@article {1347, title = {Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.}, journal = {Circ Cardiovasc Genet}, volume = {4}, year = {2011}, month = {2011 Dec}, pages = {661-72}, abstract = {

BACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.

METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 {\texttimes} 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 {\texttimes} 10(-6)), MTHFD1L (rs6922269, P=5.1 {\texttimes} 10(-10)), APOE (rs429358; P=2.7{\texttimes}10(-18)), ZNF627 (rs4804611; P=5.0 {\texttimes} 10(-8)), CXCL12 (rs501120; P=1.4 {\texttimes} 10(-6)) and LPL (rs268; P=2.7 {\texttimes} 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.

CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

}, keywords = {Aged, Aged, 80 and over, Continental Population Groups, Coronary Disease, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.111.960096}, author = {Franceschini, Nora and Carty, Cara and B{\r u}zkov{\'a}, Petra and Reiner, Alex P and Garrett, Tiana and Lin, Yi and V{\"o}ckler, Jens-S and Hindorff, Lucia A and Cole, Shelley A and Boerwinkle, Eric and Lin, Dan-Yu and Bookman, Ebony and Best, Lyle G and Bella, Jonathan N and Eaton, Charles and Greenland, Philip and Jenny, Nancy and North, Kari E and Taverna, Darin and Young, Alicia M and Deelman, Ewa and Kooperberg, Charles and Psaty, Bruce and Heiss, Gerardo} } @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 {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 {7442, title = {Association of Coronary Artery Calcium Score vs Age With Cardiovascular Risk in Older Adults: An Analysis of Pooled Population-Based Studies.}, journal = {JAMA Cardiol}, year = {2017}, month = {2017 Jul 26}, abstract = {

Importance: Besides age, other discriminators of atherosclerotic cardiovascular disease (ASCVD) risk are needed in older adults.

Objectives: To examine the predictive ability of coronary artery calcium (CAC) score vs age for incident ASCVD and how risk prediction changes by adding CAC score and removing only age from prediction models.

Design, Setting, and Participants: We conducted an analysis of pooled US population-based studies, including the Framingham Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Results were compared with 2 European cohorts, the Rotterdam Study and the Heinz Nixdorf Recall Study. Participants underwent CAC scoring between 1998 and 2006 using cardiac computed tomography. The participants included adults older than 60 years without known ASCVD at baseline.

Exposures: Coronary artery calcium scores.

Main Outcomes and Measures: Incident ASCVD events including coronary heart disease (CHD) and stroke.

Results: The study included 4778 participants from 3 US cohorts, with a mean age of 70.1 years; 2582 (54.0\%) were women, and 2431 (50.9\%) were nonwhite. Over 11 years of follow-up (44 152 person-years), 405 CHD and 228 stroke events occurred. Coronary artery calcium score (vs age) had a greater association with incident CHD (C statistic, 0.733 vs 0.690; C statistics difference, 0.043; 95\% CI of difference, 0.009-0.075) and modestly improved prediction of incident stroke (C statistic, 0.695 vs 0.670; C statistics difference, 0.025; 95\% CI of difference, -0.015 to 0.064). Adding CAC score to models including traditional cardiovascular risk factors, with only age being removed, provided improved discrimination for incident CHD (C statistic, 0.735 vs 0.703; C statistics difference, 0.032; 95\% CI of difference, 0.002-0.062) but not for stroke. Coronary artery calcium score was more likely than age to provide higher category-free net reclassification improvement among participants who experienced an ASCVD event (0.390; 95\% CI, 0.312-0.467 vs 0.08; 95\% CI -0.001 to 0.181) and to result in more accurate reclassification of risk for ASCVD events among these individuals. The findings were similar in the 2 European cohorts (n = 4990).

