@article {1066, title = {Prevalence, prognosis, and implications of isolated minor nonspecific ST-segment and T-wave abnormalities in older adults: Cardiovascular Health Study.}, journal = {Circulation}, volume = {118}, year = {2008}, month = {2008 Dec 16}, pages = {2790-6}, abstract = {

BACKGROUND: The prevalence and prognostic significance of isolated minor nonspecific ST-segment and T-wave abnormalities (NSSTTAs) in older adults are poorly understood.

METHODS AND RESULTS: Cardiovascular Health Study participants free of both clinical cardiovascular disease and major ECG abnormalities were included. We examined the prospective association of isolated minor NSSTTAs (defined by Minnesota Codes 4-3, 4-4, 5-3, and 5-4) with total, cardiovascular, and coronary mortality and incident nonfatal myocardial infarction. Among 3224 participants (61.9\% women; mean age, 72 years), 233 (7.2\%) had isolated NSSTTAs at baseline. Covariates associated with isolated NSSTTAs included older age, nonwhite race (20.5\% of blacks versus 4.8\% of whites; P<0.001), diabetes, and higher blood pressure and body mass index but not the presence of subclinical cardiovascular disease. After 39 518 person-years of follow-up, the presence of isolated NSSTTAs was associated with significantly increased risk for coronary heart disease mortality (multivariable-adjusted hazards ratio, 1.76; 95\% CI, 1.18 to 2.61) but not with incident nonfatal myocardial infarction (multivariable-adjusted hazards ratio, 0.71; 95\% CI, 0.43 to 1.17). The association of isolated NSSTTAs with coronary death was independent of subclinical atherosclerosis and left ventricular mass measures. In secondary analyses, among those with cardiac death, there was a significantly higher rate of primary arrhythmic death (32.3\% versus 15.4\%; P=0.02) in participants with isolated NSSTTAs versus those without NSSTTAs.

CONCLUSIONS: Isolated NSSTTAs are common in older Americans and are associated with significantly increased risk for coronary death. However, isolated NSSTTAs are not associated with incident nonfatal myocardial infarction, suggesting that they are associated particularly with increased risk for primary arrhythmic death.

}, keywords = {Age Factors, Aged, Arrhythmias, Cardiac, Cardiovascular Diseases, Cohort Studies, Electrocardiography, Female, Health Status, Humans, Male, Middle Aged, Prevalence, Prognosis, Prospective Studies}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.108.772541}, author = {Kumar, Anita and Prineas, Ronald J and Arnold, Alice M and Psaty, Bruce M and Furberg, Curt D and Robbins, John and Lloyd-Jones, Donald M} } @article {1292, title = {Association of annular calcification and aortic valve sclerosis with brain findings on magnetic resonance imaging in community dwelling older adults: the cardiovascular health study.}, journal = {J Am Coll Cardiol}, volume = {57}, year = {2011}, month = {2011 May 24}, pages = {2172-80}, abstract = {

OBJECTIVES: The objective of this study was to investigate the associations of mitral annular calcification, aortic annular calcification, and aortic valve sclerosis with covert magnetic resonance imaging (MRI)-defined brain infarcts.

BACKGROUND: Clinically silent brain infarcts defined by MRI are associated with increased risk for cognitive decline, dementia, and future overt stroke. Left-sided cardiac valvular and annular calcifications are suspected as risk factors for clinical ischemic stroke.

METHODS: A total of 2,680 CHS (Cardiovascular Health Study) participants without clinical histories of stroke or transient ischemic attack underwent brain MRI in 1992 and 1993, 1 to 2 years before echocardiographic exams (1994 to 1995).

RESULTS: The mean age of the participants was 74.5 {\textpm} 4.8 years, and 39.3\% were men. The presence of any annular or valvular calcification (mitral annular calcification, aortic annular calcification, or aortic valve sclerosis), mitral annular calcification alone, or aortic annular calcification alone was significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular or valve calcification remained associated with covert brain infarcts (risk ratio: 1.24; 95\% confidence interval: 1.05 to 1.47). The degree of annular or valvular calcification severity showed a direct relation with the presence of covert MRI findings.

CONCLUSIONS: Left-sided cardiac annular and valvular calcifications are associated with covert MRI-defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening in the progression of annular and valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk for cognitive impairment and future stroke.

}, keywords = {Aged, Aortic Valve Stenosis, Brain, Brain Infarction, Calcinosis, Cohort Studies, Female, Humans, Magnetic Resonance Imaging, Male, Mitral Valve Stenosis, Retrospective Studies}, issn = {1558-3597}, doi = {10.1016/j.jacc.2011.01.034}, author = {Rodriguez, Carlos J and Bartz, Traci M and Longstreth, W T and Kizer, Jorge R and Barasch, Eddy and Lloyd-Jones, Donald M and Gottdiener, John S} } @article {1316, title = {Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute{\textquoteright}s Candidate Gene Association Resource (CARe) project.}, journal = {Circ Cardiovasc Genet}, volume = {4}, year = {2011}, month = {2011 Oct}, pages = {557-64}, abstract = {

BACKGROUND: The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.

METHODS AND RESULTS: We examined a panel of approximately 50,000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18,524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute{\textquoteright}s Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95\% confidence interval [CI], 0.85-0.95; P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95\% CI, 0.72-1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95\% CI, 0.57-0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95\% CI, 1.16-1.69; P=0.0005).

CONCLUSIONS: In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.

