In both the CARE and the WOSCOPS trials, carriers of the KIF6 719Arg allele had an increased risk of coronary events, and pravastatin treatment substantially reduced that risk.

Objective-We asked whether single nucleotide polymorphisms (SNPs) that had been nominally associated with cardiovascular disease in antecedent studies were also associated with cardiovascular disease in a population-based prospective study of 4522 individuals aged 65 or older. Methods and Results-Based on antecedent studies, we prespecified a risk allele and an inheritance model for each of 74SNPs. We then tested the association of these SNPs with myocardial infarction (MI) in the Cardiovascular Health Study (CHS). The prespecified risk alleles of 8 SNPs were nominally associated (1-sided PϽ0.05) with increased risk of MI in White CHS participants. The false discovery rate for these 8 was 0.43, suggesting that about 4 of these 8 are likely to be true positives. The 4 of these 8 SNPs that had the strongest evidence for association with cardiovascular disease before testing in CHS (association in 3 antecedent studies) were in KIF6 (CHS HRϭ1.29; 90%CI 1.1 to 1.52), VAMP8 (HRϭ1.2; 90%CI 1.02 to 1.41), TAS2R50 (HRϭ1.13; 90%CI 1 to 1.27), and LPA (HRϭ1.62; 90%CI 1.09 to 2.42). Key Words: coronary disease Ⅲ myocardial infarction Ⅲ genetics Ⅲ polymorphisms C ardiovascular disease is a complex disease with a genetic component, 1 and many genetic polymorphisms have been reported to be associated with cardiovascular disease. 2 However, to confirm these associations, they should be examined in other populations, ideally in population-based prospective studies that have sufficient power to detect the hypothesized associations. One such population-based prospective study is the Cardiovascular Health Study (CHS), a study of American men and women 65 years and older sponsored by the National Heart, Lung, and Blood Institute. 3,4 CHS offers several strengths, including a large population-based cohort, collection of baseline data for traditional risk factors, long follow-up, and central adjudication of cardiovascular events. Conclusions-AlthoughWe have been investigating the association between cardiovascular disease and single nucleotide polymorphisms (SNPs) using a panel of Ϸ12 000 mostly nonsynonymous SNPs. [5][6][7] The discovery studies for these investigations were conducted in case-control studies that included patients enrolled by investigators at the Cleveland Clinic Foundation (CCF) and the University of California, San Francisco (UCSF) [5][6][7] ; the association between 9 of these SNPs and cardiovascular disease in multiple discovery studies has been previously described. [5][6][7][8][9] We have used these 9 SNPs to build multiplex assays that are suitable for genotyping thousands of samples even when only a limited quantity of DNA is available for each sample. These multiplex assays also contain assays for 65 additional SNPs that were found to be associated with cardiovascular disease in one or more of the discovery studies (for these 65 SNPs, the results of the antecedent discovery studies are presented in the online supplement of this article, available online at http://atvb. ahajournals.org). We investigated wheth...

Family history is a major risk factor for myocardial infarction (MI). However, known gene variants associated with MI cannot fully explain the genetic component of MI risk. We hypothesized that a gene-centric association study that was not limited to candidate genes could identify novel genetic associations with MI. We studied 11,053 single-nucleotide polymorphisms (SNPs) in 6,891 genes, focusing on SNPs that could influence gene function to increase the likelihood of identifying disease-causing gene variants. To minimize false-positive associations generated by multiple testing, two studies were used to identify a limited number of nominally associated SNPs; a third study tested the hypotheses that these SNPs are associated with MI. In the initial study (of 340 cases and 346 controls), 637 SNPs were associated with MI (P<.05); these were evaluated in a second study (of 445 cases and 606 controls), and 31 of the 637 SNPs were associated with MI (P<.05) and had the same risk allele as in the first study. For each of these 31 SNPs, we tested the hypothesis that it is associated with MI, using a third study (of 560 cases and 891 controls). We found that four of these gene variants were associated with MI (P<.05; false-discovery rate <10%) and had the same risk allele as in the first two studies. These gene variants encode the cytoskeletal protein palladin (KIAA0992 [odds ratio (OR) 1.40]), a tyrosine kinase (ROS1 [OR 1.75]), and two G protein-coupled receptors (TAS2R50 [OR 1.58] and OR13G1 [OR 1.40]); all ORs are for carriers of two versus zero risk alleles. These findings could lead to a better understanding of MI pathophysiology and improved patient risk assessment.

Carriers of 719Arg receive significantly greater benefit from intensive statin therapy than do noncarriers, a superior benefit that appears to be due to a mechanism distinct from lipid or CRP lowering. Functional studies of the KIF6 kinesin are warranted, given the consistent association of Trp719Arg with risk of coronary events and statin benefit.