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Genetic variation in cyclooxygenase 1: effects on response to aspirin
Marc K Halushka1, Linda P Walker, Perry V Halushka
1Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, USA. halushpv@musc.edu
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.
Insights
Genetic variations in cyclooxygenase 1 (COX-1) influence how individuals respond to aspirin. This study identified a specific COX-1 gene variant that enhances aspirin
Area of Science:
- Pharmacogenomics
- Molecular Biology
- Human Genetics
Background:
- The Human Genome Project aims to identify gene variations linked to disease and xenobiotic response.
- Cyclooxygenase 1 (COX-1), also known as PTGS1, is a therapeutic target gene involved in prostaglandin synthesis.
- Understanding COX-1 genetic variation is crucial for personalized medicine.
Purpose of the Study:
- To correlate functional and genetic variations of cyclooxygenase 1 (COX-1).
- To identify single-nucleotide polymorphisms (SNPs) in the COX-1 gene.
- To assess the impact of these SNPs on aspirin's effect on prostaglandin production.
Main Methods:
- Sequencing of COX-1 cDNA and upstream genomic DNA in 38 healthy participants.
- Stimulation of prostaglandin H(2) formation in human platelets using arachidonic acid with and without aspirin.
- Measurement of prostaglandin F(2 alpha) (PGF(2 alpha)) to quantify COX-1 activity.
- Identification of 9 single-nucleotide polymorphisms (SNPs).
Main Results:
- Two SNPs, A-842G and C50T, were found in complete linkage disequilibrium, forming a specific haplotype.
- Individuals heterozygous for the A-842G/C50T haplotype exhibited significantly greater inhibition of prostaglandin H(2) formation by aspirin.
- This enhanced inhibition was observed compared to individuals with the common allele homozygotes (P =.01).
Conclusions:
- A functional single-nucleotide polymorphism (SNP) was identified in the cyclooxygenase 1 locus.
- This discovery has implications for improving the safe and effective use of aspirin.
- Tailoring aspirin dosage based on individual genetic variation in COX-1 may enhance therapeutic outcomes.