Polymorphisms in one-carbon metabolism and trans-sulfuration pathway genes and susceptibility to bladder cancer.
We have previously reported significant inverse associations between bladder cancer risk and dietary intake of vitamins B2, B6, B12, folate and protein in a hospital-based bladder cancer case-control study conducted in Spain (1,150 cases;1,149 controls). Because these dietary factors are involved in the one-carbon metabolism pathway, we evaluated associations between bladder cancer risk and 33 single nucleotide polymorphisms (SNPs) in 8 genes (CBS, CTH, MTHFR, MTR, MTRR, SHMT1, SLC19A1 and TYMS) and interactions with dietary variables involved in this pathway. Two SNPs in the CTH gene were significantly associated with bladder cancer risk. OR (95% CI) for heterozygous and the homozygous variants compared to homozygous wild-type individuals were: 1.37 (1.04-1.80) IVS3-66 A > C and 1.22 (1.02-1.45) IVS10-430 C > T. Because the CTH gene is important for glutathione synthesis, we examined interactions with the GSTM1 gene, which codes for glutathione S-transferase muu. Increased risk for individuals with the IVS10-430 CT or TT genotype was limited to those with the GSTM1 null genotype (p-interaction = 0.02). No other SNPs were associated with risk of bladder cancer. These findings suggest that common genetic variants in the one-carbon pathway may not play an important role in the etiology of bladder cancer. However, our results provide some evidence that variation in glutathione synthesis may contribute to risk, particularly among individuals who carry a deletion in GSTM1. Additional work is needed to comprehensively evaluate genomic variation in CTH and related genes in the trans-sulfuration pathway and bladder cancer risk.
Moore
Lee E
LE
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD, USA. moorele@mail.nih.gov
Malats
Núria
N
Rothman
Nathaniel
N
Real
Francisco X
FX
Kogevinas
Manolis
M
Karami
Sara
S
García-Closas
Reina
R
Silverman
Debra
D
Chanock
Stephen
S
Welch
Robert
R
Tardón
Adonina
A
Serra
Consol
C
Carrato
Alfredo
A
Dosemeci
Mustafa
M
García-Closas
Montserrat
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002244:Carbon / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013455:Sulfur / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism
D013455:Sulfur; D002244:Carbon