Functional effects and gender association of COX-2 gene polymorphism G-765C in bronchial asthma
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BACKGROUND: Prostaglandins, generated via the COX pathways, are essential mediators of inflammation in bronchial asthma. The promoter polymorphism of COX-2 gene (G-765C), which might affect binding of transcription factors, has recently been described OBJECTIVE: To study distribution and function of the genetic COX-2 variant in patients with asthma compared with healthy controls. METHODS: Three groups of adults were studied: (1) patients with aspirin-induced asthma (AIA; n=112), (2) asthmatic patients who tolerated aspirin (ATA; n=198), and (3) a random population sample from city of Krakow (n=547). The COX-2 promoter region was genotyped for the G-765C polymorphism. Ex vivo production of prostaglandin E2 and prostaglandin D2 by peripheral blood monocytes was measured. RESULTS: In the 2 asthmatic groups, the G-765C allele frequency was similar (AIA, 0.18; ATA, 0.19) and did not differ from that of controls (0.17). In asthmatic women, but not in men, CC homozygotes were overrepresented compared with controls (odds ratio, 3.08; 95% CI, 1.35-6.63; P=.01). There was no relationship between genotype and FEV1, serum IgE, blood eosinophil count, or duration of the disease. In AIA but not in ATA patients, CC homozygosity was associated with more severe course of the disease, as reflected by need for oral corticotherapy. Production of 2 prostaglandins by monocytes was more than 10-fold higher in CC than in GG homozygotes, and the magnitude of this difference was not changed by LPS stimulation. CONCLUSION: In asthma, the COX-2 -765C homozygosity is associated with female sex. The CC homozygosity has functional effects resulting in increased capacity of monocytes to produce prostaglandins.
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