Abstract
Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72–0.97, P = 1.86 × 10–2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10–3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.
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The data that support the findings of this study is available from the corresponding authors upon reasonable request.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant Numbers: 82130096 and 82103878) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine). We are grateful to all the people who helped us accomplish this project.
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Z.Z., R.Z., and M.D. conceived and designed the study. Y.X., Y.S., Z.M., F.G., and H.S. recruited study subjects. Y.X, Y.S., and H.S. performed statistical analyses and summarized results. H.C., D.W., and M.W. contributed reagents/materials/analysis tools. Y.X, Y.S., and H.S. wrote the paper. Z.Z., R.Z., and M.D. revised the paper, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Xiao, Y., Shen, Y., Song, H. et al. AKR1C2 genetic variants mediate tobacco carcinogens metabolism involving bladder cancer susceptibility. Arch Toxicol (2024). https://doi.org/10.1007/s00204-024-03737-y
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DOI: https://doi.org/10.1007/s00204-024-03737-y