}, keywords = {African Americans, Aged, Alleles, Atrial Fibrillation, Chromosomes, Human, Pair 4, Cohort Studies, European Continental Ancestry Group, Female, Humans, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Polymorphism, Single Nucleotide, Receptors, Interleukin-6, Risk Factors, Stroke, United States}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.110.959197}, author = {Schnabel, Renate B and Kerr, Kathleen F and Lubitz, Steven A and Alkylbekova, Ermeg L and Marcus, Gregory M and Sinner, Moritz F and Magnani, Jared W and Wolf, Philip A and Deo, Rajat and Lloyd-Jones, Donald M and Lunetta, Kathryn L and Mehra, Reena and Levy, Daniel and Fox, Ervin R and Arking, Dan E and Mosley, Thomas H and M{\"u}ller-Nurasyid, Martina and Young, Taylor R and Wichmann, H-Erich and Seshadri, Sudha and Farlow, Deborah N and Rotter, Jerome I and Soliman, Elsayed Z and Glazer, Nicole L and Wilson, James G and Breteler, Monique M B and Sotoodehnia, Nona and Newton-Cheh, Christopher and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T and Alonso, Alvaro and Benjamin, Emelia J and Heckbert, Susan R} } @article {1294, title = {Systolic blood pressure and incident heart failure in the elderly. The Cardiovascular Health Study and the Health, Ageing and Body Composition Study.}, journal = {Heart}, volume = {97}, year = {2011}, month = {2011 Aug}, pages = {1304-11}, abstract = {

BACKGROUND: The exact form of the association between systolic blood pressure (SBP) and heart failure (HF) risk in the elderly remains incompletely defined, especially in individuals not receiving antihypertensive drugs.

OBJECTIVE: To examine the association between SBP and HF risk in the elderly.

DESIGN: Competing-risks proportional hazards modelling of incident HF risk, using 10-year follow-up data from two NIH-sponsored cohort studies: the Cardiovascular Health Study (inception: 1989-90 and 1992-3) and the Health ABC Study (inception: 1997-8).

SETTING: Community-based cohorts.

PARTICIPANTS: 4408 participants (age, 72.8 (4.9) years; 53.1\% women, 81.7\% white; 18.3\% black) without prevalent HF and not receiving antihypertensive drugs at baseline.

MAIN OUTCOME MEASURES: Incident HF, defined as first adjudicated hospitalisation for HF.

RESULTS: Over 10 years, 493 (11.2\%) participants developed HF. Prehypertension (120-139 mm Hg), stage 1 (140-159 mm Hg), and stage 2 (>=160 mm Hg) hypertension were associated with escalating HF risk; HRs versus optimal SBP (<120 mm Hg) in competing-risks models controlling for clinical characteristics were 1.63 (95\% CI 1.23 to 2.16; p=0.001), 2.21 (95\% CI 1.65 to 2.96; p<0.001) and 2.60 (95\% CI 1.85 to 3.64; p<0.001), respectively. Overall 255/493 (51.7\%) HF events occurred in participants with SBP <140 mm Hg at baseline. Increasing SBP was associated with higher HF risk in women than in men; no race-SBP interaction was seen. In analyses with continuous SBP, HF risk had a continuous positive association with SBP to levels as low as 113 mm Hg in men and 112 mm Hg in women.

CONCLUSIONS: There is a continuous positive association between SBP and HF risk in the elderly for levels of SBP as low as <115 mm Hg; over half of incident HF events occur in individuals with SBP <140 mm Hg.

}, keywords = {Aged, Aged, 80 and over, Aging, Blood Pressure, Body Composition, Epidemiologic Methods, Female, Heart Failure, Humans, Hypertension, Male, Myocardial Infarction, Sex Factors, Stroke, Stroke Volume}, issn = {1468-201X}, doi = {10.1136/hrt.2011.225482}, author = {Butler, Javed and Kalogeropoulos, Andreas P and Georgiopoulou, Vasiliki V and Bibbins-Domingo, Kirsten and Najjar, Samer S and Sutton-Tyrrell, Kim C and Harris, Tamara B and Kritchevsky, Stephen B and Lloyd-Jones, Donald M and Newman, Anne B and Psaty, Bruce M} } @article {1408, title = {Development and validation of a coronary risk prediction model for older U.S. and European persons in the Cardiovascular Health Study and the Rotterdam Study.}, journal = {Ann Intern Med}, volume = {157}, year = {2012}, month = {2012 Sep 18}, pages = {389-97}, abstract = {

BACKGROUND: Risk scores for prediction of coronary heart disease (CHD) in older adults are needed.

OBJECTIVE: To develop a sex-specific CHD risk prediction model for older adults that accounts for competing risks for death.

DESIGN: 2 observational cohort studies, using data from 4946 participants in the Cardiovascular Health Study (CHS) and 4303 participants in the Rotterdam Study (RS).

SETTING: Community settings in the United States (CHS) and Rotterdam, the Netherlands (RS).

PARTICIPANTS: Persons aged 65 years or older who were free of cardiovascular disease.

MEASUREMENTS: A composite of nonfatal myocardial infarction and coronary death.

RESULTS: During a median follow-up of 16.5 and 14.9 years, 1166 CHS and 698 RS participants had CHD events, respectively. Deaths from noncoronary causes largely exceeded the number of CHD events, complicating accurate CHD risk predictions. The prediction model had moderate ability to discriminate between events and nonevents (c-statistic, 0.63 in both U.S. and European men and 0.67 and 0.68 in U.S. and European women). The model was well-calibrated; predicted risks were in good agreement with observed risks. Compared with the Framingham point scores, the prediction model classified elderly U.S. persons into higher risk categories but elderly European persons into lower risk categories. Differences in classification accuracy were not consistent and depended on cohort and sex. Adding newer cardiovascular risk markers to the model did not substantially improve performance.

LIMITATION: The model may be less applicable in nonwhite populations, and the comparison Framingham model was not designed for adults older than 79 years.

CONCLUSION: A CHD risk prediction model that accounts for deaths from noncoronary causes among older adults provided well-calibrated risk estimates but was not substantially more accurate than Framingham point scores. Moreover, adding newer risk markers did not improve accuracy. These findings emphasize the difficulties of predicting CHD risk in elderly persons and the need to improve these predictions.

PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; The Netherlands Organisation for Scientific Research; and the Netherlands Organisation for Health Research and Development.

