Polymorphisms of MTHFD, plasma homocysteine levels, and risk of gastric cancer in a high-risk Chinese population.
OBJECTIVE
Accumulative evidence suggests that folate has a protective effect on gastric cancer. The methylenetetrahydrofolate dehydrogenase (MTHFD) plays an important role in folate and homocysteine metabolisms, and polymorphisms of MTHFD may result in disturbance of the folate-mediated homocysteine pathway. The aim of this study is to test the hypothesis that genetic variants of MTHFD and plasma homocysteine levels are associated with risk of gastric cancer and modulated by genotypes of methylenetetrahydrofolate reductase (MTHFR).


METHODS
We genotyped G1958A and T401C in MTHFD and C677T in MTHFR and detected total plasma homocysteine (tHcy) levels in a case-control study of 589 gastric cancer cases and 635 cancer-free controls in a high-risk Chinese population.


RESULTS
The variant genotypes of MTHFD 1958AA and 401CC were associated with a significantly increased risk of gastric cancer [adjusted odds ratio (OR), 2.05; 95% confidence interval (95% CI), 1.34-3.13 for 1958AA; adjusted OR, 1.43; 95% CI, 1.14-1.80 for 401CC] compared with 1958GG/GA and 401TT/TC genotypes, respectively. Both of the effects were more evident in the subjects carrying MTHFR 677CT/TT genotypes. The average tHcy level was significantly higher in gastric cancer cases than in controls (P < 0.01), and the upper quartile of tHcy (>13.6 micromol/L) was associated with an 82% significantly increased risk of gastric cancer, compared with the lowest quartile of tHcy (<or=8.0 micromol/L; adjusted OR, 1.82; 95% CI, 1.20-2.75).


CONCLUSIONS
The strong associations between MTHFD variants and the plasma tHcy levels and gastric cancer risk suggest, for the first time, a possible gene-environment interaction between genetic variants of folate-metabolizing genes and high tHcy levels in gastric carcinogenesis.
Wang
Lina
L
Department of Epidemiology and Biostatistics, Institute of Toxicology, Nanjing Medical University, Nanjing, China.
Ke
Qiao
Q
Chen
Wensen
W
Wang
Jianming
J
Tan
Yongfei
Y
Zhou
Yan
Y
Hua
Zhaolai
Z
Ding
Weiliang
W
Niu
Juying
J
Shen
Jing
J
Zhang
Zuofeng
Z
Wang
Xinru
X
Xu
Yaochu
Y
Shen
Hongbing
H
D044466:Asian People / Q000235:genetics; D002681:China; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012016:Reference Values; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000401:mortality
D004273:DNA, Neoplasm; D006710:Homocysteine; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP)