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 x 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (P-interaction = 5.04 x 10(-3)), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (P-trend < 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.
[1]Nanjing Med Univ, Ctr Global Hlth,Jiangsu Key Lab Canc Biomarkers, Key Lab Modern Toxicol Minist Educ,Collaborat Inno, Dept Environm Genom & Genet Toxicol,Sch Publ Hlth, Nanjing 211166, Peoples R China.
[2]Nanjing Med Univ, Affiliated Taizhou Peoples Hosp, Inst Clin Res, Nanjing 211166, Peoples R China.
[3]Nanjing Med Univ, Ctr Global Hlth Prevent & Treatment, Jiangsu Key Lab Canc Biomarkers, Nanjing 211166, Peoples R China.
[4]Nanjing Med Univ, Yancheng Sch Clin Med, Peoples Hosp Yancheng 3, Dept Urol, Nanjing 211166, Peoples R China.
[5]Univ Chinese Med, Jiangsu Prov Chinese Med Hosp 2, Affiliated Hosp Nanjing 2, Dept Urol, Nanjing 210017, Peoples R China.
[6]Nanjing Med Univ, Ctr Global Hlth,Jiangsu Key Lab Canc Biomarkers Pr, Key Lab Modern Toxicol Minist Educ,Collaborat Inno, Sch Publ Hlth,Dept Environm Genom & Genet Toxicol, Nanjing 211166, Peoples R China.
[7]Southeast Univ, Sch Publ Hlth, Key Lab Environm Med Engn, Minist Educ, Nanjing 210009, Peoples R China.
[8]Nanjing Med Univ, Affiliated Hosp 1, Dept Urol, Nanjing 210036, Peoples R China.
[9]Jiangsu Prov Hosp Tradit Chinese Med, Dept Urol, Nanjing 210029, Peoples R China.
[10]Nanjing Med Univ, Ctr Global Hlth, Sch Publ Hlth, Dept Biostat, Nanjing 211166, Peoples R China.
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