}, keywords = {Aged, Aged, 80 and over, Algorithms, Cause of Death, Coronary Disease, European Continental Ancestry Group, Female, Humans, Incidence, Male, Models, Statistical, Multivariate Analysis, Netherlands, Prospective Studies, Risk Assessment, Risk Factors, United States}, issn = {1539-3704}, doi = {10.7326/0003-4819-157-6-201209180-00002}, author = {Koller, Michael T and Leening, Maarten J G and Wolbers, Marcel and Steyerberg, Ewout W and Hunink, M G Myriam and Schoop, Rotraut and Hofman, Albert and Bucher, Heiner C and Psaty, Bruce M and Lloyd-Jones, Donald M and Witteman, Jacqueline C M} } @article {6085, title = {Impact of blood pressure and blood pressure change during middle age on the remaining lifetime risk for cardiovascular disease: the cardiovascular lifetime risk pooling project.}, journal = {Circulation}, volume = {125}, year = {2012}, month = {2012 Jan 03}, pages = {37-44}, abstract = {

BACKGROUND: Prior estimates of lifetime risk (LTR) for cardiovascular disease (CVD) examined the impact of blood pressure (BP) at the index age and did not account for changes in BP over time. We examined how changes in BP during middle age affect LTR for CVD, coronary heart disease, and stroke.

METHODS AND RESULTS: Data from 7 diverse US cohort studies were pooled. Remaining LTRs for CVD, coronary heart disease, and stroke were estimated for white and black men and women with death free of CVD as a competing event. LTRs for CVD by BP strata and by changes in BP over an average of 14 years were estimated. Starting at 55 years of age, we followed up 61 585 men and women for 700 000 person-years. LTR for CVD was 52.5\% (95\% confidence interval, 51.3-53.7) for men and 39.9\% (95\% confidence interval, 38.7-41.0) for women. LTR for CVD was higher for blacks and increased with increasing BP at index age. Individuals who maintained or decreased their BP to normal levels had the lowest remaining LTR for CVD, 22\% to 41\%, compared with individuals who had or developed hypertension by 55 years of age, 42\% to 69\%, suggesting a dose-response effect for the length of time at high BP levels.

CONCLUSIONS: Individuals who experience increases or decreases in BP in middle age have associated higher and lower remaining LTR for CVD. Prevention efforts should continue to emphasize the importance of lowering BP and avoiding or delaying the incidence of hypertension to reduce the LTR for CVD.

}, keywords = {Aged, Aged, 80 and over, Blood Pressure, Cardiovascular Diseases, Cohort Studies, Female, Follow-Up Studies, Humans, Hypertension, Life Tables, Longitudinal Studies, Male, Middle Aged, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.002774}, author = {Allen, Norrina and Berry, Jarett D and Ning, Hongyan and Van Horn, Linda and Dyer, Alan and Lloyd-Jones, Donald M} } @article {5861, title = {Lifetime risk and years lived free of total cardiovascular disease.}, journal = {JAMA}, volume = {308}, year = {2012}, month = {2012 Nov 07}, pages = {1795-801}, abstract = {

CONTEXT: Estimates of lifetime risk for total cardiovascular disease (CVD) may provide projections of the future population burden of CVD and may assist in clinician-patient risk communication. To date, no lifetime risk estimates of total CVD have been reported.

OBJECTIVES: To calculate lifetime risk estimates of total CVD by index age (45, 55, 65, 75 years) and risk factor strata and to estimate years lived free of CVD across risk factor strata.

DESIGN, SETTING, AND PARTICIPANTS: Pooled survival analysis of as many as 905,115 person-years of data from 1964 through 2008 from 5 National Heart, Lung, and Blood Institute-funded community-based cohorts: Framingham Heart Study, Framingham Offspring Study, Atherosclerosis Risk in Communities Study, Chicago Heart Association Detection Project in Industry Study, and Cardiovascular Health Study. All participants were free of CVD at baseline with risk factor data (blood pressure [BP], total cholesterol [TC], diabetes, and smoking status) and total CVD outcome data.

MAIN OUTCOME MEASURES: Any total CVD event (including fatal and nonfatal coronary heart disease, all forms of stroke, congestive heart failure, and other CVD deaths).

RESULTS: At an index age of 45 years, overall lifetime risk for total CVD was 60.3\% (95\% CI, 59.3\%-61.2\%) for men and 55.6\% (95\% CI, 54.5\%-56.7\%) for women. Men had higher lifetime risk estimates than women across all index ages. At index ages 55 and 65 years, men and women with at least 1 elevated risk factor (BP, 140-149/90-99 mm Hg; or TC, 200-239 mg/dL; but no diabetes or smoking), 1 major risk factor, or at least 2 major risk factors (BP, >=160/100 mm Hg or receiving treatment; TC, >=240 mg/dL or receiving treatment; diabetes mellitus; or current smoking) had lifetime risk estimates to age 95 years that exceeded 50\%. Despite an optimal risk factor profile (BP, <120/80 mm Hg; TC, <180 mg/dL; and no smoking or diabetes), men and women at the index age of 55 years had lifetime risks (through 85 years of age) for total CVD of greater than 40\% and 30\%, respectively. Compared with participants with at least 2 major risk factors, those with an optimal risk factor profile lived up to 14 years longer free of total CVD.

CONCLUSIONS: Lifetime risk estimates for total CVD were high (>30\%) for all individuals, even those with optimal risk factors in middle age. However, maintenance of optimal risk factor levels in middle age was associated with substantially longer morbidity-free survival.

