Abstract 3569: Genetic Contribution to Collagen-Induced Platelet Aggregation Following Low-Dose Aspirin in Families with Premature Coronary Artery Disease
Background: Lesser suppression by aspirin (ASA) of collagen-induced platelet aggregation predicts myocardial infarction and stroke. Variability in platelet aggregation to collagen was recently shown to be under genetic control; however, the specific genes that contribute to phenotypic variation are not known.
Methods: We examined platelet function in 955 Caucasian (mean age 47+/−13.54, 52% female) and 541 African-American (mean age 45.71+/−12.7, 60% female) healthy subjects with a family history of early onset coronary artery disease (CAD). Collagen-induced platelet aggregation was measured by optical aggregometry after subjects were treated with low dose ASA (81 mg/day) for 2 weeks. 2638 single nucleotide polymorphisms (SNPs) from 191 candidate genes were evaluated using the Illumina platform. The ASSOC subroutine of SAGE was used to examine genotype-phenotype associations. To help discriminate true from false positive associations, while at the same time maintaining sensitivity, we propose a new approach in which SNPs are considered “significant” only when alpha < 0.05 in both whites and blacks, combined with a locus specific heritability (LSH) ≥1% in both groups.
Results: Using the Bonferroni correction to establish a p value threshold, no SNPs were associated with the phenotype. However, SNPs in 8 genes (ITGA2G, ITGB2, MAPK10, RAP1A, RGS10, VAV1, PEAR1 (platelet endothelial aggregation receptor 1), and PAFAH1B (platelet-activating factor acetylhydrolase) met the criteria of having significant p values in both groups, and SNPs in only 2 of the genes (PEAR1 and PAFAH1B) also contributed 31% to LSH (Table⇓). For both genes, the allele associated with a decreased response to ASA was the major allele among Caucasians, but the minor allele among African-Americans.
Conclusions: Variants in PEAR1 and PAFAH1B are associated with decreased response to ASA in both African-Americans and Caucasians. Each contributes more than 1% to the genetic variance.