COX-2 gene polymorphisms and association with premalignant changes in the stomach

Background: Cyclooxygenase-2 (COX-2) plays a number of key roles in carcinogenesis including stimulation of cellular proliferation and angiogenesis and inhibition of apoptosis. COX-2 expression is upregulated in gastric premalignant lesions and adenocarcinomas and this increased expression has been correlated with poor clinicopathological variables. Single nucleotide polymorphisms have been described in the COX-2 gene: three promoter polymorphisms (−197 G>C, −765 G>C, and −899 G>C), one exonic (exon 3-8C>G) and one within the 3′- untranslated region (3′ UTR T>C). All polymorphisms are potentially functional and in particular the polymorphism at position −765 affects a putative Sp1 binding site. Carriage of the COX-2–765 G allele is associated with higher COX-2 expression, and individuals with the G/G genotype have an increased risk of myocardial infarction and ischaemic stroke. Aim: To evaluate the effect of these five described COX-2 polymorphisms on the risk of developing premalignant gastric changes. Subjects and Methods: We used 5′ nuclease assays or PCR-RFLP to genotype the various COX-2 polymorphisms in a population of 153 healthy first degree relatives of individuals with gastric carcinoma to assess the influence of the polymorphism on pre-malignant gastric abnormalities. Of these, 66 infected subjects had hypochlorhydria/atrophy (HC/ATR), 49 infected subjects did not have the abnormalities and 53 were H pylori negative. All groups were compared with 100 population controls. Odds ratios and 95% confidence intervals (CI) were calculated and logistic regression was used to adjust for confounding variables. Genotyping was confirmed by direct sequencing. Results: The promoter polymorphisms at positions −197 and −899 were not present in our population. The exon 3 and 3′UTR polymorphisms were present within the study group, but were not associated with an increased risk of pre-malignant changes. Homozygous carriage of the COX-2 −765 G allele was associated with an increased risk of having the pre-malignant abnormalities of hypochlorhydria and gastric atrophy, compared to heterozygotes and subjects homozygotes for the C allele (OR = 5.7, 95% CI 2.3 to 14.1). Conclusion: The COX-2 −765 G>C polymorphism influences the development of pre-malignant changes in the stomach in H pylori infected subjects, with individuals homozygous for the high expressing G allele having an increased risk of HC/ATR. This polymorphism is a candidate for further study in relation to the inflammatory response to H pylori and the development of gastric cancer and other malignancies.