Abstract 14028: Exome Sequencing Identifies Rare Alleles Contributing to the Inherited Basis of Early-Onset Myocardial Infarction
Myocardial infarction (MI) is the leading cause of death and disability worldwide and is heritable. Studies of common genetic variation have discovered more than 45 genes and loci associated with risk for MI. Whereas rare genetic variation has long been recognized to underlie the inheritance of Mendelian diseases, the extent to which rare variation contributes to complex genetic disorders such as MI has been widely debated. The purpose of this study was to test the hypothesis that rare (frequency < 1%) DNA sequence variation contributes to risk for MI. The protein-coding regions of ~18,500 genes (the “exome”) were deeply sequenced in each of 4,000 individuals with early-onset MI (men with MI ≤ age 50; women with MI ≤ age 60) and in 3,800 individuals without MI. From this initial discovery study, we sought replication using targeted re-sequencing in larger populations (n=13,432). Rare non-synonymous mutations in two genes were more frequent in early-onset MI patients versus MI-free controls at a level of statistical significance exceeding a stringent correction for the number of genes in the genome (threshold = 2x10-6). Deleterious mutations in the low-density lipoprotein receptor (LDLR) gene were present in 4.0% of cases compared with 1.3% of controls, representing an odds ratio for disease of 3.1 for mutation carriers (p = 4x10-10). In the gene apolipoprotein A-V (APOA5), 1.3% of cases carried a non-synonymous mutation compared with 0.6% of controls, representing an odds ratio for disease of 2.2 for mutation carriers (p = 5x10-7). The mutations associated with MI risk in LDLR and APOA5 prominently relate to elevations in low-density lipoprotein cholesterol and triglyceride levels, respectively. We demonstrate, for the first time, that a burden of rare variants in individual genes contributes to risk for a common, complex disease and definitively establish APOA5 as a gene responsible for MI in the population.
- © 2013 by American Heart Association, Inc.