Combined effect of NAT2, MTR and MTHFR genotypes and tobacco on bladder cancer susceptibility in Tunisian population

Background: Cigarette smoking is the predominant risk factor for bladder cancer. This risk may be modified by polymorphisms in carcinogens metabolism genes; including those involving the N-acetyl transferase 2 (NAT2) which have been correlated with decreased enzyme activities. Moreover, folate insufficiency can induces carcinogenesis by decreasing DNA methylation. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are enzymes that play central roles in the folate metabolic pathway. The MTHFR 677*T and MTR 2756*G variants are associated with decreased enzyme activity. Methods: In this work, we have conducted a case-control study in order to assess the combined effect of tobacco, slow NAT2 variants, MTHFR 677*T and MTR 2756*G alleles on bladder cancer development in North Tunisia. Results: For MTR A2756G, alleles and genotypic distributions differed significantly between cases and controls (p = 0.00009, OR = 3.27, CI 95% 1.76–6.12). While, in non-smokers patients the slow NAT2 did not appear to influence bladder cancer susceptibility; our results suggested that it might act with an additive contribution with tobacco as well as with that determined by MTR 2756 AG or 2756 GG genotypes (p = 0.0008). Identical cumulative effect was detected for slow NAT2 and MTHFR 677*T variant (p = 0.0003; OR = 36.6; CI 95% 3.4–935.3). Conclusion: The strongest result obtained by this study was for an additive effect between smoking status, slow NAT2 variants, MTR 2756*G and MTHFR 677*T alleles, in affecting bladder cancer risk.