Polymorphisms in one-carbon metabolism pathway genes and risk for bladder cancer in a Tunisian population

Cigarette smoking is the most important risk factor for bladder cancer. Moreover, epidemiologic studies have implicated several genetic variations interfering with methyl group metabolisms in susceptibility for a variety of cancers. Examples of these variations can be found in genes of the folate metabolic pathway, which is crucial in the provision of methyl groups for DNA, RNA, and protein methylation, as well as in purine and pyrimidine synthesis. We conducted a case–control study to examine the relationship between the methylenetetrahydrofolate reductase (MTHFR C677 T and MTHFR A1298C), methionine synthase (5-methyltetrahydrofolate-homocysteine methyltransferase, MTR A2756 G), methionine synthase reductase (5-methyltetrahydrofolate-homocysteine methyltransferase reductase, MTRR A66 G and MTRR C524 T), and thymidylate synthase (TYMS 2R→3R and G/C) genotypes and the risk for bladder cancer in a Tunisian population. The isolated MTHFR 677∗T, MTRR 66∗G and MTRR 524∗T variants did not appear to influence bladder cancer susceptibility. The 3R∗C/3R∗C genotype for the TYMS gene appears to be a protective factor against bladder cancer development (P=0.0001; OR=0.12; 95% CI=0.03–0.40). However, patients heterozygous for MTHFR A1298C or MTR A2756 G genotypes have 1.62- and 2.13-fold higher risk, respectively, of developing bladder cancer. Moreover, the combined study of MTHFR 1298∗C and MTR 2756∗G variants with either or both MTRR 66GG and TYMS 3R∗G/3R∗G genotypes suggests a cumulative effect. Finally, this study evidenced that interaction between gene variations involved in folate metabolism and risk of bladder cancer increased dramatically among smokers.