Cumulative Burden of Atherosclerotic Risk Genotypes and the Age at Onset of a First Myocardial Infarction: A Case‐Only Carriership Approach

Abstract

Previously identified atherosclerotic genetic factors have been studied mostly in case-control studies and in nonuniform ethnic populations, whereas data on the cumulative contribution of genetic factors to an earlier onset of a first myocardial infarction (MI) are limited. We hypothesized that several genetic atherosclerotic single nucleotide polymorphisms (SNPs) may exert an additive effect on the earlier occurrence of coronary atherothrombotic disease after adjustment for clinical factors. Eighteen atherosclerotic high-risk SNPs were selected based upon meta-analyses of 614 published reports, and were incorporated into a carriership model. Multivariate regression analysis was used to identify the independent contribution of selected genotypes to the age at onset of a first MI in a cohort of 814 white (n = 622) and nonwhite (n = 192) patients enrolled in the Thrombogenic Factors and Coronary Events Study. The analysis demonstrated that selected genotypes were significantly associated with an earlier occurrence of a first MI among white patients (an average of 0.6 year reduction per carried genotype; P = 0.027), whereas the contribution of genotypes to MI onset among nonwhite patients was not significant (an average of 0.7 year increase per carried genotype; P = 0.16), with a significant ethnic x genotype interaction effect (P = 0.02). Our findings suggest that currently identified atherosclerotic genetic factors confer an independent additive contribution to the earlier onset of coronary atherothrombotic disease among white patients. The lack of a significant association between these genotypes and outcome in other ethnic groups suggests that cardiovascular genetic risk should be studied directly in these populations.