}, keywords = {Adult, Aged, Blood Pressure, Cardiovascular Diseases, Cohort Studies, Diabetes Mellitus, Female, Forecasting, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Morbidity, Risk, Risk Factors, Smoking}, issn = {1538-3598}, doi = {10.1001/jama.2012.14312}, author = {Wilkins, John T and Ning, Hongyan and Berry, Jarett and Zhao, Lihui and Dyer, Alan R and Lloyd-Jones, Donald M} } @article {1541, title = {Lifetime risks of cardiovascular disease.}, journal = {N Engl J Med}, volume = {366}, year = {2012}, month = {2012 Jan 26}, pages = {321-9}, abstract = {

BACKGROUND: The lifetime risks of cardiovascular disease have not been reported across the age spectrum in black adults and white adults.

METHODS: We conducted a meta-analysis at the individual level using data from 18 cohort studies involving a total of 257,384 black men and women and white men and women whose risk factors for cardiovascular disease were measured at the ages of 45, 55, 65, and 75 years. Blood pressure, cholesterol level, smoking status, and diabetes status were used to stratify participants according to risk factors into five mutually exclusive categories. The remaining lifetime risks of cardiovascular events were estimated for participants in each category at each age, with death free of cardiovascular disease treated as a competing event.

RESULTS: We observed marked differences in the lifetime risks of cardiovascular disease across risk-factor strata. Among participants who were 55 years of age, those with an optimal risk-factor profile (total cholesterol level, <180 mg per deciliter [4.7 mmol per liter]; blood pressure, <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking status; and nondiabetic status) had substantially lower risks of death from cardiovascular disease through the age of 80 years than participants with two or more major risk factors (4.7\% vs. 29.6\% among men, 6.4\% vs. 20.5\% among women). Those with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6\% vs. 37.5\% among men, <1\% vs. 18.3\% among women) and fatal or nonfatal stroke (2.3\% vs. 8.3\% among men, 5.3\% vs. 10.7\% among women). Similar trends within risk-factor strata were observed among blacks and whites and across diverse birth cohorts.

CONCLUSIONS: Differences in risk-factor burden translate into marked differences in the lifetime risk of cardiovascular disease, and these differences are consistent across race and birth cohorts. (Funded by the National Heart, Lung, and Blood Institute.).

}, keywords = {Adult, African Americans, Aged, Cardiovascular Diseases, Cohort Effect, European Continental Ancestry Group, Female, Humans, Male, Middle Aged, Risk, Risk Assessment, Risk Factors, United States}, issn = {1533-4406}, doi = {10.1056/NEJMoa1012848}, author = {Berry, Jarett D and Dyer, Alan and Cai, Xuan and Garside, Daniel B and Ning, Hongyan and Thomas, Avis and Greenland, Philip and Van Horn, Linda and Tracy, Russell P and Lloyd-Jones, Donald M} } @article {1390, title = {Racial differences in risks for first cardiovascular events and noncardiovascular death: the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis.}, journal = {Circulation}, volume = {126}, year = {2012}, month = {2012 Jul 03}, pages = {50-9}, abstract = {

BACKGROUND: No studies have compared first cardiovascular disease (CVD) events and non-CVD death between races in a competing risks framework, which examines risks for numerous events simultaneously.

METHODS AND RESULTS: We used competing Cox models to estimate hazards for first CVD events and non-CVD death within and between races in 3 multicenter, National Heart, Lung, and Blood Institute-sponsored cohorts. Of 14 569 Atherosclerosis Risk in Communities (ARIC) study participants aged 45 to 64 years with mean follow-up of 10.5 years, 11.6\% had CVD and 5.0\% had non-CVD death as first events; among 4237 Cardiovascular Health Study (CHS) study participants aged 65 to 84 years and followed for 8.5 years, these figures were 43.2\% and 15.7\%, respectively. Middle-aged blacks were significantly more likely than whites to experience any CVD as a first event; this disparity disappeared by older adulthood and after adjustment for CVD risk factors. The pattern of results was similar for Multi-Ethnic Study of Atherosclerosis (MESA) participants. Traditional Cox and competing risks models yielded different results for coronary heart disease risk. Black men appeared somewhat more likely than white men to experience coronary heart disease with use of a standard Cox model (hazard ratio 1.06; 95\% CI 0.90, 1.26), whereas they appeared less likely than white men to have a first coronary heart disease event with use of a competing risks model (hazard ratio, 0.77; 95\% CI, 0.60, 1.00).

CONCLUSIONS: CVD affects blacks at an earlier age than whites; this may be attributable in part to elevated CVD risk factor levels among blacks. Racial disparities in first CVD incidence disappear by older adulthood. Competing risks analyses may yield somewhat different results than traditional Cox models and provide a complementary approach to examining risks for first CVD events.

}, keywords = {African Continental Ancestry Group, Age Factors, Aged, Aged, 80 and over, Atherosclerosis, Cardiovascular Diseases, Cohort Studies, Continental Population Groups, Ethnic Groups, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Middle Aged, Residence Characteristics, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.111.057232}, author = {Feinstein, Matthew and Ning, Hongyan and Kang, Joseph and Bertoni, Alain and Carnethon, Mercedes and Lloyd-Jones, Donald M} } @article {6167, title = {Impact of inflammatory biomarkers on relation of high density lipoprotein-cholesterol with incident coronary heart disease: cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {231}, year = {2013}, month = {2013 Dec}, pages = {246-51}, abstract = {

BACKGROUND: Inflammatory factors and low HDL-C relate to CHD risk, but whether inflammation attenuates any protective association of high HDL-C is unknown.

OBJECTIVE: Investigate inflammatory markers{\textquoteright} individual and collective impact on the association of HDL-C with incident coronary heart disease (CHD).

METHODS: In 3888 older adults without known cardiovascular disease (CVD), we examined if the inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and lipoprotein-associated phospholipase A2 (Lp-PLA$_{2}$) modify the relation of HDL-C with CHD. HDL-C, CRP, IL-6, and Lp-PLA$_{2}$ values were grouped as using gender-specific tertiles. Also, an inflammation index of z-score sums for CRP, IL-6, and Lp-PLA$_{2}$ was categorized into tertiles. We calculated CHD incidence for each HDL-C/inflammation group and performed Cox regression, adjusted for standard CVD risk factors and triglycerides to examine the relationship of combined HDL-C-inflammation groups with incident events.

