Justin G. Sibert

PTGS2 (COX-2) −765G > C Promoter Variant Reduces Risk of Colorectal Adenoma among Nonusers of Nonsteroidal Anti-inflammatory Drugs

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) −765G > 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 −765G > C promoter polymorphism. Multiple logistic regression analysis 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 −765GG 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 −765G > 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 −765GG (wild type) and possibly −765CG 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 −765GG (wild type) individuals and by the −765 CC variant genotype in nonusers of NSAIDs.

C-reactive protein genotypes and haplotypes, polymorphisms in NSAID-metabolizing enzymes, and risk of colorectal polyps

Introduction C-reactive protein (CRP) is a nonspecific marker of inflammation linked to cardiovascular disease and possibly colon cancer. Polymorphisms in CRP have been associated with differential CRP concentrations among healthy adults, with some evidence for functional effects on CRP expression. Methods A linkage disequilibrium-based tag single nucleotide polymorphism (SNP)-selection algorithm identified six tagSNPs for Europeans (−821A>G, −390C>T/A, 90A>T, 838G>C, 2043G>A, and 4363C>A), defining six haplotypes with more than 1% frequency. In a case–control study of adenomatous (n=491) or hyperplastic (n=184) polyps versus polyp-free controls (n=583) we investigated these SNPs in relation to colorectal polyp risk. Results Individuals with 838 GC or CC genotypes had a modestly, although not statistically significantly, increased risk of adenomas (odds ratio: 1.4 95% confidence interval: 0.9–2.1) and a nearly 2-fold increased risk of concurrent adenomas and hyperplastic polyps (odds ratio: 2.0 95% confidence interval: 1.1–3.6). Increased risk for concurrent adenomas and hyperplastic polyps was also observed for haplotype ACACAC. No other main associations were detected. Risk of adenomas associated with 2043G>A differed with nonsteroidal anti-inflammatory drug (NSAID) use. Among NSAID nonusers, there was a suggestion that the GA or AA genotypes were associated with decreased risk of adenomas; this was not seen among NSAID users (P interaction=0.03). We also observed interactions between UGT1A1 [TA](7) promoter repeat polymorphism and CRP tagSNPs −390C>T/A and 90A>T, in which only the homozygous variant CRP genotype was associated with increased risk of adenoma among those with the UGT1A1 6rpt/6rpt genotype (P interaction=0.02 and 0.04 for −390C>T/A and 90A>T, respectively). Conclusion These results provide limited support for associations between genetic variation in CRP and colorectal polyp risk. The observed interactions should be evaluated further.