Cyclooxygenase‐2 gene polymorphisms in an Australian population: association of the −1195G > A promoter polymorphism with mild asthma

Abstract

Cyclooxygenase (COX)-2 is an inducible enzyme responsible for catalysing the formation of prostaglandins (PGs) in settings of inflammation. Single nucleotide polymorphisms (SNPs) of the COX-2 gene may influence gene transcription and PG production in the asthmatic airway. To evaluate the frequencies of COX-2 SNPs in an Australian Caucasian population, and determine potential associations between common COX-2 promoter SNPs and asthma, asthma severity and aspirin-intolerant asthma (AIA). The frequencies of 25 COX-2 SNPs were determined in a random population (n=176). The SNPs with a minor allele frequency of >10% were then studied in asthmatic (n=663), non-asthmatic controls (n=513) and AIA subjects (n=58). Genotype, allele and haplotype associations were assessed. Functional assessment of SNPs was performed by transfection into HeLa cells measured using the luciferase dual-reporter assay system. Eighteen COX-2 SNPs were not detected, five were rare and two promoter SNPs, -1195G>A (rs689465), and -1290A>G (rs689466), were further studied. The A allele of the -1195 SNP was present at a significantly higher frequency among all asthmatic subjects (P=0.012). Over 60% of the asthmatic individuals were -1195A homozygotes compared with 54.6% of the control subjects (odds ratio, 1.35; 95% CI, 1.06-1.72, P=0.03). After classifying for severity, the mild asthmatics represented 64.6% of -1195AA individuals, the highest of all the asthma groups compared with 54.6% of the control subjects (odds ratio, 1.5; 95% CI, 1.12-2.02, P=0.02). The -1290A/-1195G/-765G haplotype was associated with a reduced incidence of asthma (odds ratio, 0.76; 95% CI, 0.61-0.95, P=0.017). The -1195G>A polymorphism appears to be associated with asthma, and in particular with mild asthma.