Abstract 15641: Genome-Wide Association Study and Meta-Analysis of Aspirin Responsiveness in Individuals of European Descent
While familial studies have established that inter-individual variability in platelet response to aspirin (ASA) is partly due to genetic variation, a genome-wide association study (GWAS) has not been reported. Fasting blood samples were obtained from healthy participants of European descent enrolled in the GeneSTAR (N=1257) and HAPI Heart (N=730) cohorts. Impedance aggregometry in whole blood after arachidonic acid (AA)-, ADP-, and collagen-induced platelet aggregation was used to measure lag-time and maximal platelet aggregation before and after 14-days of 81 mg/day ASA. In each cohort, mixed effects models accounting for family structure were used to test for association between each SNP and each age- and sex-adjusted phenotype. We analyzed data with adjustment for pre-ASA platelet studies to examine the pure effect of ASA and without adjustment which is likely to be more relevant to the clinically observed effect. Effect sizes were pooled using meta-analysis. We sought region-based replication in African Americans from GeneSTAR (N=868) with adjustment for linkage disequilibrium. We observed SNPs in 7 regions for 5 platelet phenotypes that crossed GWAS significance threshold (p<5 x 10-8). Without adjusting for pre-ASA platelet function, rs7126105 (p=3.03 x 10-10), rs1335783 (p = 3.05 x 10-8), and rs133955 (SYN3, p = 3.8 x 10-8) were associated with lag-time to AA (1.6 mmol), and rs9483319 (ENPP3, p=4.52 x 10-8) was associated with lag-time to collagen (5 ug/mL). After adjustment for pre-ASA platelet aggregation, rs7126105 and rs1335783 remained associated with lag-time to AA. Additionally, we found association of rs3821025 (EPHA4, p = 1.33 x 10-8) with lag-time to AA, rs16833022 (p = 4.1 x 10-9) with lag-time to collagen, and rs11595587 (MAT1A, p=1.9 x 10-8) with lag-time to ADP (10 umol). In the replication sample, two SNPs (rs470006 and rs1430216) adjacent to rs133955 and rs3821025 were significantly associated with lag-time to AA (both p = 0.02). In this first GWAS and meta-analysis of platelet response to ASA, we show a relationship between post-ASA platelet response and 7 regions, two of which were replicated in an independent sample. In particular, EPHA4 is expressed in megakaryocytes and represents a good candidate for functional studies.
- © 2011 by American Heart Association, Inc.