Abstract 477: Genetic Variation in Cyclooxygenase-Dependent Platelet Activation is an Uncommon Cause of Diminished Aspirin Responsiveness
Background: Cardioprotection from low dose aspirin (ASA) is attributed to its ability to inhibit platelet activation and thromboxane formation through irreversible acetylation of cycoloxygenase-1 (COX-1). Gene variants may be responsible for differences among individuals in the inhibitory effect of ASA. We evaluated the impact of gene variants involving proteins directly involved in COX-dependent platelet activation and the ability of ASA to inhibit platelet aggregation and thromboxane formation.
Methods and Results: Platelet aggregation to arachidonic acid (AA), thromboxane B2 (TxB2) formation in response to collagen, and thromboxane formation in vivo (urinary Tx-M) were evaluated in 1636 subjects (mean age 46 +/− 13 yrs, 55% female, 37% black) from families with coronary heart disease before and after ASA (81 mg/day for 2 weeks). Single nucleotide polymorphisms (SNPs) in COX-1, COX-2, thromboxane A2 synthase (TBXAS1), and thromboxane A2 receptor (TBXA2R) were selected to optimize coverage of each gene sequence at 2–4-kb density, and genotyping was performed 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). After ASA, <10% of subjects had any aggregation response to AA, and ex vivo TxB2 release was inhibited >95%. Inhibition of Tx-M was more variable. The inhibitory effect of ASA was diminished in heterozygotes with a minor allele variant in the thromboxane A2 synthase gene (table⇓). We did not find a significant association between ASA response phenotype and variants of COX-1, COX-2, or TBXA2R.
Conclusions: Genetic variation in TBXAS1 is associated with reduced platelet ASA responsiveness but this variant is uncommon.