Four SNPS on Chromosome 9p21 Confer Risk to Premature, Familial CAD and MI in an American Caucasian Population (GeneQuest)

Genome-wide association studies have separately identified four single nucleotide polymorphisms (SNPs) on chromosome 9p21 that confer susceptibility to coronary artery disease (CAD) and myocardial infarction (MI). This study presents the first analysis of these SNPs (rs10757274, rs2383206, rs2383207, and rs10757278) in a premature, familial CAD/MI population (GeneQuest). We performed a case-control analysis of the GeneQuest Caucasian population with 310 cases with premature CAD and MI (average age at onset of 40.3 ± 5.1) and 560 non-CAD controls to determine if these SNPs are associated with risk of CAD using both the population-based and family-based association study designs. The four SNPs are significantly associated with premature and familial MI and CAD in the GeneQuest Caucasian population (allelic P = 6.61 × 10⁻⁷ to 1.87 × 10⁻⁸). Sib-TDT analysis showed that three of the four SNPs could confer significant susceptibility to premature CAD and MI. These results indicate that the four SNPs on chromosome 9p21 are also associated with premature, familial CAD.     

Association of SNP rs17465637 on chromosome 1q41 and rs599839 on 1p13.3 with myocardial infarction in an American caucasian population

Recent genome-wide single nucleotide polymorphism (SNP) association studies (GWAS) have identified a number of SNPs that were significantly associated with coronary artery disease and myocardial infarction (MI). However, many independent replication studies in other populations are needed to unequivocally confirm the GWAS association. To assess GWAS association, we have established a case-control cohort consisting of 1231 well-characterised MI patients and 560 controls without detectable coronary stenosis, all selected from the Cleveland Genebank population. The Genebank cohort has sufficient power to detect the association between MI and four GWAS SNPs, including rs17465637 within the MIA3 gene, rs2943634 (intergenic), rs6922269 in MTHFD1L, and rs599839 near SORT1. SNPs were genotyped by TaqMan assays and follow-up multivariate logistic regression analysis with incorporation of significant covariates showed significant association with MI for MIA3 SNP rs17465637 (P-adj= 0.0034) and SORT1 SNP rs599839 (P-adj= 0.009). The minor allele G of rs599839 was also associated with a decreased LDL-C level of 5-9 mg/dL per allele, but not with HDL-C or triglyceride levels. No association for MI or lipid levels was found for SNPs rs2943634 and rs6922269 (P-adj > 0.05). Our results establish two SNPs, rs17465637 in MIA3 and rs599839 near SORT1 as significant risk factors for MI in the American Genebank Caucasian population.