title: Genetic polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase and risk of pancreatic cancer.
abstract: OBJECTIVE
  Human pancreatic cancer might be associated with folate deficiency and impaired metabolism. We tested this hypothesis by examining the contribution of functional polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) to risk of cancer.
  
  
  METHODS
  DNA from 163 pancreatic cancer patients and 337 control subjects was genotyped for MTHFR (677C > T and 1298A > C) and TS (5'-untranslated region tandem repeat and G/C). Association with risk of pancreatic cancer was estimated by logistic regression. All statistical tests were two-sided.
  
  
  RESULTS
  We observed an increased risk of pancreatic cancer associated with the MTHFR 677CT (odds ratio [OR], 2.60; 95% confidence interval [CI], 1.61-4.29; P = .0005) or 677TT (OR, 5.12; 95% CI, 2.94-9.10; P < .0001) genotype compared with the MTHFR CC genotype. An increased risk of pancreatic cancer was also associated with the TS 3Rc/3Rc genotype (OR, 2.19, 95% CI, 1.13-4.31; P = .022) compared with the TS 3Rg/3Rg genotype. Joint effect between MTHFR C677T polymorphism and smoking or drinking increased risk of pancreatic cancer in a super-multiplicative manner. The ORs for smoking, the polymorphism, and both factors combined were 0.70 (95% CI, 0.30-1.63), 2.17 (95% CI, 1.17-4.21), and 3.10 (95% CI, 1.54-6.51), respectively. This joint effect was much stronger in heavy smokers (OR, 6.69; 95% CI, 3.39-13.63; P < .0001). The ORs for drinking, the polymorphism, and both factors combined were 0.98 (95% CI, 0.40-2.30), 2.81 (95% CI, 1.65-4.98), and 4.39 (95% CI, 2.25-8.78), respectively.
  
  
  CONCLUSIONS
  The MTHFR and TS polymorphisms are genetic determinants for developing pancreatic cancer.
authors.affiliation: Department of Epidemiology, Institute of Basic Medical Sciences, Cancer Institute & Hospital, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.forename: Xinghua
authors.initials: X
authors.lastname: Lu
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Zhao
authors.forename: Yi
authors.initials: Y
authors.lastname: Shan
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Dongxin
authors.initials: D
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000428:Alcohol Drinking / Q000009:adverse effects; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase