Mutations within the cyclooxygenase-1 gene in aspirin non-responders with recurrence of stroke.
BACKGROUND
Aspirin is a common antiplatelet drug used in the prevention of ischemic stroke due to its inhibitory effect on platelet cyclooxygenase-1 (Cox-1). Patients can be categorized as either aspirin 'responders' or 'non-responders' depending on whether they are protected against a secondary stroke event or not. In this study, we have searched for variants of the Cox-1 gene that could possibly result in an unblocked and thus, aspirin-resistant Cox-1 enzyme and phenotype.


METHODS
The Cox-1 gene was sequenced in 68 patients with recurrent ischemic stroke despite taking aspirin. The genotype distribution of identified variants was determined and compared with healthy control subjects. Mutations that involved amino acid substitutions of the mature Cox-1 molecule were analysed by molecular modelling and functional analysis using whole blood aggregometry.


RESULTS
Fourteen variants of the Cox-1 gene were identified. Seven of the variants involved amino acid substitutions of the Cox-1 molecule. None of the mutations were located near the catalytic site as judged from a three-dimensional model of the human Cox-1. Carriers and non-carriers of one of the mutations behaved similarly when aggregation and granule content release function were studied using collagen, ADP and arachidonic acid as agonists.


CONCLUSIONS
The results do not support the hypothesis that common variants of the Cox-1 gene results in unblocked Cox-1 molecules in aspirin non-responders.
Hillarp
Andreas
A
Department of Clinical Chemistry, Malmo University Hospital, SE-20502 Malmö, Sweden. andreas.hillarp@klkemi.mas.lu.se
Palmqvist
Barbro
B
Lethagen
Stefan
S
Villoutreix
Bruno O
BO
Mattiasson
Ingrid
I
D000368:Aged; D000369:Aged, 80 and over; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D016022:Case-Control Studies; D051545:Cyclooxygenase 1; D004252:DNA Mutational Analysis; D004351:Drug Resistance / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010597:Pharmacogenetics; D010974:Platelet Aggregation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012008:Recurrence; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics*
D007527:Isoenzymes; D008565:Membrane Proteins; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin