His595Tyr Polymorphism in the Methionine Synthase Reductase (MTRR) Gene Is Associated With Pancreatic Cancer Risk

Shumpei Ohnami, Yasunori Sato, Kimio Yoshimura, Sumiko Ohnami, Hiromi Sakamoto, Kazunori Aoki, Hideki Ueno, Masafumi Ikeda, Chigusa Morizane, Kazuaki Shimada, Yoshihiro Sakamoto, Minoru Esaki, Ikuo Saito, Hiroshi Hirose, Daizo Saito, Haruhiko Sugimura, Tomoo Kosuge, Takuji Okusaka, Teruhiko Yoshida

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15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)477-488.e3
JournalGastroenterology
Volume135
Issue number2
DOIs
Publication statusPublished - 2008 Aug

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Ohnami, S., Sato, Y., Yoshimura, K., Ohnami, S., Sakamoto, H., Aoki, K., Ueno, H., Ikeda, M., Morizane, C., Shimada, K., Sakamoto, Y., Esaki, M., Saito, I., Hirose, H., Saito, D., Sugimura, H., Kosuge, T., Okusaka, T., & Yoshida, T. (2008). His595Tyr Polymorphism in the Methionine Synthase Reductase (MTRR) Gene Is Associated With Pancreatic Cancer Risk. Gastroenterology, 135(2), 477-488.e3. https://doi.org/10.1053/j.gastro.2008.04.016