RESULTS: CHD incidence (per 1000 person years) was higher for higher levels of CRP, IL-6, and the index, and lower for higher levels of HDL-C. Compared to high HDL-C/low-inflammation categories (referent), adjusted HRs for incident CHD were increased for those with high HDL-C and high CRP (HR = 1.50, p < 0.01) or highest IL-6 tertile (HR = 1.40, p < 0.05), but not with highest Lp-PLA$_{2}$ tertile. Higher CHD incidence was similarly seen for those with intermediate or low HDL-C accompanied by high CRP, high IL-6, or a high inflammatory index.

CONCLUSION: The protective relation of high HDL-C for incident CHD appears to be attenuated by greater inflammation.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, African Americans, Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, HDL, Coronary Disease, European Continental Ancestry Group, Female, Humans, Incidence, Inflammation, Interleukin-6, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2013.08.036}, author = {Tehrani, David M and Gardin, Julius M and Yanez, David and Hirsch, Calvin H and Lloyd-Jones, Donald M and Stein, Phyllis K and Wong, Nathan D} } @article {5847, title = {Lifetime risk for heart failure among white and black Americans: cardiovascular lifetime risk pooling project.}, journal = {J Am Coll Cardiol}, volume = {61}, year = {2013}, month = {2013 Apr 09}, pages = {1510-7}, chapter = {1510}, abstract = {

OBJECTIVES: This study sought to estimate lifetime risk for heart failure (HF) by sex and race.

BACKGROUND: Prior estimates of lifetime risk for developing HF range from 20\% to 33\% in predominantly white cohorts. Short-term risks for HF appear higher for blacks than whites, but only limited comparisons of lifetime risk for HF have been made.

METHODS: Using public-release and internal datasets from National Heart, Lung, and Blood Institute-sponsored cohorts, we estimated lifetime risks for developing HF to age 95 years, with death free of HF as the competing event, among participants in the CHA (Chicago Heart Association Detection Project in Industry), ARIC (Atherosclerosis Risk in Communities), and CHS (Cardiovascular Health Study) cohorts.

RESULTS: There were 39,578 participants (33,652 [85\%] white; 5,926 [15\%] black) followed for 716,976 person-years; 5,983 participants developed HF. At age 45 years, lifetime risks for HF through age 95 years in CHA and CHS were 30\% to 42\% in white men, 20\% to 29\% in black men, 32\% to 39\% in white women, and 24\% to 46\% in black women. Results for ARIC demonstrated similar lifetime risks for HF in blacks and whites through age 75 years (limit of follow-up). Lifetime risk for HF was higher with higher blood pressure and body mass index at all ages in both blacks and whites, and did not diminish substantially with advancing index age.

CONCLUSIONS: These are among the first data to compare lifetime risks for HF between blacks and whites. Lifetime risks for HF are high and appear similar for black and white women, yet are somewhat lower for black compared with white men due to competing risks.

}, keywords = {Adolescent, Adult, African Americans, Age Factors, Aged, Anthropometry, Body Mass Index, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Female, Health Surveys, Heart Failure, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Predictive Value of Tests, Prognosis, Risk Assessment, Severity of Illness Index, Sex Factors, Survival Analysis, Time Factors, United States, Young Adult}, issn = {1558-3597}, doi = {10.1016/j.jacc.2013.01.022}, author = {Huffman, Mark D and Berry, Jarett D and Ning, Hongyan and Dyer, Alan R and Garside, Daniel B and Cai, Xuan and Daviglus, Martha L and Lloyd-Jones, Donald M} } @article {6366, title = {Coronary heart disease risks associated with high levels of HDL cholesterol.}, journal = {J Am Heart Assoc}, volume = {3}, year = {2014}, month = {2014 Mar 13}, pages = {e000519}, abstract = {

BACKGROUND: The association between high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) events is not well described in individuals with very high levels of HDL-C (>80 mg/dL).

METHODS AND RESULTS: Using pooled data from 6 community-based cohorts we examined CHD and total mortality risks across a broad range of HDL-C, including values in excess of 80 mg/dL. We used Cox proportional hazards models with penalized splines to assess multivariable, adjusted, sex-stratified associations of HDL-C with the hazard for CHD events and total mortality, using HDL-C 45 mg/dL and 55 mg/dL as the referent in men and women, respectively. Analyses included 11 515 men and 12 925 women yielding 307 245 person-years of follow-up. In men, the association between HDL-C and CHD events was inverse and linear across most HDL-C values; however at HDL-C values >90 mg/dL there was a plateau effect in the pattern of association. In women, the association between HDL-C and CHD events was inverse and linear across lower values of HDL-C, however at HDL-C values >75 mg/dL there were no further reductions in the hazard ratio point estimates for CHD. In unadjusted models there were increased total mortality risks in men with very high HDL-C, however mortality risks observed in participants with very high HDL-C were attenuated after adjustment for traditional risk factors.

CONCLUSIONS: We did not observe further reductions in CHD risk with HDL-C values higher than 90 mg/dL in men and 75 mg/dL in women.

}, keywords = {Aged, Biomarkers, Cholesterol, HDL, Coronary Disease, Female, Humans, Linear Models, Male, Middle Aged, Multivariate Analysis, Prognosis, Proportional Hazards Models, Risk Assessment, Risk Factors, Time Factors, United States, Up-Regulation}, issn = {2047-9980}, doi = {10.1161/JAHA.113.000519}, author = {Wilkins, John T and Ning, Hongyan and Stone, Neil J and Criqui, Michael H and Zhao, Lihui and Greenland, Philip and Lloyd-Jones, Donald M} } @article {8626, title = {Performance of the Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Body Mass Index.}, journal = {JAMA Netw Open}, volume = {3}, year = {2020}, month = {2020 10 01}, pages = {e2023242}, abstract = {

Importance: Obesity is a global health challenge and a risk factor for atherosclerotic cardiovascular disease (ASVCD). Performance of the pooled cohort equations (PCE) for ASCVD risk by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown.

