Heritability of platelet responsiveness to aspirin in activation pathways directly and indirectly related to cyclooxygenase-1.
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.


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 > or = 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.
Faraday
Nauder
N
Department of Anesthesiology/Critical Care Medicine, Division of Cardiac Surgical Intensive Care, Johns Hopkins Medical Institutions, Baltimore, MD, USA. nfaraday@jhmi.edu
Yanek
Lisa R
LR
Mathias
Rasika
R
Herrera-Galeano
J Enrique
JE
Vaidya
Dhananjay
D
Moy
Taryn F
TF
Fallin
M Daniele
MD
Wilson
Alexander F
AF
Bray
Paul F
PF
Becker
Lewis C
LC
Becker
Diane M
DM
D000328:Adult; D001741:Black or African American / Q000235:genetics*; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology* / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000517:prevention & control; D003327:Coronary Disease / Q000097:blood*; D051545:Cyclooxygenase 1 / Q000097:blood / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics; D050171:Dyslipidemias / Q000453:epidemiology; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D006943:Hyperglycemia / Q000453:epidemiology; D006973:Hypertension / Q000453:epidemiology; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000502:physiology; D008875:Middle Aged; D010641:Phenotype; D015539:Platelet Activation / Q000187:drug effects / Q000235:genetics*; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011446:Prospective Studies; D012307:Risk Factors; D012727:Sex Characteristics; D012907:Smoking / Q000453:epidemiology; D019851:Thrombophilia / Q000188:drug therapy / Q000235:genetics*; D013927:Thrombosis / Q000517:prevention & control; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine; D044465:White People / Q000235:genetics*; D001620:beta-Thromboglobulin / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D001620:beta-Thromboglobulin; C081960:11-dehydro-2,3-dinor-thromboxane B2; D016718:Arachidonic Acid; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D001241:Aspirin