5,10-Methylenetetrahydrofolate reductase polymorphisms and the risk of pancreatic cancer

To test the hypothesis that 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms modify the risk of pancreatic cancer, we conducted a hospital-based, case-control study involving 347 patients with newly diagnosed pancreatic adenocarcinoma and 348 healthy controls, frequency matched by age, sex, and race. MTHFR polymorphisms were determined using the PCR-RFLP method. Association of these polymorphisms with the risk of pancreatic cancer was estimated by unconditional logistic regression analysis. We found that the C667T (but not the A1298C) polymorphism had a significant main effect on the risk of pancreatic cancer. The frequencies of the MTHFR 667CC, 667CT, and 667TT genotypes were 49.5%, 38.6%, and 11.9%, respectively, among cases compared with 48.5%, 45.0%, and 6.5%, respectively, among controls. Individuals with the 66711 genotype displayed a 2-fold increased risk for pancreatic cancer compared with those with the CC/CT genotypes [adjusted odds ratio (OR), 2.14; 95% confidence interval (95% CI), 1.14-4.01]. Multivariate analyses found that the effect of the 677TT genotype on the risk of pancreatic cancer was present among ever smokers (OR, 5.53; 95% CI, 2.0-15.3) and ever alcohol drinkers (OR, 3.16; 95% CI, 1.30-7.69) but not in never smokers (OR, 0.82; 95% CI, 0.33-2.06) and never drinkers (OR, 1.42; 95% CI, 0.56-3.62). Furthermore, a positive interaction between the MTHFR TT genotype and heavy smoking or heavy alcohol consumption was detected. The OR (95% CI) of pancreatic cancer was 6.83 (1.91-24.38) for heavy smokers among the TT carriers compared with never smokers with the CC/CT genotypes and 4.23 (0.88-20.3) for heavy drinkers with the TT genotype compared with non-drinkers with the CC/CT genotypes. These observations support a role for folate metabolism in pancreatic cancer, especially among smokers and heavy drinkers.