Dataset Information

Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.

ABSTRACT: BACKGROUND:The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. METHODS AND RESULTS:We studied a total of 25?109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52?869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247?870 DNA sequence variants (231?539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10-10). The APOE ?2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10-12) and 1.4% reduced carotid intima-media thickness (P=4×10-14) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ?2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ?2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10-11). CONCLUSIONS:Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ?2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

SUBMITTER: Natarajan P

PROVIDER: S-EPMC5418659 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.

Natarajan Pradeep P Bis Joshua C JC Bielak Lawrence F LF Cox Amanda J AJ Dörr Marcus M Feitosa Mary F MF Franceschini Nora N Guo Xiuqing X Hwang Shih-Jen SJ Isaacs Aaron A Jhun Min A MA Kavousi Maryam M Li-Gao Ruifang R Lyytikäinen Leo-Pekka LP Marioni Riccardo E RE Schminke Ulf U Stitziel Nathan O NO Tada Hayato H van Setten Jessica J Smith Albert V AV Vojinovic Dina D Yanek Lisa R LR Yao Jie J Yerges-Armstrong Laura M LM Amin Najaf N Baber Usman U Borecki Ingrid B IB Carr J Jeffrey JJ Chen Yii-Der Ida YI Cupples L Adrienne LA de Jong Pim A PA de Koning Harry H de Vos Bob D BD Demirkan Ayse A Fuster Valentin V Franco Oscar H OH Goodarzi Mark O MO Harris Tamara B TB Heckbert Susan R SR Heiss Gerardo G Hoffmann Udo U Hofman Albert A Išgum Ivana I Jukema J Wouter JW Kähönen Mika M Kardia Sharon L R SL Kral Brian G BG Launer Lenore J LJ Massaro Joe J Mehran Roxana R Mitchell Braxton D BD Mosley Thomas H TH de Mutsert Renée R Newman Anne B AB Nguyen Khanh-Dung KD North Kari E KE O'Connell Jeffrey R JR Oudkerk Matthijs M Pankow James S JS Peloso Gina M GM Post Wendy W Province Michael A MA Raffield Laura M LM Raitakari Olli T OT Reilly Dermot F DF Rivadeneira Fernando F Rosendaal Frits F Sartori Samantha S Taylor Kent D KD Teumer Alexander A Trompet Stella S Turner Stephen T ST Uitterlinden Andre G AG Vaidya Dhananjay D van der Lugt Aad A Völker Uwe U Wardlaw Joanna M JM Wassel Christina L CL Weiss Stefan S Wojczynski Mary K MK Becker Diane M DM Becker Lewis C LC Boerwinkle Eric E Bowden Donald W DW Deary Ian J IJ Dehghan Abbas A Felix Stephan B SB Gudnason Vilmundur V Lehtimäki Terho T Mathias Rasika R Mook-Kanamori Dennis O DO Psaty Bruce M BM Rader Daniel J DJ Rotter Jerome I JI Wilson James G JG van Duijn Cornelia M CM Völzke Henry H Kathiresan Sekar S Peyser Patricia A PA O'Donnell Christopher J CJ

Circulation. Cardiovascular genetics 20161121 6

<h4>Background</h4>The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease.<h4>Methods and results</h4>We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured ...[more]