Objective: To assess performance of the PCE across clinical BMI categories.

Design, Setting, and Participants: This cohort study used pooled individual-level data from 8 community-based, prospective, longitudinal cohort studies with 10-year ASCVD event follow-up from 1996 to 2016. We included all adults ages 40 to 79 years without baseline ASCVD or statin use, resulting in a sample size of 37 311 participants. Data were analyzed from August 2017 to July 2020.

Exposures: Participant BMI category: underweight (<18.5), normal weight (18.5 to <25), overweight (25 to <30), mild obesity (30 to <35), and moderate to severe obesity (>=35).

Main Outcomes and Measures: Discrimination (Harrell C statistic) and calibration (Nam-D{\textquoteright}Agostino χ2 goodness-of-fit test) of the PCE across BMI categories. Improvement in discrimination and net reclassification with addition of BMI, waist circumference, and high-sensitivity C-reactive protein (hsCRP) to the PCE.

Results: Among 37 311 participants (mean [SD] age, 58.6 [11.8] years; 21 897 [58.7\%] women), 380 604 person-years of follow-up were conducted. Mean (SD) baseline BMI was 29.0 (6.2), and 360 individuals (1.0\%) were in the underweight category, 9937 individuals (26.6\%) were in the normal weight category, 13 601 individuals (36.4\%) were in the overweight category, 7783 individuals (20.9\%) were in the mild obesity category, and 5630 individuals (15.1\%) were in the moderate to severe obesity category. Median (interquartile range [IQR]) 10-year estimated ASCVD risk was 7.1\% (2.5\%-15.4\%), and 3709 individuals (9.9\%) developed ASCVD over a median (IQR) 10.8 [8.5-12.6] years. The PCE overestimated ASCVD risk in the overall cohort (estimated/observed [E/O] risk ratio, 1.22; 95\% CI, 1.18-1.26) and across all BMI categories except the underweight category. Calibration was better near the clinical decision threshold in all BMI groups but worse among individuals with moderate or severe obesity (E/O risk ratio, 1.36; 95\% CI, 1.25-1.47) and among those with the highest estimated ASCVD risk >=20\%. The PCE C statistic overall was 0.760 (95\% CI, 0.753-0.767), with lower discrimination in the moderate or severe obesity group (C statistic, 0.742; 95\% CI, 0.721-0.763) compared with the normal-range BMI group (C statistic, 0.785; 95\% CI, 0.772-0.798). Waist circumference (hazard ratio, 1.07 per 1-SD increase; 95\% CI, 1.03-1.11) and hsCRP (hazard ratio, 1.07 per 1-SD increase; 95\% CI, 1.05-1.09), but not BMI, were associated with increased ASCVD risk when added to the PCE. However, these factors did not improve model performance (C statistic, 0.760; 95\% CI, 0.753-0.767) with or without added metrics.

Conclusions and Relevance: These findings suggest that the PCE had acceptable model discrimination and were well calibrated at clinical decision thresholds but overestimated risk of ASCVD for individuals in overweight and obese categories, particularly individuals with high estimated risk. Incorporation of the usual clinical measures of obesity did not improve risk estimation of the PCE. Future research is needed to determine whether incorporation of alternative high-risk obesity markers (eg, weight trajectory or measures of visceral or ectopic fat) into the PCE may improve risk prediction.

}, keywords = {Adult, Aged, Body Mass Index, Cardiovascular Diseases, Cohort Studies, Correlation of Data, Female, Humans, Longitudinal Studies, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2020.23242}, author = {Khera, Rohan and Pandey, Ambarish and Ayers, Colby R and Carnethon, Mercedes R and Greenland, Philip and Ndumele, Chiadi E and Nambi, Vijay and Seliger, Stephen L and Chaves, Paulo H M and Safford, Monika M and Cushman, Mary and Xanthakis, Vanessa and Vasan, Ramachandran S and Mentz, Robert J and Correa, Adolfo and Lloyd-Jones, Donald M and Berry, Jarett D and de Lemos, James A and Neeland, Ian J} } @article {9006, title = {Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 12 09}, pages = {7173}, abstract = {

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are~correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6\% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

