Abstract 3563: Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Missense Variant is Reproducibly Associated with Early-Onset Myocardial Infarction in >1500 Cases and 1500 Controls
Background: There are few, if any, replicable genetic associations for myocardial infarction (MI). We sought to replicate a set of single nucleotide polymorphisms (SNPs) reported to be associated with MI or related cardiovascular disease outcomes.
Materials and Methods: We studied 27 SNPs at 20 loci in the MI Genetics Consortium, consisting of 1544 cases of early-onset MI (men≤50y or women≤60y) and 1700 age- and gender-matched controls free of MI from five international sites:Spain, Finland, Sweden, Seattle, and Boston. We studied SNPs in ALOX5AP,CFH,ESR1,F5,F7,FGB,GATA2,KCNMB1,LGALS2,LTA,LTA4H,PCSK9, PLAT,PSMA6,PTGS2,SERPINE1,TNFSF4,USF1,VKORC1,and ZNF627. Nearly all participants were of self-reported European ancestry. Genotyping was performed using the Sequenom MassARRAY platform. Within each study site, Fisher’s exact test was used to study the association of SNPs with MI status. To summarize the statistical evidence across study sites, we performed a Cochran-Mantel-Haenszel (CMH) test stratified by study site.
Results: Mean age of MI cases was 45y among women and 48y among men. Of 1544 cases, 578 (37%) were women. Given our sample size, we had 90% power to detect a 1.25-fold effect size per allele at an alpha of 0.003 (alpha=0.05/20 loci) and a risk allele frequency of 25%. Nonetheless, only a single SNP achieved a P<0.003, that being a PCSK9 missense variant (rs11591147, R46L) recently identified by Cohen et al. (N Engl J Med 2006). In a meta-analysis of all five sites, the minor T allele (2.3% frequency in controls) was associated with a 60% lower odds of MI (OR 0.40, 95% CI 0.26 – 0.61, P=1.0x10−5 across all studies, Table⇓).
Conclusion: A common missense SNP at the PCSK9 locus confers decreased risk for early-onset MI. This DNA sequence variant represents among the first genetic associations for MI to be replicated in multiple populations. Efforts are ongoing to confirm an additional locus (Chr 9p near CDKN2A/CDKN2B) recently reported to be associated with MI.