Published Online
on April 30, 2007

A more recent version of this article appeared on May 15, 2007

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Submitted on September 30, 2006
Accepted on February 23, 2007

Heritability of Platelet Responsiveness to Aspirin in Activation Pathways Directly and Indirectly Related to Cyclooxygenase-1

Nauder Faraday MD^*, Lisa R. Yanek MPH, Rasika Mathias PhD, J. Enrique Herrera-Galeano MS, Dhananjay Vaidya MBBS, PhD, MPH, Taryn F. Moy MS, M. Daniele Fallin PhD, Alexander F. Wilson PhD, Paul F. Bray MD, Lewis C. Becker MD, and Diane M. Becker ScD

From the Department of Anesthesiology/Critical Care Medicine, Division of Cardiac Surgical Intensive Care (N.F.), Department of Medicine, Division of General Internal Medicine (L.R.Y., J.E.H.-G., D.V., T.F.M., D.M.B.), and Department of Medicine, Division of Cardiology (L.C.B.), Johns Hopkins Medical Institutions, Baltimore, Md; Inherited Disease Research Branch, National Human Genome Research Institute/National Institutes of Health, Baltimore, Md (R.M., A.F.W.); Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md (M.D.F.); and Department of Medicine, Division of Hematology, Jefferson Medical College, Philadelphia, Pa (P.F.B.).

^* To whom correspondence should be addressed. E-mail: nfaraday{at}jhmi.edu.

Background--The inability of aspirin (acetylsalicylic acid [ASA]) to adequately suppress platelet function is associated with future risk of myocardial infarction, stroke, and cardiovascular death. Genetic variation is a proposed but unproved mechanism for insufficient ASA responsiveness.

Methods and Results--We examined platelet ASA responsiveness in 1880 asymptomatic subjects (mean age, 44±13 years; 58% women) recruited from 309 white and 208 black families with premature coronary heart disease. Ex vivo platelet function was determined before and after ingestion of ASA (81 mg/d for 2 weeks) with the use of a panel of measures that assessed platelet activation in pathways directly and indirectly related to cyclooxygenase-1, the enzyme inhibited by ASA. The proportion of phenotypic variance related to CHD risk factor covariates was determined by multivariable regression. Heritability of phenotypes was determined with the use of variance components models unadjusted and adjusted for covariates. ASA inhibited arachidonic acid-induced aggregation and thromboxane B₂ production by 99% (P<0.0001). Inhibition of urinary thromboxane excretion and platelet activation in pathways indirectly related to cyclooxygenase-1 was less pronounced and more variable (inhibition of 0% to 100%). Measured covariates contributed modestly to variability in ASA response phenotypes (r²=0.001 to 0.133). Phenotypes indirectly related to cyclooxygenase-1 were strongly and consistently heritable across races (h²=0.266 to 0.762; P<0.01), but direct cyclooxygenase-1 phenotypes were not.

Conclusions--Heritable factors contribute prominently to variability in residual platelet function after ASA exposure. These data suggest a genetic basis for the adequacy of platelet suppression by ASA and potentially for differences in the clinical efficacy of ASA.

Key words: antiplatelet agents • aspirin • genetics • platelets

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