Abstract 2381: Heritability of Platelet Aspirin Responsiveness
Background: Variability in platelet responsiveness to the inhibitory effect of aspirin (ASA) is associated with differences in cardiovascular outcome among individuals at increased risk. Genetic variation has been proposed as a mechanism to explain variability in ASA responsiveness; however, the contribution of heritable factors to platelet response to ASA has not been characterized.
Methods and Results: We examined platelet ASA responsiveness in 1880 asymptomatic subjects (mean age 44 +/− 13 yr, 58% female) at moderate risk for coronary heart disease (CHD), representing 309 Caucasian and 208 African American families. Ex vivo platelet function was assessed before and after ingestion of ASA (81 mg/day for 2 weeks) using a panel of measures that assessed platelet activation in pathways directly and indirectly related to ASA’s inhibitory action on COX-1. A variance components model was used to determine the proportion of variance in each platelet measurement attributable to heritable factors (h2). ASA inhibited arachidonic acid-induced aggregation and collagen-induced thromboxane A2 production by >95% (P <0.0001). Inhibition of urinary thromboxane excretion and platelet activation in pathways indirectly related to COX-1 was less pronounced and more variable (inhibition 0 –100% of baseline). Heritability estimates for ASA response phenotypes are shown in the table⇓, which were adjusted for CHD risk factor covariates (age, sex, hypertension, cigarette smoking, cholesterol, diabetes, body mass index, and fibrinogen levels). CHD covariates jointly accounted for 1–12% of phenotypic variance.
Conclusions: Heritable factors contribute prominently to variability in platelet responsiveness to ASA, particularly in pathways indirectly related to COX-1. These data suggest a genetic basis for variability in ASA’s inhibitory effect on platelets and potentially a genetic basis for differences in ASA’s clinical efficacy.