Genetic variation in cyclooxygenase 1: Effects on response to aspirin

• Published in: Clinical pharmacology and therapeutics 2003-01, Vol.73 (1), p.122-130
• Main Authors: Halushka, Marc K., Walker, Linda P., Halushka, Perry V.
• Format: Article
• Language: English
• Subjects: Adult; Alanine - genetics; Aspirin - pharmacology; Biological and medical sciences; Blood Platelets - metabolism; Blotting, Western; Bones, joints and connective tissue. Antiinflammatory agents; Cyclooxygenase 1; Cyclooxygenase Inhibitors - pharmacology; Cysteine - genetics; Dinoprost - blood; DNA, Complementary - analysis; Ethanol - pharmacology; Female; Glycine - genetics; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - blood; Isoenzymes - genetics; Male; Medical sciences; Membrane Proteins; Middle Aged; Pharmacology. Drug treatments; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Polymerase Chain Reaction; Polymorphism, Genetic; Prostaglandin-Endoperoxide Synthases - blood; Prostaglandin-Endoperoxide Synthases - genetics; Radioimmunoassay; Reference Values; Sequence Analysis, DNA; Sex Characteristics; Threonine - genetics; Thromboxane B2 - blood
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1067/mcp.2003.1

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 H2, which is subsequently metabolized to thromboxane A2. 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 H2, measured as prostaglandin F2α (PGF2α), 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 H2 formation by acetylsalicylic acid (30 μmol/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. Clinical Pharmacology & Therapeutics (2003) 73, 122–130; doi: 10.1067/mcp.2003.1