Cyclooxygenase-2 gene polymorphism G −765C and prostaglandin synthesis in patients with bronchial asthma

Abstract

Rationale Promoter polymorphism of COX-2 gene (G −765C), recently described by Papafili et al., lowered transcriptional activity of the gene by 30% in cultured fibroblasts (Arterioscler Thromb Vasc Biol. 22; 2002; 1631). The goal of the study was to investigate the genetic association and function of the polymorphism in adult patients with bronchial asthma. Methods COX-2 promoter region for G −765C SNP was genotyped by PCR-based RFLP. Three groups were studied: 1) a random sample from Cracow (n=549;M/F=237/312); 2) Patients with Aspirin-induced asthma (AIA) (n=117;M/F=41/76); 3) Asthmatics tolerating aspirin (ATA) (n=217;M/F=73/144). We studied ex vivo production of prostaglandins (PGs) by monocytes isolated from blood of asthmatic patients with GG (n=6) and CC (n=9) genotypes. Results In asthmatic patients the −765C allele frequency was similar (AIA=0.16; ATA=0.186), to the controls (Con=0.16). All groups followed Hardy-Weinberg equilibrium. Variant allele homozygotes (CC) were detected only in asthmatic women (p=0.004). In controls, distribution of CC genotypes did not differ between men and women. The baseline monocyte PGs production was nearly tenfold higher in CC homozygotes than in GG group (p=0.0003). Response to stimulation with LPS gave similar increase of PGs in both groups. Conclusions We demonstrated a functional effect of COX-2 −765C homozygocity resulting in increased PGs production by monocytes. However, genetic association with COX-2 was detected only in women patients.