Functional effects and gender association of COX-2 gene polymorphism G-765C in bronchial asthma.
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.


CONCLUSIONS
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.
Department of Medicine, Jagiellonian University School of Medicine, Kraków, Poland.
Wojciech
W
Szczeklik
Marek
M
Sanak
Andrew
A
Szczeklik
D001249:Asthma / Q000201:enzymology* / Q000235:genetics; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000096:biosynthesis; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*
D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D015230:Prostaglandin D2