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

Abstract

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.