PMID: 27872105

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Project description:BackgroundThe association between subclinical cardiovascular disease and subsequent development of erectile dysfunction (ED) remains poorly described.HypothesisAmong multiple subclinical atherosclerosis and vascular dysfunction measurements, coronary artery calcium (CAC) score best predicts ED.MethodsAfter excluding participants taking ED medications at baseline, we studied 1862 men age 45 to 84 years free of known cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA) with comprehensive baseline subclinical vascular disease phenotyping and ED status assessed at MESA visit 5 (9.4 ± 0.5 years after baseline) using a standardized question on ED symptoms. Multivariable logistic regression was used to assess the associations between baseline measures of vascular disease (atherosclerosis domain: CAC, carotid intima-media thickness, carotid plaque, ankle-brachial index; vascular stiffness/function domain: aortic stiffness, carotid stiffness, brachial flow-mediated dilation) and ED symptoms at follow-up.ResultsMean baseline age was 59.5 ± 9 years, and 839 participants (45%) reported ED symptoms at follow-up. Compared with symptom-free individuals, participants with ED had higher baseline prevalence of CAC score >100 (36.4% vs 17.2%), carotid intima-media thickness Z score >75th percentile (35.3% vs 16.6%), carotid plaque score ≥2 (39% vs 21.1%), carotid distensibility <25th percentile (34.6% vs 17.1%), aortic distensibility <25th percentile (34.2% vs 18.7%), and brachial flow-mediated dilation <25th percentile (28.4% vs 21.3%); all P < 0.01. Only CAC >100 (odds ratio: 1.43, 95% confidence interval: 1.09-1.88) and carotid plaque score ≥2 (odds ratio: 1.33, 95% confidence interval: 1.02-1.73) were significantly associated with ED.ConclusionsSubclinical vascular disease is common in men who later self-report ED. Early detection of subclinical atherosclerosis, particularly advanced CAC and carotid plaque, may provide opportunities for predicting the onset of subsequent vascular ED.

Project description:OBJECTIVES:To examine the contemporary effect of smoking in a multiethnic sample, and to explore the respective contributions of inflammation and subclinical atherosclerosis to the cardiovascular consequences of smoking. APPROACH AND RESULTS:We studied 6814 participants free of cardiovascular disease and coronary heart disease (CHD) from the Multiethnic Study of Atherosclerosis. Smoking status and cumulative exposure were determined by self-report and confirmed by urinary cotinine. Multivariable Cox regression was used to estimate the association between smoking parameters and all-cause cardiovascular disease, all-cause CHD, and hard CHD events. We further adjusted for high-sensitivity C-reactive protein and coronary artery calcium (CAC) in hierarchical Cox models. We identified 3218 never smokers, 2607 former smokers, and 971 current smokers. Median follow-up was 10.2 years. Compared with never smokers, adjusted hazard ratios in current smokers were 1.7 (95% confidence interval, 1.3-2.2) for all-cause cardiovascular disease, 1.6 (1.1-2.1) for all-cause CHD, and 1.7 (1.2-2.4) for hard CHD. Similarly, among current smokers, hazard ratios were higher in the 4th versus 1st quartile of pack-years (eg, all-cause CHD hazard ratio=2.7 [1.1-6.6]). Both CAC>100 and high-sensitivity C-reactive protein ?3 mg/L identified higher relative risk among current smokers (eg, all-cause CHD hazard ratio of 3.0 [1.5-6.0, compared with CAC=0] and 2.6 [1.4-4.8, compared with high-sensitivity C-reactive protein <2 mg/L], respectively). However, CAC was a stronger mediator of events and adversely modified the effect of smoking on events (eg, P-interaction=0.02 for hard CHD). Compared with never smokers, former smokers (median cessation interval=22 years) had similar adjusted hazard for events. CONCLUSIONS:In this multiethnic cohort, current smoking and cumulative exposure remain important modifiable determinants of cardiovascular disease. Both high-sensitivity C-reactive protein ?3 mg/L and, particularly, CAC>100 identified high-risk smokers who may benefit from more intensive smoking-cessation efforts.

