Cyclooxygenase-1 haplotype modulates platelet response to aspirin.
BACKGROUND
Aspirin (acetylsalicylic acid) irreversibly inhibits platelet cyclooxygenase (COX)-1, the enzyme that converts arachidonic acid (AA) to the potent platelet agonist thromboxane (TX) A2. Despite clear benefit from aspirin in patients with cardiovascular disease (CAD), evidence of heterogeneity in the way individuals respond has given rise to the concept of 'aspirin resistance.'


OBJECTIVE
To evaluate the hypothesis that incomplete suppression of platelet COX as a consequence of variation in the COX-1 gene may affect aspirin response and thus contribute to aspirin resistance.


METHODS
Aspirin response, determined by serum TXB2 levels and AA-induced platelet aggregation, was prospectively studied in patients (n = 144) with stable CAD taking aspirin (75-300 mg). Patients were genotyped for five single nucleotide polymorphisms in COX-1 [A-842G, C22T (R8W), G128A (Q41Q), C644A (G213G) and C714A (L237M)]. Haplotype frequencies and effect of haplotype on two platelet phenotypes were estimated by maximum likelihood. The four most common haplotypes were considered separately and less common haplotypes pooled.


RESULTS
COX-1 haplotype was significantly associated with aspirin response determined by AA-induced platelet aggregation (P = 0.004; 4 d.f.). Serum TXB2 generation was also related to genotype (P = 0.02; 4 d.f.).


CONCLUSIONS
Genetic variability in COX-1 appears to modulate both AA-induced platelet aggregation and thromboxane generation. Heterogeneity in the way patients respond to aspirin may in part reflect variation in COX-1 genotype.
Maree
A O
AO
Department of Clinical Pharmacology, Royal College of Surgeons, Ireland. amaree@partners.org
Curtin
R J
RJ
Chubb
A
A
Dolan
C
C
Cox
D
D
O'Brien
J
J
Crean
P
P
Shields
D C
DC
Fitzgerald
D J
DJ
D000328:Adult; D016718:Arachidonic Acid; D001241:Aspirin / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000235:genetics; D051545:Cyclooxygenase 1 / Q000235:genetics* / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D010597:Pharmacogenetics; D010974:Platelet Aggregation / Q000187:drug effects* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013928:Thromboxane A2 / Q000097:blood
D016861:Cyclooxygenase Inhibitors; D016718:Arachidonic Acid; D013928:Thromboxane A2; D051545:Cyclooxygenase 1; D001241:Aspirin