PTGS2 (COX-2 ) -765G > C Promoter Variant Reduces Risk of Colorectal Adenoma among Nonusers of Nonsteroidal Anti-inflammatory Drugs Cornelia M. Ulrich, 1,2 John Whitton, 1 Joon-Ho Yu, 1,2 Justin Sibert, 1 Rachel Sparks, 1 John D. Potter, 1,2 and Jeannette Bigler 1 1 Fred Hutchinson Cancer Research Center and 2 Department of Epidemiology, Seattle, Washington Abstract Prostaglandin H synthase 2 (PTGS2) or cyclooxygenase-2 (COX-2) has been shown to play a key role in the regulation of inflammation, and its inhibition is associated with a reduced risk of colon cancer. The PTGS2 (COX-2 ) À765G > C promoter variant is located in a putative SP1 binding site and reduces PTGS2 expression. In a Minnesota-based case- control study of cases with adenomatous (n = 494) or hyperplastic polyps (n = 186) versus polyp-free controls (n = 584), we investigated the role of the PTGS2 À765G > C promoter polymorphism. Multiple logistic regression ana- lysis was used, adjusting for age, body mass index, caloric intake, alcohol, fiber, sex, hormone use, and smoking. For colorectal adenoma, odds ratios (OR) compared with PTGS2 À765GG as reference were GC 1.00 [95% confidence interval (95% CI), 0.74-1.35] and CC 0.53 (95% CI, 0.22-1.28). For hyperplastic polyps, the comparable adjusted odds ratios were GC 0.97 (95% CI, 0.65-1.46) and CC 0.24 (95% CI, 0.05- 1.11). Risk associated with the À765G > C variant differed by aspirin or other nonsteroidal anti-inflammatory drug (NSAID) use. Among nonusers of aspirin or other NSAIDs, the CC genotype conferred a significant decrease in risk of adenoma (OR, 0.26; 95% CI, 0.07-0.89). Use of aspirin or other NSAIDs reduced risk of adenoma only among those with the À765GG (wild type) and possibly À765CG genotypes (OR, 0.66; 95% CI, 0.48-0.92 and OR, 0.64; 95% CI, 0.40-1.02, respectively). These data suggest that COX-2 expression or activity may be beneficially suppressed, and risk of colorectal polyps reduced, by aspirin or other NSAIDs in PTGS2 À765GG (wild type) individuals and by the À765 CC variant genotype in nonusers of NSAIDs. (Cancer Epidemiol Biomarkers Prev 2005; 14(3):616 – 9) Introduction Prostaglandin H synthase (PTGS) or cyclooxygenase (COX) is a key enzyme in prostaglandin synthesis. This enzyme is bifunctional; the initial COX reaction converts arachidonic acid to prostaglandin G2; subsequently, the peroxidase reaction converts prostaglandin G2 to prostaglandin H2. Whereas PTGS1 has been generally found to be constitutively expressed and involved in cell-cell signaling and maintenance of tissue homeostasis, PTGS2 expression occurs in a more limited number of cell types and is regulated or induced by specific stimulatory events (1-10). Thus, PTGS2 plays a role in the prostanoid synthesis involved in inflammation and mitogene- sis. A possible PTGS3 mRNA has been reported by several groups, although expression of a functional PTGS3 protein in vivo remains controversial (11-14). Whereas PTGS2 expression is low in normal colonic epithe- lium, its expression is elevated in up to 90% of colon carcinomas and 40% of colon adenoma (15-17). Furthermore, evidence from mouse experiments implicates PTGS2 in colorectal carcinogen- esis (18, 19), potentially through effects on prostaglandin E2 levels (20, 21). Oshima et al. (18) crossed Min mice (carrying an APC-truncating mutation) with a PTGS2-deficient strain and showed a substantial reduction in polyps at 10 weeks among the PTGS2 À/À compared with PTGS2 +/+ Min mice. These results provide direct genetic evidence that PTGS2 plays a key role in tumorigenesis at the stage of adenoma formation. No nonsynonymous PTGS2 polymorphisms have yet been reported among Caucasians (22, 23). A V511A polymorphism, which occurs at about 5% allele frequency among African Americans, has been found to possibly decrease risk of both colorectal adenoma and colorectal cancer (24). A common polymorphism in the regulatory region of PTGS2 has been recently described (À765G > C; dbSNP rs20417); it results in reduced gene expression and is also associated with decreased serum concentrations of C-reactive protein in patients following coronary bypass surgery (25) and reduced risk of myocardial infarction and stroke (26). We investigated associations between the PTGS2 promoter variant and risk of colorectal adenomatous and hyperplastic polyps. Furthermore, we investigated inter- actions between the PTGS2 polymorphism and use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAID), poly- morphisms in TGFb1 (a PTGS2 inducer; ref. 27) and PTGS1 . Materials and Methods Study Subjects. Participant recruitment for the Minnesota case-control study has been described previously (28). Briefly, cases with colorectal adenomatous and/or hyperplastic polyps and polyp-free control subjects were recruited through a large multiclinical private gastroenterology practice in metropolitan Minneapolis. Patients ages 30 to 74 years who were scheduled for a colonoscopy between April 1991 and April 1994 were recruited before colonoscopy so as to blind patients and recruiters to the final diagnosis. The study was approved by the internal review boards of the University of Minnesota and each endoscopy site. Written informed consent was obtained. Cases were identified as meeting eligibility criteria: resident of Twin Cities metropolitan area, English speaking, no known genetic syndrome associated with predisposition to colonic Received 7/13/04; revised 9/23/04; accepted 10/1/04. Grant support: Grants R01CA89445 and R01CA59045. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Cornelia M. Ulrich, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, M4-B402, Seattle, WA 98109-1024. Phone: 206-667-7617; Fax: 206-667-7850. E-mail: nulrich@fhcrc.org Copyright D 2005 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 616 Cancer Epidemiol Biomarkers Prev 2005;14(3). March 2005 on June 18, 2020. © 2005 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from