Abstract 638: Gene Variants in Collagen Signaling Alter Platelet Function and Response to Aspirin
Introduction: Collagen is a critical physiologic platelet agonist that activates platelets by direct binding to platelet surface proteins, causing outside-in signaling. Few studies have examined the impact of variants in genes that encode platelet collagen receptors and signaling molecules and responsiveness to antiplatelet therapy. We examined the association between ex vivo collagen-induced platelet activation and collagen-related platelet genes before and after aspirin (ASA 81 mg/day x 14 days).
Methods and Results: Collagen-induced platelet aggregation and platelet function analyzer closure time (collagen-epinephrine cartridge) were evaluated in 1650 subjects from families with coronary heart disease (mean age 46 +/− 13 yrs, 55% women, 38% black). Single nucleotide polymorphisms (SNPs) in the genes for integrin alpha2 (ITGA2), integrin beta1 (ITGB1), GPVI, and phospholipase C gamma2 (PLCG2) were selected to optimize coverage of each gene sequence at a density of 2– 4kb. DNA was genotyped using the Illumina platform. Associations between SNPs and phenotypes were determined by multivariable linear regression after adjusting for familial correlations and coronary risk factor covariates. Associations were considered significant at an alpha of P <0.00005 to account for multiple comparisons (~50 SNPs x 20 phenotypes). Multiple SNPs in the gene for ITGA2 were in complete linkage disequilibrium and each was significantly related to aggregation lag time. Genotypes with the minor allele were associated with shorter lag times to collagen, which persisted after ASA treatment. The strongest SNP-phenotype association occurred for rs12517446 (table⇓), which is 20 kb 3′ of the previously described C807T polymorphism. There was a trend toward greater aggregation after ASA for minor allele homozygotes of SNP rs4889383 of the PLCG2 gene.
Conclusions: Genetic variants of ITGA2 and PLCG2 enhance platelet activation by collagen and diminish ASA responsiveness.