Conclusions and Relevance: Coronary artery calcium may be an alternative marker besides age to better discriminate between lower and higher CHD risk in older adults. Whether CAC score can assist in guiding the decision to initiate statin treatment for primary prevention in older adults requires further investigation.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2017.2498}, author = {Yano, Yuichiro and O{\textquoteright}Donnell, Christopher J and Kuller, Lewis and Kavousi, Maryam and Erbel, Raimund and Ning, Hongyan and D{\textquoteright}Agostino, Ralph and Newman, Anne B and Nasir, Khurram and Hofman, Albert and Lehmann, Nils and Dhana, Klodian and Blankstein, Ron and Hoffmann, Udo and M{\"o}hlenkamp, Stefan and Massaro, Joseph M and Mahabadi, Amir-Abbas and Lima, Jo{\~a}o A C and Ikram, M Arfan and J{\"o}ckel, Karl-Heinz and Franco, Oscar H and Liu, Kiang and Lloyd-Jones, Donald and Greenland, Philip} } @article {7356, title = {Relationship Between Physical Activity, Body Mass Index, and Risk of Heart Failure.}, journal = {J Am Coll Cardiol}, volume = {69}, year = {2017}, month = {2017 Mar 07}, pages = {1129-1142}, abstract = {

BACKGROUND: Lower leisure-time physical activity (LTPA) and higher body mass index (BMI) are independently associated with risk of heart failure (HF). However, it is unclear if this relationship is consistent for both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF).

OBJECTIVES: This study sought to quantify dose-response associations between LTPA, BMI, and the risk of different HF subtypes.

METHODS: Individual-level data from 3 cohort studies (WHI [Women{\textquoteright}s Health Initiative], MESA [Multi-Ethnic Study of Atherosclerosis], and CHS [Cardiovascular Health Study]) were pooled and participants were stratified into guideline-recommended categories of LTPA and BMI. Associations between LTPA, BMI, and risk of overall HF, HFpEF (ejection fraction~>=45\%), and HFrEF (ejection fraction~<45\%) were assessed by using multivariable adjusted Cox models and restricted cubic splines.

RESULTS: The study included 51,451 participants with 3,180 HF events (1,252 HFpEF, 914 HFrEF, and 1,014 unclassified HF). In the adjusted analysis, there was a dose-dependent association between higher LTPA levels, lower BMI, and overall~HF risk. Among HF subtypes, LTPA in any dose range was not associated with HFrEF risk. In contrast, lower levels of LTPA (<500 MET-min/week) were not associated with HFpEF risk, and dose-dependent associations with lower HFpEF risk were observed at higher levels. Compared with no LTPA, higher than twice the guideline-recommended minimum LTPA levels (>1,000 MET-min/week) were associated with an 19\% lower risk of HFpEF (hazard ratio: 0.81; 95\% confidence interval: 0.68 to 0.97). The dose-response relationship for BMI with HFpEF risk was also more consistent than with HFrEF risk, such that increasing BMI above the normal range (>=25 kg/m(2)) was associated with a greater increase in risk of HFpEF than HFrEF.

CONCLUSIONS: Our study findings show strong, dose-dependent associations between LTPA levels, BMI, and risk~of~overall HF. Among HF subtypes, higher LTPA levels and lower BMI were more consistently associated with~lower~risk of HFpEF compared with HFrEF.

}, issn = {1558-3597}, doi = {10.1016/j.jacc.2016.11.081}, author = {Pandey, Ambarish and LaMonte, Michael and Klein, Liviu and Ayers, Colby and Psaty, Bruce M and Eaton, Charles B and Allen, Norrina B and de Lemos, James A and Carnethon, Mercedes and Greenland, Philip and Berry, Jarett D} } @article {7678, title = {Association of lipoprotein-associated phospholipase A and risk of incident atrial fibrillation: Findings from 3 cohorts.}, journal = {Am Heart J}, volume = {197}, year = {2018}, month = {2018 Mar}, pages = {62-69}, abstract = {

BACKGROUND: Multiple prospective studies have established an association between inflammation and higher risk of atrial fibrillation (AF), but the association between lipoprotein-associated phospholipase A (Lp-PLA) mass and activity and incident AF has not been extensively evaluated.

