His595Tyr polymorphism in the methionine synthase reductase (MTRR) gene is associated with pancreatic cancer risk.
OBJECTIVE
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.
Genetics Division, National Cancer Center Research Institute, Tokyo, Japan.
Shumpei
S
Ohnami
Yasunori
Y
Sato
Kimio
K
Yoshimura
Sumiko
S
Ohnami
Hiromi
H
Sakamoto
Kazunori
K
Aoki
Hideki
H
Ueno
Masafumi
M
Ikeda
Chigusa
C
Morizane
Kazuaki
K
Shimada
Yoshihiro
Y
Sakamoto
Minoru
M
Esaki
Ikuo
I
Saito
Hiroshi
H
Hirose
Daizo
D
Saito
Haruhiko
H
Sugimura
Tomoo
T
Kosuge
Takuji
T
Okusaka
Teruhiko
T
Yoshida
D000328:Adult; D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D003470:Culture Media / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D007564:Japan; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016017:Odds Ratio; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D014162:Transfection
D003470:Culture Media; D006710:Homocysteine; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase