title: Polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR C677T) and thymidylate synthase enhancer region (TSER) as a risk factor of cholangiocarcinoma in a Korean population.
abstract: BACKGROUND
  5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, plays a major role in the provision of methyl groups for DNA methylation; thymidylate synthase (TS) is a rate-limiting enzyme in the synthesis of dTMP and DNA repair. The clinical role of genetic polymorphisms of MTHFR and that of the TS enhancer region (TSER) were demonstrated in several clinical studies with colorectal, esophageal, gastric and breast cancer. However, there have never been any studies on the association between cholangiocarcinoma (CCC) and genetic polymorphisms of MTHFR and TSER. Therefore, the polymorphism of MTHFR and TSER, which share a common substrate, 5,10-methylenetetrahydrofolate, in CCC was examined, concurrently. The influence of these polymorphisms on plasma homocysteine levels was also investigated.
  
  
  METHODS
  Blood samples were obtained from 47 patients with CCC and 204 healthy control donors. Using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), the C to T transition at position 677 of MTHFR and tandem repeat of 28bp in the enhancer region of TS gene were analyzed. Plasma homocysteine levels were also determined.
  
  
  RESULTS
  According to the logistic regression model, a combination of MTHFR 677CC with the TSER 2R(+) genotype had a relative risk of 5.38 (95% CI, 1.23-23.56) of developing CCC compared to MTHFR 677CC with TSER 2R(-) (p = 0.0257). The level of homocysteine was lower in CCC patients than healthy controls without statistical significance (8.27 +/- 4.17 vs. 9.40 +/- 2.57, p = 0.093).
  
  
  CONCLUSIONS
  Our data suggest a role of MTHFR 677CC with the TSER 2R(+) genotype in increasing the risk of CCC. This study is the first to suggest an association between CCC and the polymorphisms of MTHFR and TSER.
authors.affiliation: Department of Internal Medicine, College of Medicine, Pochon CHA University, Seongnam, South Korea.
authors.forename: Kwang Hyun
authors.initials: KH
authors.lastname: Ko
authors.forename: Nam Keun
authors.initials: NK
authors.lastname: Kim
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Yim
authors.forename: Sung Pyo
authors.initials: SP
authors.lastname: Hong
authors.forename: Pil Won
authors.initials: PW
authors.lastname: Park
authors.forename: Kyu Sung
authors.initials: KS
authors.lastname: Rim
authors.forename: Sehyun
authors.initials: S
authors.lastname: Kim
authors.forename: Seong Gyu
authors.initials: SG
authors.lastname: Hwang
mesh_terms: D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2) / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000235:genetics*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D016022:Case-Control Studies; D018281:Cholangiocarcinoma / Q000235:genetics*; D017931:DNA Primers; D004742:Enhancer Elements, Genetic; D005828:Genetics, Population; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007723:Korea; D008875:Middle Aged; D011110:Polymorphism, Genetic
chemical_list: D017931:DNA Primers; D006710:Homocysteine; D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2)