Polymorphisms in one‐carbon metabolism and trans‐sulfuration pathway genes and susceptibility to bladder cancer

Abstract

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 lu. Increased risk for individuals with the IVS10-430 CT or TT genotype was limited to those with the GSTM1 null genotype (p-interaction 5 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. ' 2007 Wiley-Liss, Inc.Key words: bladder cancer; folate metabolism; one-carbon metabolism; GSTM1; CTH; genetic susceptibility Epidemiological studies have shown associations between low folate intake and increased cancer risk.1-5 Recently, we observed inverse associations for several B vitamins including folate, which are involved in one-carbon metabolism and bladder cancer risk. 6 Although epidemiologic evidence strongly supports an association between low folate and higher risk of colon cancer, the association with bladder cancer has not been observed. [7][8][9][10][11] Efficient functioning of the one-carbon metabolism pathway is dependent upon dietary intake of folate, B vitamins as co-factors, and methionine, an essential amino acid that is derived from protein intake. This pathway is also fundamental to many cellular processes including genomic DNA methylation and nucleotide synthesis and repair.12 Among several genetic polymorphisms in the folate metabolic pathway characterized thus far, 2 SNPs in the methylene tetrahydrofolate reductase (MTHFR) gene, A222V and E429A, have received the most attention and may be associated with decreased enzyme function. [13][14][15] In relation to cancer, polymorphisms in other genes in this pathway have been studied less frequently. [16][17][18][19] However, like MTHFR, variation in these genes can result in elevated levels of plasma homocysteine, presum...

Association of Folate-Pathway Gene Polymorphisms with the Risk of Prostate Cancer: a Population-Based Nested Case-Control Study, Systematic Review, and Meta-analysis

“…The SHMT1 1420T allele was associated with elevated plasma and RBC levels of folate in one (59) but not another study (60). In studies of associations with cancer risk, the SHMT1 1420T allele was reported to be associated with reduced risk of acute lymphocytic leukemia (58) and malignant lymphoma (61), but null findings have been reported for colorectal (60), bladder (62), breast (48), lung (63), and ovarian cancers (64). In the absence of a phenotypic effect of SHMT1 C1420T, and given the generally null findings of dietary and blood level studies with regard to vitamin B6 (8, 9, 11, 13), our result could be attributable to chance.…”

5-Methyltetrahydrofolate-homocysteine methyltransferase gene polymorphism (MTR) and risk of head and neck cancer

“…Some studies have shown associations with colon (14), lung (15) and breast cancer (16), and relationships with tumor aggressiveness and variable responses to esophageal cancer treatment (17). Other studies did not confirm associations between the polymorphism and different types of cancer, including colorectal (18), lung (19), bladder (20), and stomach cancer (21).…”

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

“…[1][2][3][4] These studies have focused, primarily, on identifying associations between disease risk and non-synonymous (ns) and previously well-characterized polymorphisms. However, given the number of genes that are involved in the folate pathway (Figure 1), investigation of disease associations with other, less-well investigated genomic loci may be warranted and may uncover new genetic associations.…”