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
Gastroenterologyjournal_title
Gastroenterologyauthors
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 Tdoi
10.1053/j.gastro.2008.04.016subject
Has Abstractpub_date
2008-08-01 00:00:00pages
477-88issue
2eissn
0016-5085issn
1528-0012pii
S0016-5085(08)00668-9journal_volume
135pub_type
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