METHODS: Using data from 10,794 Atherosclerosis Risk In Communities (ARIC) study participants aged 53-75 years, 5,181 Cardiovascular Health Study (CHS) participants aged 65 to 100 years, and 5,425 Multi-Ethnic Study of Atherosclerosis (MESA) participants aged 45-84 years, we investigated the association between baseline Lp-PLA levels and the risk of developing AF. Incident AF was identified in each cohort by follow-up visit electrocardiograms, hospital discharge coding of AF, or Medicare claims data.

RESULTS: Over a mean of 13.1, 11.5, and 10.0 years of follow-up, 1,439 (13\%), 2,084 (40\%), and 615 (11\%) incident AF events occurred in ARIC, CHS, and MESA, respectively. In adjusted analyses, each SD increment in Lp-PLA activity was associated with incident AF in both ARIC (hazard ratio [HR] 1.13, 95\% CI 1.06-1.20) and MESA (HR 1.24, 95\% CI 1.05-1.46). Each SD increment in Lp-PLA mass was also associated with incident AF in MESA (HR 1.25, 95\% CI 1.11-1.41). No significant associations were observed among CHS participants.

CONCLUSIONS: Although higher Lp-PLA mass and activity were associated with development of AF in ARIC and MESA, this relationship was not observed in CHS, a cohort of older individuals.

}, issn = {1097-6744}, doi = {10.1016/j.ahj.2017.11.010}, author = {Garg, Parveen K and Bartz, Traci M and Norby, Faye L and Jorgensen, Neal W and McClelland, Robyn L and Ballantyne, Christie M and Chen, Lin Y and Gottdiener, John S and Greenland, Philip and Hoogeveen, Ron and Jenny, Nancy S and Kizer, Jorge R and Rosenson, Robert S and Soliman, Elsayed Z and Cushman, Mary and Alonso, Alvaro and Heckbert, Susan R} } @article {7923, title = {Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.}, journal = {Eur Heart J}, year = {2018}, month = {2018 Nov 22}, abstract = {

Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after {\textquoteright}recalibration{\textquoteright}, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.

Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at {\textquoteright}high{\textquoteright} 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10\%, 52\%, and 41\%, respectively, whereas RRS under-predicted by 10\%. Original versions of algorithms classified 29-39\% of individuals aged >=40 years as high risk. By contrast, recalibration reduced this proportion to 22-24\% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.

Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehy653}, author = {Pennells, Lisa and Kaptoge, Stephen and Wood, Angela and Sweeting, Mike and Zhao, Xiaohui and White, Ian and Burgess, Stephen and Willeit, Peter and Bolton, Thomas and Moons, Karel G M and van der Schouw, Yvonne T and Selmer, Randi and Khaw, Kay-Tee and Gudnason, Vilmundur and Assmann, Gerd and Amouyel, Philippe and Salomaa, Veikko and Kivimaki, Mika and Nordestgaard, B{\o}rge G and Blaha, Michael J and Kuller, Lewis H and Brenner, Hermann and Gillum, Richard F and Meisinger, Christa and Ford, Ian and Knuiman, Matthew W and Rosengren, Annika and Lawlor, Debbie A and V{\"o}lzke, Henry and Cooper, Cyrus and Mar{\'\i}n Iba{\~n}ez, Alejandro and Casiglia, Edoardo and Kauhanen, Jussi and Cooper, Jackie A and Rodriguez, Beatriz and Sundstr{\"o}m, Johan and Barrett-Connor, Elizabeth and Dankner, Rachel and Nietert, Paul J and Davidson, Karina W and Wallace, Robert B and Blazer, Dan G and Bj{\"o}rkelund, Cecilia and Donfrancesco, Chiara and Krumholz, Harlan M and Nissinen, Aulikki and Davis, Barry R and Coady, Sean and Whincup, Peter H and J{\o}rgensen, Torben and Ducimetiere, Pierre and Trevisan, Maurizio and Engstr{\"o}m, Gunnar and Crespo, Carlos J and Meade, Tom W and Visser, Marjolein and Kromhout, Daan and Kiechl, Stefan and Daimon, Makoto and Price, Jackie F and G{\'o}mez de la C{\'a}mara, Agustin and Wouter Jukema, J and Lamarche, Beno{\^\i}t and Onat, Altan and Simons, Leon A and Kavousi, Maryam and Ben-Shlomo, Yoav and Gallacher, John and Dekker, Jacqueline M and Arima, Hisatomi and Shara, Nawar and Tipping, Robert W and Roussel, Ronan and Brunner, Eric J and Koenig, Wolfgang and Sakurai, Masaru and Pavlovic, Jelena and Gansevoort, Ron T and Nagel, Dorothea and Goldbourt, Uri and Barr, Elizabeth L M and Palmieri, Luigi and Nj{\o}lstad, Inger and Sato, Shinichi and Monique Verschuren, W M and Varghese, Cherian V and Graham, Ian and Onuma, Oyere and Greenland, Philip and Woodward, Mark and Ezzati, Majid and Psaty, Bruce M and Sattar, Naveed and Jackson, Rod and Ridker, Paul M and Cook, Nancy R and D{\textquoteright}Agostino, Ralph B and Thompson, Simon G and Danesh, John and Di Angelantonio, Emanuele} } @article {7685, title = {Sex and Race Differences in Lifetime Risk of Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction.}, journal = {Circulation}, volume = {137}, year = {2018}, month = {2018 Apr 24}, pages = {1814-1823}, abstract = {

