Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients.
The antiplatelet effect of aspirin varies individually. This study evaluated whether the antiplatelet effect of aspirin associates with polymorphisms in the genes coding for cyclo-oxygenase-1 (COX-1) and several platelet glycoprotein (GP) receptors in patients with stable coronary artery disease (CAD). Blood samples were collected from 101 aspirin-treated (mean 100 mg/d) patients. Compliance to treatment was assessed by plasma salicylate measurement. Platelet functions were assessed by two methods: 1) Response to arachidonic acid (AA, 1.5 mmol/L in aggregometry, and 2) PFA-100, evaluating platelet activation under high shear stress in the presence of collagen and epinephrine (CEPI). Aspirin non-response was defined as: 1) slope steeper than 12%/min in AA-aggregations, and 2) by closure time shorter than 170 s in PFA-100. The methods used detected different individuals as being aspirin non-responders. Five and 21 patients, respectively, were non-responders according to AA-induced aggregation and PFA-100. Increased plasma thromboxane B2 levels correlated with poor aspirin-response measured with both AA-induced aggregations and PFA-100 (P = 0.02 and P = 0.003, respectively). Of the non-responders detected by AA, 3 of 5 (60%) carried the rare G allele for the -A842G polymorphism of COX-1 in contrast to 16 of 96 (17%) responders (P = 0.016). Diabetes was associated with poor response. Aspirin non-response detected by PFA-100 associated with C13254T polymorphism of GP VI and female gender (P = 0.012 and P = 0.019, respectively). Although two patients were possibly non-compliant, this did not effect present conclusions. Evaluation of aspirin efficacy by AA-induced aggregation and PFA-100 detected different individuals, with different genotypic profiles, as being aspirin non-responders.
Department of Internal Medicine, Division of Hematology, Helsinki University Central Hospital, PO Box 340, Fin-00029 HUCH, Helsinki, Finland. aino.lepantalo@uta.fi
Aino
A
Lepäntalo
Jussi
J
Mikkelsson
Julio C
JC
Reséndiz
Leena
L
Viiri
Janne T
JT
Backman
Esko
E
Kankuri
Pekka J
PJ
Karhunen
Riitta
R
Lassila
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000097:blood / Q000494:pharmacology*; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics*; D051545:Cyclooxygenase 1 / Q000235:genetics* / Q000502:physiology; D003920:Diabetes Mellitus / Q000188:drug therapy; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010979:Platelet Function Tests; D010980:Platelet Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D013929:Thromboxane B2 / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D016718:Arachidonic Acid; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D001241:Aspirin