Dataset Information

Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.

ABSTRACT: 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.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 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 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.Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

SUBMITTER: Franceschini N

PROVIDER: S-EPMC3293207 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.

Franceschini Nora N Carty Cara C Bůzková Petra P Reiner Alex P AP Garrett Tiana T Lin Yi Y Vöckler Jens-S JS Hindorff Lucia A LA Cole Shelley A SA Boerwinkle Eric E Lin Dan-Yu DY Bookman Ebony E Best Lyle G LG Bella Jonathan N JN Eaton Charles C Greenland Philip P Jenny Nancy N North Kari E KE Taverna Darin D Young Alicia M AM Deelman Ewa E Kooperberg Charles C Psaty Bruce B Heiss Gerardo G

Circulation. Cardiovascular genetics 20111031 6

<h4>Background</h4>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.<h4>Methods and results</h4>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), ...[more]

PMID: 22042884

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Project description:Aims/hypothesisSleep duration is a risk factor for incident diabetes mellitus and CHD. The primary aim of the present study was to investigate, in sex-specific analyses, the role of incident diabetes as the possible biological mechanism for the reported association between short/long sleep duration and incident CHD. Considering that diabetes is a major risk factor for CHD, we hypothesised that any association with sleep duration would not hold for cases of incident CHD occurring before incident diabetes ('non-diabetes CHD') but would hold true for cases of incident CHD following incident diabetes ('diabetes-CHD').MethodsA total of 6966 men and 9378 women aged 45-73 years from the Malmö Diet Cancer Study, a population-based, prospective cohort, who had answered questions on habitual sleep duration and did not have a history of prevalent diabetes or CHD were included in the analyses. Incident cases of diabetes and CHD were identified using national registers. Sex-specific Cox proportional hazards regression models were stratified by BMI and adjusted for known covariates of diabetes and CHD.ResultsMean follow-up times for incident diabetes (n = 1137/1016 [men/women]), incident CHD (n = 1170/578), non-diabetes CHD (n = 1016/501) and diabetes-CHD (n = 154/77) were 14.2-15.2 years for men, and 15.8-16.5 years for women. In men, short sleep duration (< 6 h) was associated with incident diabetes (HR 1.35, 95% CI 1.01, 1.80), CHD (HR 1.41, 95% CI 1.06, 1.89) and diabetes-CHD (HR 2.34, 95% CI 1.20, 4.55). Short sleep duration was not associated with incident non-diabetes CHD (HR 1.35, 95% CI 0.98, 1.87). Long sleep duration (≥ 9 h) was associated with incident diabetes (HR 1.37, 95% CI 1.03, 1.83), CHD (HR 1.33, 95% CI 1.01, 1.75) and diabetes-CHD (HR 2.10, 95% CI 1.11, 4.00). Long sleep duration was not associated with incident non-diabetes CHD (HR 1.33, 95% CI 0.98, 1.80). In women, short sleep duration was associated with incident diabetes (HR 1.53, 95% CI 1.16, 2.01), CHD (HR 1.46, 95% CI 1.03, 2.07) and diabetes-CHD (HR 2.88, 95% CI 1.37, 6.08). Short sleep duration was not associated with incident non-diabetes CHD (HR 1.29, 95% CI 0.86, 1.93).Conclusions/interpretationThe associations between sleep duration and incident CHD directly reflect the associations between sleep duration and incident diabetes. Incident diabetes may thus be the explanatory mechanism for the association between short and long sleep duration and incident CHD.

Project description:BackgroundGenome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.Methods and resultsUsing samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.ConclusionThis study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

Dataset Information

Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.

Publications

Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.

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