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Cyclooxygenase-2 and Inducible Nitric Oxide Synthase Gene Polymorphisms and Risk of Reflux Esophagitis, Barrett's Esophagus, and Esophageal Adenocarcinoma

¹ Division of Gastroenterology, Belfast City Hospital; ² Centre for Clinical and Population Sciences, Queen's University; Divisions of ³ Gastroenterology and ⁴ Surgery, Royal Group of Hospitals, Belfast, United Kingdom; ⁵ Centre for Epidemiology and Biostatistics, University of Leeds, Leeds, United Kingdom; ⁶ Division of Gastroenterology, Daisy Hill Hospital, Newry, United Kingdom; and ⁷ Division of Surgery, St James's Hospital, Dublin, Ireland

Requests for reprints: Heather R. Ferguson, Level 6 North, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland. Phone: 44-2890-632602; Fax: 44-2890-231907. E-mail: hrferguson{at}doctors.net.uk

The incidence of esophageal adenocarcinoma has increased in recent years, and Barrett's esophagus is a recognized risk factor. Gastroesophageal reflux of acid and/or bile is linked to these conditions and to reflux esophagitis. Inflammatory disorders can lead to carcinogenesis through activation of "prosurvival genes," including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Increased expression of these enzymes has been found in esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Polymorphic variants in COX-2 and iNOS genes may be modifiers of risk of these conditions. In a population-based case-control study, we examined associations of the COX-2 8473 T>C and iNOS Ser⁶⁰⁸ Leu (C>T) polymorphisms with risk of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barrett's esophagus (n = 212), and reflux esophagitis (n = 230) and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. The presence of at least one COX-2 8473 C allele was associated with a significantly increased risk of esophageal adenocarcinoma (adjusted odds ratio, 1.58; 95% confidence interval, 1.04-2.40). There was no significant association between this polymorphism and risk of Barrett's esophagus or reflux esophagitis or between the iNOS Ser⁶⁰⁸ Leu polymorphism and risk of these esophageal conditions. Our study suggests that the COX-2 8473 C allele is a potential genetic marker for susceptibility to esophageal adenocarcinoma. (Cancer Epidemiol Biomarkers Prev 2008;17(3):727–31)