Abstract 365: Genetic Variants in ALOX5 and ALOX5AP are Associated with Reduced Response to Aspirin in African American Families with Premature Coronary Artery Disease

Abstract

Background: ALOX5 (arachidonate 5-lipoxygenase) and ALOX5AP (arachidonate 5-lipoxygenase activating protein) are involved in the production of leukotrienes, which may interact with cyclo-oxygenase to alter the formation of thromboxane. Reduced suppression of thromboxane production by aspirin (ASA) was associated with worse cardiovascular outcomes in the HOPE study. We therefore examined whether genetic variants in ALOX5 or ALOX5AP could modify the effect of ASA on thromboxane production. Methods: We measured urinary 11-dehydro-thromboxane B2 (UTX) levels after 2 weeks of ASA, 81 mg/day, in 1546 healthy individuals from 2-generational families with premature coronary heart disease (CHD) (n=573 African Americans from 120 families; n = 973 whites from 202 families). We genotyped 18 SNPs in ALOX5 and 10 SNPs in ALOX5AP with about 4 kb density. FBAT software was used to determine whether any SNPs were associated with the upper quartile of UTX (the least ASA suppression). The analysis was adjusted for known risk factors such as smoking, high blood pressure, sex, age, obesity, fibrinogen, diabetes and cholesterol. Results: We obtained significant associations between SNPs in both genes and the upper quartile of UTX in African Americans, but not in whites (Table ). The SNPs were not in linkage disequilibrium except for rs7896431 and rs901681 (r 2 =0.80) in African Americans. Conclusion: Both the ALOX5 and ALOX5AP genes have polymorphisms associated in African Americans with less suppression of UTX by ASA. The response to ASA may be affected by an interaction between the leukotriene and thromboxane pathways. Association of SNPs and the upper quartile of UTX