Project description:Cardiovascular disease (CVD) is a major comorbidity among HIV-infected individuals. Common carotid artery intima-media thickness (cCIMT) is a valid and reliable subclinical measure of atherosclerosis and is known to predict CVD. We performed genome-wide association (GWA) and admixture analysis among 682 HIV-positive and 288 HIV-negative Black, non-Hispanic women from the Women's Interagency HIV study (WIHS) cohort using a combined and stratified analysis approach. We found some suggestive associations but none of the SNPs reached genome-wide statistical significance in our GWAS analysis. The top GWAS SNPs were rs2280828 in the region intergenic to mediator complex subunit 30 and exostosin glycosyltransferase 1 (MED30 | EXT1) among all women, rs2907092 in the catenin delta 2 (CTNND2) gene among HIV-positive women, and rs7529733 in the region intergenic to family with sequence similarity 5, member C and regulator of G-protein signaling 18 (FAM5C | RGS18) genes among HIV-negative women. The most significant local European ancestry associations were in the region intergenic to the zinc finger and SCAN domain containing 5D gene and NADH: ubiquinone oxidoreductase complex assembly factor 1 (ZSCAN5D | NDUF1) pseudogene on chromosome 19 among all women, in the region intergenic to vomeronasal 1 receptor 6 pseudogene and zinc finger protein 845 (VN1R6P | ZNF845) gene on chromosome 19 among HIV-positive women, and in the region intergenic to the SEC23-interacting protein and phosphatidic acid phosphatase type 2 domain containing 1A (SEC23IP | PPAPDC1A) genes located on chromosome 10 among HIV-negative women. A number of previously identified SNP associations with cCIMT were also observed and included rs2572204 in the ryanodine receptor 3 (RYR3) and an admixture region in the secretion-regulating guanine nucleotide exchange factor (SERGEF) gene. We report several SNPs and gene regions in the GWAS and admixture analysis, some of which are common across HIV-positive and HIV-negative women as demonstrated using meta-analysis, and also across the two analytic approaches (i.e., GWA and admixture). These findings suggest that local European ancestry plays an important role in genetic associations of cCIMT among black women from WIHS along with other environmental factors that are related to CVD and may also be triggered by HIV. These findings warrant confirmation in independent samples.

Project description:Subclinical atherosclerosis (SCA) measures in multiple arterial beds are heritable phenotypes that are associated with increased incidence of cardiovascular disease. We conducted a genome-wide association study (GWAS) for SCA measurements in the community-based Framingham Heart Study.Over 100,000 single nucleotide polymorphisms (SNPs) were genotyped (Human 100K GeneChip, Affymetrix) in 1345 subjects from 310 families. We calculated sex-specific age-adjusted and multivariable-adjusted residuals in subjects tested for quantitative SCA phenotypes, including ankle-brachial index, coronary artery calcification and abdominal aortic calcification using multi-detector computed tomography, and carotid intimal medial thickness (IMT) using carotid ultrasonography. We evaluated associations of these phenotypes with 70,987 autosomal SNPs with minor allele frequency > or = 0.10, call rate > or = 80%, and Hardy-Weinberg p-value > or = 0.001 in samples ranging from 673 to 984 subjects, using linear regression with generalized estimating equations (GEE) methodology and family-based association testing (FBAT). Variance components LOD scores were also calculated.There was no association result meeting criteria for genome-wide significance, but our methods identified 11 SNPs with p < 10(-5) by GEE and five SNPs with p < 10(-5) by FBAT for multivariable-adjusted phenotypes. Among the associated variants were SNPs in or near genes that may be considered candidates for further study, such as rs1376877 (GEE p < 0.000001, located in ABI2) for maximum internal carotid artery IMT and rs4814615 (FBAT p = 0.000003, located in PCSK2) for maximum common carotid artery IMT. Modest significant associations were noted with various SCA phenotypes for variants in previously reported atherosclerosis candidate genes, including NOS3 and ESR1. Associations were also noted of a region on chromosome 9p21 with CAC phenotypes that confirm associations with coronary heart disease and CAC in two recently reported genome-wide association studies. In linkage analyses, several regions of genome-wide linkage were noted, confirming previously reported linkage of internal carotid artery IMT on chromosome 12. All GEE, FBAT and linkage results are provided as an open-access results resource at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.The results from this GWAS generate hypotheses regarding several SNPs that may be associated with SCA phenotypes in multiple arterial beds. Given the number of tests conducted, subsequent independent replication in a staged approach is essential to identify genetic variants that may be implicated in atherosclerosis.

