Genetic variation in cyclooxygenase 1: effects on response to aspirin.
BACKGROUND
A critical clinical application of the Human Genome Project is to identify functional variation in genes related to disease or responses to xenobiotics. This study moved toward that goal by combining polymorphism detection with functional assays for the therapeutic target gene cyclooxygenase 1 (COX-1). Cyclooxygenase 1 (prostaglandin endoperoxide G/H synthase [PTGS1]) catalyzes the metabolism of arachidonic acid to prostaglandin H(2), which is subsequently metabolized to thromboxane A(2).


METHODS
Thirty-eight healthy participants were enrolled in this study to correlate functional and genetic variation of cyclooxygenase 1. Arachidonic acid, with and without aspirin (acetylsalicylic acid) and ethanol pretreatment, was used to stimulate the formation of prostaglandin H(2), measured as prostaglandin F(2 alpha) (PGF(2 alpha)), in human platelets. The cyclooxygenase 1 complementary deoxyribonucleic acid coding sequence and genomic deoxyribonucleic acid upstream from the cyclooxygenase 1 transcription start site (2.9 kilobases) were sequenced in 38 individuals, with 9 single-nucleotide polymorphisms identified.


RESULTS
Two single-nucleotide polymorphisms, A-842G and C50T, were in complete linkage disequilibrium. Participants who were heterozygous for the A-842G/C50T haplotype showed significantly (P =.01) greater inhibition of prostaglandin H(2) formation by acetylsalicylic acid (30 micromol/L) compared with common allele homozygotes.


CONCLUSIONS
The discovery of a functional single-nucleotide polymorphism in the cyclooxygenase 1 locus may ultimately improve the safe and effective use of acetylsalicylic acid by better tailoring of dosage with an individual's genetic variation.
Halushka
Marc K
MK
Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, USA. halushpv@musc.edu
Walker
Linda P
LP
Halushka
Perry V
PV
D000328:Adult; D000409:Alanine / Q000235:genetics; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism*; D015153:Blotting, Western; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003545:Cysteine / Q000235:genetics; D018076:DNA, Complementary / Q000032:analysis; D015237:Dinoprost / Q000097:blood*; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D005998:Glycine / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood / Q000235:genetics*; D011863:Radioimmunoassay; D012016:Reference Values; D017422:Sequence Analysis, DNA; D012727:Sex Characteristics; D013912:Threonine / Q000235:genetics; D013929:Thromboxane B2 / Q000097:blood*
D016861:Cyclooxygenase Inhibitors; D018076:DNA, Complementary; D007527:Isoenzymes; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D013912:Threonine; D000431:Ethanol; D013929:Thromboxane B2; D015237:Dinoprost; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D003545:Cysteine; D000409:Alanine; D001241:Aspirin; D005998:Glycine