403231700002403255700001903279700001603298700002203314700002603336700002103362700002103383700001503404700002003419700002303439700002203462700002003484700002103504700002803525700002203553700002003575700002703595700001603622700002003638700001903658700002003677700002703697700002603724700002103750700002103771700002103792700001703813700001903830700002603849700002103875856003603896 2024 eng d a2380-659100aFamilial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol.0 aFamilial Hypercholesterolemia Variant and Cardiovascular Risk in c2024 Jan 313 aIMPORTANCE: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.
OBJECTIVE: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.
DESIGN, SETTING, AND PARTICIPANTS: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.
EXPOSURES: LDL-C, cumulative past LDL-C, FH variant status.
MAIN OUTCOMES AND MEASURES: Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.
RESULTS: Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant.
CONCLUSIONS AND RELEVANCE: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.
1 aZhang, Yiyi1 aDron, Jacqueline, S1 aBellows, Brandon, K1 aKhera, Amit, V1 aLiu, Junxiu1 aBalte, Pallavi, P1 aOelsner, Elizabeth, C1 aAmr, Sami, Samir1 aLebo, Matthew, S1 aNagy, Anna1 aPeloso, Gina, M1 aNatarajan, Pradeep1 aRotter, Jerome, I1 aWiller, Cristen1 aBoerwinkle, Eric1 aBallantyne, Christie, M1 aLutsey, Pamela, L1 aFornage, Myriam1 aLloyd-Jones, Donald, M1 aHou, Lifang1 aPsaty, Bruce, M1 aBis, Joshua, C1 aFloyd, James, S1 aVasan, Ramachandran, S1 aHeard-Costa, Nancy, L1 aCarson, April, P1 aHall, Michael, E1 aRich, Stephen, S1 aGuo, Xiuqing1 aKazi, Dhruv, S1 ade Ferranti, Sarah, D1 aMoran, Andrew, E uhttps://chs-nhlbi.org/node/9620