Project description:Levels of circulating of sex hormones are associated with glucose metabolism and adiposity, but little is known about their association with ectopic fat. We aimed to characterize the association between circulating sex hormones and liver fat.We conducted a cross-sectional analysis by using data from the Multiethnic Study of Atherosclerosis to assess the association of the circulating levels of bioavailable testosterone, estradiol, dehydroepiandrosterone, and sex hormone binding globulin (SHBG) with fatty liver. Fatty liver was defined as a reduction of ?40 Hounsfield units, measured by computed tomography, in 2835 postmenopausal women and 2899 men (45-84 years old; white, black, Hispanic, or Chinese) at 6 centers in the United States.Women in the highest tertile of bioavailable testosterone were significantly more likely to have fatty liver than women in the lowest tertile (odds ratio, 1.77; 95% confidence interval, 1.07-2.92). We found an even greater difference for level of estradiol (odds ratio, 2.49; 95% confidence interval, 1.41-4.39) after adjusting for age, race/ethnicity, waist-to-hip ratio, hypertension, total and high-density lipoprotein cholesterol, smoking, insulin sensitivity, and hormone replacement therapy use. Men in the highest tertile of estradiol level were significantly more likely to have fatty liver than men in the lowest tertile (odds ratio, 2.10; 95% confidence level, 1.29-3.40). Men in the highest tertile of SHBG were less likely to have fatty liver than those in the lowest tertile (odds ratio, 0.46; 95% confidence interval, 0.27-0.77). Other associations between hormone levels and fatty liver were not statistically significant.On the basis of a cross-sectional study, postmenopausal women with high levels of bioavailable testosterone are at greater risk for fatty liver. In men, higher levels of SHBG are associated with reduced risk for fatty liver. Higher levels of estradiol are associated with fatty liver in both sexes. This pattern is consistent with the sex-specific associations of sex hormones with other cardiometabolic risk factors.

Project description:The global rise in fatty liver is a major public health problem. Thus, it is critical to identify both global and population-specific genetic variants associated with liver fat. We conducted a genome-wide association study (GWAS) of percent liver fat and nonalcoholic fatty liver disease (NAFLD) assessed by magnetic resonance imaging in 1,709 participants from the population-based Multiethnic Cohort Adiposity Phenotype Study. Our participants comprised older adults of five U.S. racial/ethnic groups: African Americans (n = 277), Japanese Americans (n = 424), Latinos (n = 348), Native Hawaiians (n = 274), and European Americans (n = 386). The established missense risk variant rs738409 located in patatin-like phospholipase domain containing 3 (PNPLA3) at 22q13 was confirmed to be associated with percent liver fat (P = 3.52 × 10-15) but more strongly in women than men (P heterogeneity = 0.002). Its frequency correlated with the prevalence of NAFLD across the five ethnic/racial groups. Rs738409 was also associated with homeostasis model assessment of insulin resistance (HOMA-IR) (beta = 0.028; P = 0.009) and circulating levels of insulin (beta = 0.022; P = 0.020) and alanine aminotransferase (beta = 0.016; P = 0.030). A novel association of percent liver fat with rs77249491 (located at 6q13 between limb region 1 domain containing 1 [LMBRD1] and collagen type XIX alpha 1 chain [COL19A1] (P = 1.42 × 10-8) was also observed. Rs7724941 was associated with HOMA-IR (beta = 0.12; P = 0.0005), insulin (beta = 0.11; P = 0.0003), triglycerides (beta = 0.059; P = 0.01), high-density lipoprotein (beta = -0.046; P = 0.04), and sex hormone binding globulin (beta = -0.084; P = 0.0012). This variant was present in Japanese Americans (minor allele frequency [MAF], 8%) and Native Hawaiians (MAF, 2%). Conclusion: We replicated the PNPLA3 rs738409 association in a multiethnic population and identified a novel liver fat risk variant in Japanese Americans and Native Hawaiians. GWASes of percent liver fat in East Asian and Oceanic populations are needed to replicate the rs77249491 association.

Dataset Information

Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.

Publications

Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.

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