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Two chromosome 9p21 haplotype blocks distinguish between coronary artery disease and myocardial infarction risk.

ABSTRACT: Variants at the 9p21 locus associate with the risk of coronary artery disease (CAD) or myocardial infarction (MI). However, atherosclerotic plaque deposition is distinct from MI (plaque rupture and thrombosis), and recent studies showed no association between these variants and MI in patients with preexisting CAD. We performed haplotype analysis at the 9p21 locus to test whether haplotypes at distinct linkage disequilibrium blocks predict these phenotypes.Using 24 single-nucleotide polymorphisms genotyped in white patients without diabetes mellitus, we reconstructed haplotypes at the 9p21 locus. Patients with angiograhic CAD/MI had ?1 epicardial stenosis >50% (n=2352), whereas controls were asymptomatic and over the age of 60 years (n=2116). For CAD patients, regression models examined the association of haplotypes with initial age of symptomatic CAD, number of diseased vessels, and history of MI. In the case-control study, only haplotypes at 1 block tagged by rs1333049 associated with CAD more so than MI. These haplotypes also associated with early onset of CAD (?=-0.13; P=1.37×10(-4)) and disease severity (?=0.1823; P=0.006) but not with prevalent MI among patients with CAD. In contrast, haplotypes at another block tagged by rs518394 associated with prevalent MI (?=0.239; P=2.05×10(-4)), but remarkably these are inversely associated with disease severity (?=-0.196; P=0.003). This MI association was replicated in the Cleveland Clinic GeneBank premature CAD cohort (n=1385; ?=0.207; P=0.019).Variants/haplotypes at 2 blocks are distinguished at 9p21; those at 1 block predispose to atherosclerosis, whereas those at the other predispose to MI among patients with preexisting CAD.

SUBMITTER: Fan M

PROVIDER: S-EPMC3839299 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Two chromosome 9p21 haplotype blocks distinguish between coronary artery disease and myocardial infarction risk.

Fan Meng M Dandona Sonny S McPherson Ruth R Allayee Hooman H Hazen Stanley L SL Wells George A GA Roberts Robert R Stewart Alexandre F R AF

Circulation. Cardiovascular genetics 20130531 4

<h4>Background</h4>Variants at the 9p21 locus associate with the risk of coronary artery disease (CAD) or myocardial infarction (MI). However, atherosclerotic plaque deposition is distinct from MI (plaque rupture and thrombosis), and recent studies showed no association between these variants and MI in patients with preexisting CAD. We performed haplotype analysis at the 9p21 locus to test whether haplotypes at distinct linkage disequilibrium blocks predict these phenotypes.<h4>Methods and resul ...[more]

PMID: 23729007

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Project description:ObjectiveApproximately 10% of patients undergoing cardiac surgery have perioperative myocardial injury. A recent genome-wide association study identified an association between myocardial infarction in nonsurgical populations and common genetic variants on chromosome 9p21. We hypothesized that these variants are also associated with perioperative myocardial injury after isolated primary coronary artery bypass graft surgery.MethodsIn a prospective observational study of 846 Caucasian patients undergoing primary coronary bypass surgery at 2 US centers, we genotyped 61 linkage-disequilibrium tagging single nucleotide polymorphisms, encompassing 436 kbp of the 9p21 region. A multivariable logistic model was used to adjust for previously identified clinical covariates of perioperative myocardial injury. Perioperative myocardial injury was defined as a postoperative day 1 cardiac troponin I in the top 10th percentile (>9.13 microg/L) of the cohort. Multiple testing of single nucleotide polymorphisms was corrected for with family-wise errors.ResultsPrior myocardial infarction and longer cardiopulmonary bypass time were significant independent predictors of perioperative myocardial injury. Levels of postoperative cardiac troponin I were incrementally increased for each additional copy of the risk alleles of 3 single nucleotide polymorphisms: rs10116277, rs6475606, and rs2383207. Adjusted additive odds ratios ranged between 1.64 and 1.79 (asymptotic P value between 3.7 x 10(-3) and 6 x 10(-4)) and remained significantly associated with perioperative myocardial injury even after accounting for clinical covariates including severity of coronary disease, and multiple comparisons.ConclusionsWe have now demonstrated that common genetic variants in the same 9p21 locus, previously known to be associated with myocardial infarction in nonsurgical populations, are also associated with perioperative myocardial injury after coronary artery bypass grafting. Further investigation is warranted to elucidate functional mechanisms.

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Two chromosome 9p21 haplotype blocks distinguish between coronary artery disease and myocardial infarction risk.

Publications

Two chromosome 9p21 haplotype blocks distinguish between coronary artery disease and myocardial infarction risk.

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