}, keywords = {Amino Acid Transport System y+, Cohort Studies, CpG Islands, DNA Methylation, Epigenome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Transport Proteins, Facilitative, Gout, Humans, Male, Uric Acid}, issn = {2041-1723}, doi = {10.1038/s41467-021-27198-4}, author = {Tin, Adrienne and Schlosser, Pascal and Matias-Garcia, Pamela R and Thio, Chris H L and Joehanes, Roby and Liu, Hongbo and Yu, Zhi and Weihs, Antoine and Hoppmann, Anselm and Grundner-Culemann, Franziska and Min, Josine L and Kuhns, Victoria L Halperin and Adeyemo, Adebowale A and Agyemang, Charles and Arnl{\"o}v, Johan and Aziz, Nasir A and Baccarelli, Andrea and Bochud, Murielle and Brenner, Hermann and Bressler, Jan and Breteler, Monique M B and Carmeli, Cristian and Chaker, Layal and Coresh, Josef and Corre, Tanguy and Correa, Adolfo and Cox, Simon R and Delgado, Graciela E and Eckardt, Kai-Uwe and Ekici, Arif B and Endlich, Karlhans and Floyd, James S and Fraszczyk, Eliza and Gao, Xu and G{\`a}o, Xin and Gelber, Allan C and Ghanbari, Mohsen and Ghasemi, Sahar and Gieger, Christian and Greenland, Philip and Grove, Megan L and Harris, Sarah E and Hemani, Gibran and Henneman, Peter and Herder, Christian and Horvath, Steve and Hou, Lifang and Hurme, Mikko A and Hwang, Shih-Jen and Kardia, Sharon L R and Kasela, Silva and Kleber, Marcus E and Koenig, Wolfgang and Kooner, Jaspal S and Kronenberg, Florian and Kuhnel, Brigitte and Ladd-Acosta, Christine and Lehtim{\"a}ki, Terho and Lind, Lars and Liu, Dan and Lloyd-Jones, Donald M and Lorkowski, Stefan and Lu, Ake T and Marioni, Riccardo E and M{\"a}rz, Winfried and McCartney, Daniel L and Meeks, Karlijn A C and Milani, Lili and Mishra, Pashupati P and Nauck, Matthias and Nowak, Christoph and Peters, Annette and Prokisch, Holger and Psaty, Bruce M and Raitakari, Olli T and Ratliff, Scott M and Reiner, Alex P and Sch{\"o}ttker, Ben and Schwartz, Joel and Sedaghat, Sanaz and Smith, Jennifer A and Sotoodehnia, Nona and Stocker, Hannah R and Stringhini, Silvia and Sundstr{\"o}m, Johan and Swenson, Brenton R and van Meurs, Joyce B J and van Vliet-Ostaptchouk, Jana V and Venema, Andrea and V{\"o}lker, Uwe and Winkelmann, Juliane and Wolffenbuttel, Bruce H R and Zhao, Wei and Zheng, Yinan and Loh, Marie and Snieder, Harold and Waldenberger, Melanie and Levy, Daniel and Akilesh, Shreeram and Woodward, Owen M and Susztak, Katalin and Teumer, Alexander and K{\"o}ttgen, Anna} } @article {9002, title = {Meta-analyses identify DNA methylation associated with kidney function and damage.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 12 09}, pages = {7174}, abstract = {

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

}, keywords = {Adult, Aged, CpG Islands, DNA Methylation, Female, Glomerular Filtration Rate, Humans, Interferon Regulatory Factors, Kidney, Kidney Function Tests, LIM Domain Proteins, Male, Membrane Proteins, Middle Aged, Renal Insufficiency, Chronic, Transcription Factors}, issn = {2041-1723}, doi = {10.1038/s41467-021-27234-3}, author = {Schlosser, Pascal and Tin, Adrienne and Matias-Garcia, Pamela R and Thio, Chris H L and Joehanes, Roby and Liu, Hongbo and Weihs, Antoine and Yu, Zhi and Hoppmann, Anselm and Grundner-Culemann, Franziska and Min, Josine L and Adeyemo, Adebowale A and Agyemang, Charles and Arnl{\"o}v, Johan and Aziz, Nasir A and Baccarelli, Andrea and Bochud, Murielle and Brenner, Hermann and Breteler, Monique M B and Carmeli, Cristian and Chaker, Layal and Chambers, John C and Cole, Shelley A and Coresh, Josef and Corre, Tanguy and Correa, Adolfo and Cox, Simon R and de Klein, Niek and Delgado, Graciela E and Domingo-Relloso, Arce and Eckardt, Kai-Uwe and Ekici, Arif B and Endlich, Karlhans and Evans, Kathryn L and Floyd, James S and Fornage, Myriam and Franke, Lude and Fraszczyk, Eliza and Gao, Xu and G{\`a}o, Xin and Ghanbari, Mohsen and Ghasemi, Sahar and Gieger, Christian and Greenland, Philip and Grove, Megan L and Harris, Sarah E and Hemani, Gibran and Henneman, Peter and Herder, Christian and Horvath, Steve and Hou, Lifang and Hurme, Mikko A and Hwang, Shih-Jen and Jarvelin, Marjo-Riitta and Kardia, Sharon L R and Kasela, Silva and Kleber, Marcus E and Koenig, Wolfgang and Kooner, Jaspal S and Kramer, Holly and Kronenberg, Florian and Kuhnel, Brigitte and Lehtim{\"a}ki, Terho and Lind, Lars and Liu, Dan and Liu, Yongmei and Lloyd-Jones, Donald M and Lohman, Kurt and Lorkowski, Stefan and Lu, Ake T and Marioni, Riccardo E and M{\"a}rz, Winfried and McCartney, Daniel L and Meeks, Karlijn A C and Milani, Lili and Mishra, Pashupati P and Nauck, Matthias and Navas-Acien, Ana and Nowak, Christoph and Peters, Annette and Prokisch, Holger and Psaty, Bruce M and Raitakari, Olli T and Ratliff, Scott M and Reiner, Alex P and Rosas, Sylvia E and Sch{\"o}ttker, Ben and Schwartz, Joel and Sedaghat, Sanaz and Smith, Jennifer A and Sotoodehnia, Nona and Stocker, Hannah R and Stringhini, Silvia and Sundstr{\"o}m, Johan and Swenson, Brenton R and Tellez-Plaza, Maria and van Meurs, Joyce B J and van Vliet-Ostaptchouk, Jana V and Venema, Andrea and Verweij, Niek and Walker, Rosie M and Wielscher, Matthias and Winkelmann, Juliane and Wolffenbuttel, Bruce H R and Zhao, Wei and Zheng, Yinan and Loh, Marie and Snieder, Harold and Levy, Daniel and Waldenberger, Melanie and Susztak, Katalin and K{\"o}ttgen, Anna and Teumer, Alexander} } @article {8779, title = {Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 05 06}, pages = {874-893}, abstract = {