BACKGROUND: Lifetime risk of heart failure has been estimated to range from 20\% to 46\% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known.

METHODS: Participant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF >=45\%) and HFrEF (EF <45\%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks.

RESULTS: We included 12 417 participants >45 years of age (22.2\% blacks, 44.8\% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4\% versus 23.8\%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6\% versus 5.8\%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9\% versus 22.4\%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2\% versus 7.7\%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction.

CONCLUSIONS: Lifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.117.031622}, author = {Pandey, Ambarish and Omar, Wally and Ayers, Colby and LaMonte, Michael and Klein, Liviu and Allen, Norrina B and Kuller, Lewis H and Greenland, Philip and Eaton, Charles B and Gottdiener, John S and Lloyd-Jones, Donald M and Berry, Jarett D} } @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 {9094, title = {Integrative analysis of clinical and epigenetic biomarkers of mortality.}, journal = {Aging Cell}, volume = {21}, year = {2022}, month = {2022 Jun}, pages = {e13608}, abstract = {

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n~=~15,013). During a mean follow-up of 10~years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p~<~1~{\texttimes}~10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5\% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta~=~1.2, P ~=~4.1~{\texttimes}~10 ) and negatively associated with longevity (Beta~=~-1.9, P ~=~0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

}, keywords = {Biomarkers, Cardiovascular Diseases, DNA Methylation, Epigenesis, Genetic, Epigenomics, Humans, Male, Neoplasms}, issn = {1474-9726}, doi = {10.1111/acel.13608}, author = {Huan, Tianxiao and Nguyen, Steve and Colicino, Elena and Ochoa-Rosales, Carolina and Hill, W David and Brody, Jennifer A and Soerensen, Mette and Zhang, Yan and Baldassari, Antoine and Elhadad, Mohamed Ahmed and Toshiko, Tanaka and Zheng, Yinan and Domingo-Relloso, Arce and Lee, Dong Heon and Ma, Jiantao and Yao, Chen and Liu, Chunyu and Hwang, Shih-Jen and Joehanes, Roby and Fornage, Myriam and Bressler, Jan and van Meurs, Joyce B J and Debrabant, Birgit and Mengel-From, Jonas and Hjelmborg, Jacob and Christensen, Kaare and Vokonas, Pantel and Schwartz, Joel and Gahrib, Sina A and Sotoodehnia, Nona and Sitlani, Colleen M and Kunze, Sonja and Gieger, Christian and Peters, Annette and Waldenberger, Melanie and Deary, Ian J and Ferrucci, Luigi and Qu, Yishu and Greenland, Philip and Lloyd-Jones, Donald M and Hou, Lifang and Bandinelli, Stefania and Voortman, Trudy and Hermann, Brenner and Baccarelli, Andrea and Whitsel, Eric and Pankow, James S and Levy, Daniel} }