Abstract 839: A Common Allele at the GRB14 Locus is Associated with Increased Cardiovascular Risk in Type 2 Diabetes: Evidence from a Pooled DNA GWA Study

Abstract

Genetics factor have long been recognized as important modulators of the risk of coronary artery disease (CAD) in both the general and the diabetic population. Evidence from our group indicates that some of these genes may act synergistically with the diabetic milieu, resulting into an especially strong effect among diabetic individuals. To search the genome for variants having a major effect on CAD risk in type 2 diabetes (T2D), we conducted a 300K SNP genome-wide association (GWA) study using DNA pools made from 322 CAD-positive and 412 CAD-negative individuals with T2D of European origin from the Joslin Heart Study (JHS). SNPs associated with CAD were found to cluster on chromosomes 2q24, 5p14, 9p21, and 14q31. These association signals were confirmed by genotyping of individual DNA samples, with additive ORs in the 1.4–1.6 range. The signal on chromosome 9p21 corresponded to the CAD locus that had been identified in the general population in the vicinity of the CDKN2A/CDKN2B genes. Of the other three regions emerging from the GWA screen, chromosome 2q24 showed the strongest association with CAD. The most representative SNP at this location (rs631871, additive OR=1.53, 95%CI=1.24–1.88, p=7.5 × 10 −5 ) was placed in the 3′ flanking region of the Growth Factor Receptor-Bound 14 ( GRB14 ) gene, which codes for an adapter protein with inhibitory effects on insulin receptor signaling. A similar association was found between rs631871 and cardiovascular mortality in an independent group of 475 type 2 diabetic patients (mean age at baseline=57±10 y) who were recruited at the Joslin Clinic for genetic studies in 1994–1996. In this cohort, the cumulative 10-year cardiovascular mortality was 28.1% among homozygotes for the risk allele, 20.0% among heterozygotes, and 15.8% among homozygotes for the protective allele (age and sex adjusted additive HR=1.41, 95%CI 1.04–1.90, p=0.026). By contrast, the association with increased cardiovascular risk was not confirmed in this cohort for the signals on 5p14 and 14q31. These findings point to the insulin signaling inhibitor GRB14 as a possible modulator of cardiovascular risk among individuals with T2D.