TY - JOUR
T1 - His595Tyr Polymorphism in the Methionine Synthase Reductase (MTRR) Gene Is Associated With Pancreatic Cancer Risk
AU - Ohnami, Shumpei
AU - Sato, Yasunori
AU - Yoshimura, Kimio
AU - Ohnami, Sumiko
AU - Sakamoto, Hiromi
AU - Aoki, Kazunori
AU - Ueno, Hideki
AU - Ikeda, Masafumi
AU - Morizane, Chigusa
AU - Shimada, Kazuaki
AU - Sakamoto, Yoshihiro
AU - Esaki, Minoru
AU - Saito, Ikuo
AU - Hirose, Hiroshi
AU - Saito, Daizo
AU - Sugimura, Haruhiko
AU - Kosuge, Tomoo
AU - Okusaka, Takuji
AU - Yoshida, Teruhiko
PY - 2008/8
Y1 - 2008/8
N2 - Background & Aims: This study attempts to elucidate a part of the genetic predisposition to the sporadic invasive ductal adenocarcinoma of the pancreas focusing on the genes implicated in the gene-environment interactions in carcinogenesis. Methods: First, 227 single nucleotide polymorphisms (SNPs) of 46 genes were genotyped on 198 cases and 182 controls. The SNPs, which showed a significant association, were further genotyped on additional samples to perform a joint analysis (total 317 cases vs 1232 controls). The gene selected by joint analysis was resequenced for a high-density SNP typing and a haplotype analysis on 702 cases and 785 controls. Function of the risk and wild-type haplotypes was assessed using cells transfected with complementary DNA (cDNA). Results: The joint analysis with multiple testing adjustment identified 2 SNPs on the methionine synthase reductase (MTRR) gene: rs162049 (intronic SNP), Fisher exact test, P = .0018; OR, 1.33; 95% CI: 1.11-1.60 and rs10380 (His595Tyr), Fisher exact test, P = .0063; OR, 1.45; 95% CI: 1.11-1.88. The SNPs remained significant in the recessive model after the permutation test for multiple testing (rs162049, P = .024; rs10380, P = .023) in the high-density analysis. Stable transfectants of the risk haplotype MTRR cDNA showed significantly elevated homocysteine levels in a culture medium, a lower level of the LINE-1 methylation, and a lower expression of the MTRR protein than did the transfectants with the wild-type haplotype cDNA. Conclusions: Our study suggested a common missense SNP of the MTRR gene as a novel pancreatic cancer susceptibility factor with a functional significance in folate-related metabolism and the genome-wide methylation status.
AB - Background & Aims: This study attempts to elucidate a part of the genetic predisposition to the sporadic invasive ductal adenocarcinoma of the pancreas focusing on the genes implicated in the gene-environment interactions in carcinogenesis. Methods: First, 227 single nucleotide polymorphisms (SNPs) of 46 genes were genotyped on 198 cases and 182 controls. The SNPs, which showed a significant association, were further genotyped on additional samples to perform a joint analysis (total 317 cases vs 1232 controls). The gene selected by joint analysis was resequenced for a high-density SNP typing and a haplotype analysis on 702 cases and 785 controls. Function of the risk and wild-type haplotypes was assessed using cells transfected with complementary DNA (cDNA). Results: The joint analysis with multiple testing adjustment identified 2 SNPs on the methionine synthase reductase (MTRR) gene: rs162049 (intronic SNP), Fisher exact test, P = .0018; OR, 1.33; 95% CI: 1.11-1.60 and rs10380 (His595Tyr), Fisher exact test, P = .0063; OR, 1.45; 95% CI: 1.11-1.88. The SNPs remained significant in the recessive model after the permutation test for multiple testing (rs162049, P = .024; rs10380, P = .023) in the high-density analysis. Stable transfectants of the risk haplotype MTRR cDNA showed significantly elevated homocysteine levels in a culture medium, a lower level of the LINE-1 methylation, and a lower expression of the MTRR protein than did the transfectants with the wild-type haplotype cDNA. Conclusions: Our study suggested a common missense SNP of the MTRR gene as a novel pancreatic cancer susceptibility factor with a functional significance in folate-related metabolism and the genome-wide methylation status.
UR - https://www.scopus.com/pages/publications/48549101661
U2 - 10.1053/j.gastro.2008.04.016
DO - 10.1053/j.gastro.2008.04.016
M3 - Article
C2 - 18515090
AN - SCOPUS:48549101661
SN - 0016-5085
VL - 135
SP - 477-488.e3
JO - Gastroenterology
JF - Gastroenterology
IS - 2
ER -