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Association of variation in the chromosome 9p21 locus with myocardial infarction versus chronic coronary artery disease.

ABSTRACT: A chromosome 9p21 locus is associated with coronary heart disease in 25 independent populations, but multiple clinically distinct phenotypes have been evaluated. Using angiographic coronary artery disease (CAD) phenotyping, this study evaluated whether 9p21 single-nucleotide polymorphisms predict ischemic events (eg, myocardial infarction [MI]) among CAD patients.Patients undergoing coronary angiography during 1994 to 2007 (population set 1A: n=1748; set 1B: n=1014) were evaluated for association of a 9p21 tagging single-nucleotide polymorphism (rs2383206, A 224 G) with incident MI and death events among patients with angiographically significant CAD. Another hypothesis evaluated rs2383206 in 2 additional angiographic sets of both CAD and non-CAD patients (set 2A: n=2122; set 2B: n=1466) for prevalent MI versus CAD/no MI (and for MI versus non-CAD and CAD/no MI versus non-CAD). No association of rs2383206 was found with events in set 1A (odds ratio, 0.95 per G allele; P trend=0.48) and set 1B (odds ratio, 0.91 per G allele; P trend=0.28) or with MI versus CAD/no MI in set 2A (odds ratio, 0.96 per G allele; P trend=0.57) and set 2B (odds ratio, 0.89 per G allele; P trend=0.21). In contrast, rs2383206 was associated with CAD/no MI compared with non-CAD (set 2A: P trend=0.0001; set 2B: P trend=0.0008).The chromosome 9p21 locus was not associated with incident events or prevalent MI, although it did predict CAD diagnosis. This contradicts reports of a 9p21 association with MI, likely because of differences in phenotype assignment. This suggests that high-quality phenotyping for CAD and MI is required to dissect the specific contributions of genetic variation to each stage of coronary heart disease pathophysiology.

SUBMITTER: Horne BD

PROVIDER: S-EPMC2745117 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Association of variation in the chromosome 9p21 locus with myocardial infarction versus chronic coronary artery disease.

Horne Benjamin D BD Carlquist John F JF Muhlestein Joseph B JB Bair Tami L TL Anderson Jeffrey L JL

Circulation. Cardiovascular genetics 20081201 2

<h4>Background</h4>A chromosome 9p21 locus is associated with coronary heart disease in 25 independent populations, but multiple clinically distinct phenotypes have been evaluated. Using angiographic coronary artery disease (CAD) phenotyping, this study evaluated whether 9p21 single-nucleotide polymorphisms predict ischemic events (eg, myocardial infarction [MI]) among CAD patients.<h4>Methods and results</h4>Patients undergoing coronary angiography during 1994 to 2007 (population set 1A: n=1748 ...[more]

PMID: 19956784

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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.

Project description:BackgroundCase-control Genome-Wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) at the 9p21 locus as risk factors for coronary artery disease (CAD). The locus does not contain a clear candidate gene. Hence, the results of GWAS have raised an intense interest in delineating the basis for the observed association. We analyzed association of 4 SNPs at the 9p21 locus with the severity and progression of coronary atherosclerosis, as determined by serial quantitative coronary angiograms (QCA) in the well-characterized Lipoprotein Coronary Atherosclerosis Study (LCAS) population. The LCAS is a randomized placebo-control longitudinal follow-up study in patients with CAD conducted to test the effects of fluvastatin on progression or regression of coronary atherosclerosis.MethodsExtensive plasma lipid levels were measured at the baseline and 2 1/2 years after randomization. Likewise serial QCA was performed at the baseline and upon completion of the study. We genotyped the population for 4 SNPs, previously identified as the susceptibility SNPs for CAD in GWAS, using fluorogenic 5' nuclease assays. We reconstructed the haplotypes using Phase 2, analyzed SNP and haplotype effects using the Thesias software as well as by the conventional statistical methods.ResultsOnly Caucasians were included since they comprised 90% of the study population (332/371 with available DNA sample). The 4 SNPs at the 9p21 locus were in tight linkage disequilibrium, leading to 3 common haplotypes in the LCAS population. We found no significant association between quantitative indices of severity of coronary atherosclerosis, such as minimal lumen diameter and number of coronary lesions or occlusions and the 9p21 SNPs and haplotypes. Likewise, there was no association between quantitative indices of progression of coronary atherosclerosis and the SNPs or haplotypes. Similarly, we found no significant SNP or haplotype effect on severity and progression of coronary atherosclerosis.ConclusionWe conclude the 4 SNPs at the 9p21 locus analyzed in this study do not impart major effects on the severity or progression of coronary atherosclerosis. The effect size may be very modest or the observed association of the CAD with SNPs at the 9p21 locus in the case-control GWAS reflect involvement of vascular mechanisms not directly related to the severity or progression of coronary atherosclerosis.

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Association of variation in the chromosome 9p21 locus with myocardial infarction versus chronic coronary artery disease.

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Association of variation in the chromosome 9p21 locus with myocardial infarction versus chronic coronary artery disease.

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