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Cyclooxygenase‐1 haplotype modulates platelet response to aspirin
Author(s) -
MAREE A. O.,
CURTIN R. J.,
CHUBB A.,
DOLAN C.,
COX D.,
O'BRIEN J.,
CREAN P.,
SHIELDS D. C.,
FITZGERALD D. J.
Publication year - 2005
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2005.01555.x
Subject(s) - aspirin , haplotype , cyclooxygenase , platelet , arachidonic acid , thromboxane b2 , thromboxane a2 , thromboxane , medicine , genotype , pharmacology , immunology , biology , biochemistry , gene , enzyme
Summary. Background: Aspirin (acetylsalicylic acid) irreversibly inhibits platelet cyclooxygenase (COX)‐1, the enzyme that converts arachidonic acid (AA) to the potent platelet agonist thromboxane (TX) A 2 . 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.’ Aims: 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. Patients and methods: Aspirin response, determined by serum TXB 2 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 TXB 2 generation was also related to genotype ( P = 0.02; 4 d.f.). Conclusion: 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.