Genetic variants in N6-methyladenosine are associated with bladder cancer risk in the Chinese population
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GENOTOXICITY AND CARCINOGENICITY
Genetic variants in N6‑methyladenosine are associated with bladder cancer risk in the Chinese population Hanting Liu1,2 · Jingjing Gu1,2 · Yu Jin3 · Qi Yuan1,2 · Gaoxiang Ma1,2,4 · Mulong Du1,2 · Yuqiu Ge1,2 · Chao Qin5 · Qiang Lv5 · Guangbo Fu6 · Meilin Wang1,2 · Haiyan Chu1,2 · Lin Yuan7 · Zhengdong Zhang1,2 Received: 4 May 2020 / Accepted: 10 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Recently N6-Methyladenosine (m6A) has been identified to guide the interaction of RNA-binding protein hnRNP C and their target RNAs, which is termed as m6A-switches. We systematically investigated the association between genetic variants in m 6A-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 m6A-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 6A-switches. We identified that rs5746136 (G > A) of SOD2 in m 6A-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 × 10−3; validation stage: adjusted OR = 0.88, 95% CI 0.79–0.99, P = 3.0 × 10−2; combined analysis: adjusted OR = 0.85, 95% CI 0.78–0.93, P = 4.0 × 10−4). The mRNA level of SOD2 was remarkably lower in bladder cancer tissues than the paired adjacent samples. SNP rs5746136 may affect m6A 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 m6A modification. SOD2 polymorphisms may influence the expression of SOD2 via an m6A-hnRNP C-dependent mechanism and be promising predictors of bladder cancer risk. Keywords N6-methyladenosine · Bladder cancer · Susceptibility · Molecular epidemiology
Hanting Liu, Jingjing Gu and Yu Jin contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02911-2) contains supplementary material, which is available to authorized users.
Abbreviations SNP Single nucleotide polymorphism GWAS Genome-wide association study m6A N6-Methyladenosine RBP RNA-binding proteins MAF Minor allele frequency
* Haiyan Chu [email protected]
for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
* Lin Yuan [email protected]
3
Department of Laboratory Medicine, School of Public Health, Nantong University, Nantong, China
* Zhengdong Zhang [email protected]
4
The Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, Jiangsu, China
5
Department of Urology, The First
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