His595Tyr polymorphism in the methionine synthase reductase (MTRR) gene is associated with pancreatic cancer risk.

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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

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

doi

10.1053/j.gastro.2008.04.016

subject

Has Abstract

pub_date

2008-08-01 00:00:00

pages

477-88

issue

2

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(08)00668-9

journal_volume

135

pub_type

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