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.