Epidemiological studies have shown an association between low folate intake and an increased cancer risk. The few reports on polymorphisms in genes involved in one carbon metabolism and risk of bladder cancer have been inconsistent. We evaluated associations between bladder cancer and nine SNPs in six genes involved in this pathway including the cystathionine-beta-synthase (CBS; Exon 9+33 C>T rs234706 and Exon 13+41C>T rs1801181), 5,10 methylenetetrahydrofolate reductase (MTHFR; Ex5+79C>T A222V rs1801133 and Exon 8-62A>C E429A rs1801131), methyltetrahydrofolate homocysteine methyltransferase (MTR; Exon 26-20A>G D919G rs1805087), 5-methyltetrahydrofolate homocysteine methyltransferase reductase (MTRR; Exon 2-64A>G I49M rs1801394), serine hydroxymethyltransferase 1 (SHMT; Exon 12+138C>T L435F rs1979277 and +236T>C rs1979276), and solute (folate) carrier family 19 member 1 (SLC19A1; Exon 7-233G>T rs1051296). The study population included 1,150 patients with transitional cell carcinoma of the urinary bladder and 1,149 control subjects from a hospital based case-control study conducted in Spain. We also evaluated main effects and interactions with dietary variables that may alter 1-carbon metabolism including vitamin B6, B12, folate, total protein, and alcohol, in addition to smoking. A significant increase in bladder cancer risk was observed with decreasing intake of dietary vitamins B6, (OR=1.41; 95% CI: 1.03, 1.94, first vs. fourth quartile, P-trend=0.01), B12 (OR=1.40; 95% CI: 1.03, 1.90, first vs. fourth quartile, P-trend=0.03) and folate (OR=1.37; 95% CI:1.01, 1.86, first vs. fourth quartile, P-trend=0.43). None of the genotypes evaluated or haplotypes of MTHFR or SHMT genes were significantly associated with bladder cancer risk. Investigation of gene-environment interactions suggested interaction between CBS Exon 13 T allele and low vitamin B6 (P-interaction=0.02) and folate intake (P-interaction=0.03. Interaction between smoking measured as cigarettes per day and the SLC19A1 G polymorphism was also observed (P interaction=0.03). In conclusion, our findings indicate that the evaluated polymorphisms in 1-C metabolism genes do not have a substantial overall association with bladder cancer risk, and do not corroborate previous reports of interaction between MTHFR polymorphisms and folate intake. However, data suggest that low intake of B6, B12 and folate may increase bladder cancer risk.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]