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3~bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 16, Datasets as Topic, Erythrocytes, Female, Gene Editing, Genetic Variation, Genome-Wide Association Study, HEK293 Cells, Humans, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Quality Control, Reproducibility of Results, United States}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.04.003}, author = {Hu, Yao and Stilp, Adrienne M and McHugh, Caitlin P and Rao, Shuquan and Jain, Deepti and Zheng, Xiuwen and Lane, John and M{\'e}ric de Bellefon, S{\'e}bastian and Raffield, Laura M and Chen, Ming-Huei and Yanek, Lisa R and Wheeler, Marsha and Yao, Yao and Ren, Chunyan and Broome, Jai and Moon, Jee-Young and de Vries, Paul S and Hobbs, Brian D and Sun, Quan and Surendran, Praveen and Brody, Jennifer A and Blackwell, Thomas W and Choquet, Helene and Ryan, Kathleen and Duggirala, Ravindranath and Heard-Costa, Nancy and Wang, Zhe and Chami, Nathalie and Preuss, Michael H and Min, Nancy and Ekunwe, Lynette and Lange, Leslie A and Cushman, Mary and Faraday, Nauder and Curran, Joanne E and Almasy, Laura and Kundu, Kousik and Smith, Albert V and Gabriel, Stacey and Rotter, Jerome I and Fornage, Myriam and Lloyd-Jones, Donald M and Vasan, Ramachandran S and Smith, Nicholas L and North, Kari E and Boerwinkle, Eric and Becker, Lewis C and Lewis, Joshua P and Abecasis, Goncalo R and Hou, Lifang and O{\textquoteright}Connell, Jeffrey R and Morrison, Alanna C and Beaty, Terri H and Kaplan, Robert and Correa, Adolfo and Blangero, John and Jorgenson, Eric and Psaty, Bruce M and Kooperberg, Charles and Walton, Russell T and Kleinstiver, Benjamin P and Tang, Hua and Loos, Ruth J F and Soranzo, Nicole and Butterworth, Adam S and Nickerson, Debbie and Rich, Stephen S and Mitchell, Braxton D and Johnson, Andrew D and Auer, Paul L and Li, Yun and Mathias, Rasika A and Lettre, Guillaume and Pankratz, Nathan and Laurie, Cathy C and Laurie, Cecelia A and Bauer, Daniel E and Conomos, Matthew P and Reiner, Alexander P} } @article {9246, title = {Correlations between complex human phenotypes vary by genetic background, gender, and environment.}, journal = {Cell Rep Med}, volume = {3}, year = {2022}, month = {2022 Dec 20}, pages = {100844}, abstract = {

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet \~{}20{\texttimes} faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.

}, keywords = {Female, Genetic Background, Humans, Male, Phenotype}, issn = {2666-3791}, doi = {10.1016/j.xcrm.2022.100844}, author = {Elgart, Michael and Goodman, Matthew O and Isasi, Carmen and Chen, Han and Morrison, Alanna C and de Vries, Paul S and Xu, Huichun and Manichaikul, Ani W and Guo, Xiuqing and Franceschini, Nora and Psaty, Bruce M and Rich, Stephen S and Rotter, Jerome I and Lloyd-Jones, Donald M and Fornage, Myriam and Correa, Adolfo and Heard-Costa, Nancy L and Vasan, Ramachandran S and Hernandez, Ryan and Kaplan, Robert C and Redline, Susan and Sofer, Tamar} } @article {9379, title = {Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups.}, journal = {Nat Commun}, volume = {14}, year = {2023}, month = {2023 Jun 02}, pages = {3202}, abstract = {

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.

}, keywords = {Blood Pressure, Ethnicity, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Population Health, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-023-38990-9}, author = {Kurniansyah, Nuzulul and Goodman, Matthew O and Khan, Alyna T and Wang, Jiongming and Feofanova, Elena and Bis, Joshua C and Wiggins, Kerri L and Huffman, Jennifer E and Kelly, Tanika and Elfassy, Tali and Guo, Xiuqing and Palmas, Walter and Lin, Henry J and Hwang, Shih-Jen and Gao, Yan and Young, Kendra and Kinney, Gregory L and Smith, Jennifer A and Yu, Bing and Liu, Simin and Wassertheil-Smoller, Sylvia and Manson, JoAnn E and Zhu, Xiaofeng and Chen, Yii-Der Ida and Lee, I-Te and Gu, C Charles and Lloyd-Jones, Donald M and Z{\"o}llner, Sebastian and Fornage, Myriam and Kooperberg, Charles and Correa, Adolfo and Psaty, Bruce M and Arnett, Donna K and Isasi, Carmen R and Rich, Stephen S and Kaplan, Robert C and Redline, Susan and Mitchell, Braxton D and Franceschini, Nora and Levy, Daniel and Rotter, Jerome I and Morrison, Alanna C and Sofer, Tamar} } @article {9637, title = {Development and Validation of the American Heart Association{\textquoteright}s PREVENT Equations.}, journal = {Circulation}, volume = {149}, year = {2024}, month = {2024 Feb 06}, pages = {430-449}, abstract = {

BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD.

METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets.

RESULTS: Among 6 612 004 adults included, mean{\textpm}SD age was 53{\textpm}12 years, and 56\% were women. Over a mean{\textpm}SD follow-up of 4.8{\textpm}3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; =0.01).

CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.

}, keywords = {Adult, Aged, Albumins, American Heart Association, Atherosclerosis, Cardiovascular Diseases, Creatinine, Female, Glycated Hemoglobin, Heart Failure, Humans, Male, Middle Aged, Risk Assessment, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.123.067626}, author = {Khan, Sadiya S and Matsushita, Kunihiro and Sang, Yingying and Ballew, Shoshana H and Grams, Morgan E and Surapaneni, Aditya and Blaha, Michael J and Carson, April P and Chang, Alexander R and Ciemins, Elizabeth and Go, Alan S and Gutierrez, Orlando M and Hwang, Shih-Jen and Jassal, Simerjot K and Kovesdy, Csaba P and Lloyd-Jones, Donald M and Shlipak, Michael G and Palaniappan, Latha P and Sperling, Laurence and Virani, Salim S and Tuttle, Katherine and Neeland, Ian J and Chow, Sheryl L and Rangaswami, Janani and Pencina, Michael J and Ndumele, Chiadi E and Coresh, Josef} }