Methylenetetrahydrofolate reductase (MTHFR) variants and bladder cancer: A population-based case-control study

Park, Sunyeong; Nelson, Heather H.; Andrew, Angeline S.; Mott, Leila A.; Schned, Alan R.; Kelsey, Karl T.

doi:10.1016/j.ijheh.2005.04.005

Cited by 32 publications

(17 citation statements)

References 22 publications

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“…One earlier study of cancer mortality in a population based cohort of elderly men identified an increased risk of kidney and bladder cancer (combined) among men with the MTHFR 222VV genotype (RR 5 5.48; 95% CI: 1.67-18.0), although the exact number of cases of each cancer type was not reported. 19 Previous studies have generally not shown significant associations between the MTHFR 222VV genotype and bladder cancer risk, [19][20][21][22] suggesting that the excess risk reported by Heijmans et al, 19 might have been driven by kidney cancer.…”

Section: Discussionmentioning

confidence: 97%

Folate metabolism genes, vegetable intake and renal cancer risk in central Europe

Moore

Hung

Karami

et al. 2007

Intl Journal of Cancer

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In a multicenter case‐control study of renal cell carcinoma (RCC) conducted in central and eastern Europe, we reported a strong inverse association with high vegetable intake and RCC risk. The odds ratio (OR) for high compared to the lowest tertile of vegetable intake was OR = 0.67; (95% confidence interval (CI): 0.53–0.83; p‐trend < 0.001). We hypothesized that variation in key folate metabolism genes may modify this association. Common variation in 5 folate metabolism genes (CBS: Ex9+33C > T (rs234706), Ex13 +41C > T (rs1801181), Ex18 −391 G > A (rs12613); MTHFR: A222V Ex5+79C > T (rs1801133), Ex8−62A > C (rs1801131); MTR: Ex26 20A > G (rs1805087), MTRR: Ex5+136 T > C (rs161870), and TYMS:IVS2−405 C > T (rs502396), Ex8+157 C > T (rs699517), Ex8+227 A > G (rs2790)) were analyzed among 1,097 RCC cases and 1,555 controls genotyped in this study. Having at least 1 variant T allele of MTHFR A222V was associated with higher RCC risk compared to those with 2 common (CC) alleles (OR = 1.44; 95% CI: 1.17–1.77; p = 0.001). After stratification by tertile of vegetable intake, the higher risk associated with the variant genotype was only observed in the low and medium tertiles (p‐trend = 0.001), but not among those in the highest tertile (p‐interaction = 0.22). The association remained robust after calculation of the false discovery rate (FDR = 0.05). Of the 3 TYMS SNPs examined, only the TYMS IVS2 −405 C (rs502396) variant was associated with a significantly lower risk compared to the common genotype (OR = 0.73; 95% CI: 0.57–0.93). Vegetable intake modified the association between all 3 TYMS SNPs and RCC risk (p‐interaction < 0.04 for all). In summary, these findings suggest that common variation in MTHFR and TYMS genes may be associated with RCC risk, particularly when vegetable intake is low. © 2007 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 97%

Folate metabolism genes, vegetable intake and renal cancer risk in central Europe

Moore

Hung

Karami

et al. 2007

Intl Journal of Cancer

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“…As shown in Table 6, seven original and independent published literatures were analyzed [10][11][12][13][14][15][16], together with our data. Most samples in the eligible studies were primarily Caucasians.…”

Section: Meta-analysismentioning

confidence: 99%

“…A number of molecular epidemiologic studies have been conducted to investigate the associations between the MTHFR C677T and A1298C polymorphisms and bladder cancer risk [10][11][12][13][14][15][16]. However, the results remain conflicting rather than conclusive.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms of methylenetetrahydrofolate reductase and methionine synthase genes and bladder cancer risk: a case–control study with meta-analysis

Wang

Zhu

et al. 2008

Clin Exp Med

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Folate deficiency due to the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) variants leads to carcinogenesis by affecting DNA synthesis, repair, and methylation. We hypothesized that the MTHFR C677T, A1298C, and MS A2756G polymorphisms are associated with risk of bladder cancer. In a case-control study of 239 bladder cancer cases and 250 cancer-free controls, we found that the MTHFR 677TT genotype was statistically significantly associated with an increased risk of bladder cancer compared with the 677CC genotype (OR = 2.06, 95% CI = 1.16-3.64). Furthermore, the TA haplotype was associated with a significantly increased bladder cancer risk (OR = 1.38, 95% CI = 1.05-1.81) than was the most common haplotype, CA (e.g., CA denotes MTHFR 677C -1298A). We also found that the combined genotypes with 4-6 variant (risk) alleles (i.e., MTHFR 677T, 1298A, and MS 2756G alleles) were associated with an increased risk of bladder cancer (OR = 1.62, 95% CI = 1.03-2.53) compared with those with 0-3 variants, and this increased risk was more pronounced among subgroup of older people (OR = 1.71, 95% CI = 1.03-2.83). A meta-analysis of seven studies did not show a significant risk of bladder cancer in the MTHFR polymorphisms. The MTHFR polymorphisms and their haplotypes appear to jointly contribute to risk of bladder cancer.

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“…18,[20][21][22][23][24] Of these, 1 study (457 bladder cancer cases and 457 controls) also examined dietary folate intake and observed significant interactive effects among subjects that had both low folate and at least 1 variant MTHFR A222V allele. 19 To further investigate the role of this pathway in bladder cancer, we determined the association between SNPs in several key genes involved in one-carbon metabolism with bladder cancer risk among 1,150 cases and 1,149 controls participating in the Spanish Bladder Cancer Study.…”

mentioning

confidence: 99%

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

Moore

Malats

Rothman

et al. 2007

Intl Journal of Cancer

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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...

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Methylenetetrahydrofolate reductase (MTHFR) variants and bladder cancer: A population-based case-control study

Cited by 32 publications

References 22 publications

Folate metabolism genes, vegetable intake and renal cancer risk in central Europe

Folate metabolism genes, vegetable intake and renal cancer risk in central Europe

Polymorphisms of methylenetetrahydrofolate reductase and methionine synthase genes and bladder cancer risk: a case–control study with meta-analysis

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

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