Genetic variants in N6-methyladenosine are associated with bladder cancer risk in the Chinese population

Recently N-6-Methyladenosine (m(6)A) has been identified to guide the interaction of RNA-binding protein hnRNP C and their target RNAs, which is termed as m(6)A-switches. We systematically investigated the association between genetic variants in m(6)A-switches and bladder cancer risk. A two-stage case-control study was performed to systematically calculate the association of single nucleotide polymorphisms (SNPs) in 2798 m(6)A-switches with bladder cancer risk in 3,997 subjects. A logistic regression model was used to assess the effects of SNPs on bladder cancer risk. A series of experiments were adopted to explore the role of genetic variants of m(6)A-switches. We identified that rs5746136 (G > A) of SOD2 in m(6)A-switches was significantly associated with the reduced risk of bladder cancer (additive model in discovery stage: OR = 0.80, 95% CI 0.69-0.93,P = 3.6 x 10(-3); validation stage: adjusted OR = 0.88, 95% CI 0.79-0.99,P = 3.0 x 10(-2); combined analysis: adjusted OR = 0.85, 95% CI 0.78-0.93,P = 4.0 x 10(-4)). The mRNA level of SOD2 was remarkably lower in bladder cancer tissues than the paired adjacent samples. SNP rs5746136 may affect m(6)A modification and regulate SOD2 expression by guiding the binding of hnRNP C to SOD2, which played a critical tumor suppressor role in bladder cancer cells by promoting cell apoptosis and inhibiting proliferation, migration and invasion. In conclusion, our findings suggest the important role of genetic variants in m(6)A modification. SOD2 polymorphisms may influence the expression of SOD2 via an m(6)A-hnRNP C-dependent mechanism and be promising predictors of bladder cancer risk.