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.
摘要：
烟草致癌物代谢相关基因(TCMGs)可产生烟草致癌物的活性代谢产物,随后导致多种疾病。然而,TCMGs中的遗传变异与膀胱癌易感性之间的关联尚不清楚.在这项研究中,我们从多环芳烃和烟草特有的亚硝胺的代谢途径中获得TCMG，然后在两个人群中探索了TCMG与膀胱癌风险之间的遗传关联：中国人580例和1101例对照，以及5930例病例和5468例对照的欧洲人口，以及相互作用和联合分析。TCMG的表达模式来源于南京膀胱癌(NJBC)研究和公开可用的数据集。在43个TCMG中，我们观察到AKR1C2中rs7087341T>A与中国人群膀胱癌风险降低相关[比值比(OR)=0.84,95%置信区间(CI)=0.72~0.97,P=1.86×10-2].值得注意的是,AKR1C2rs7087341显示与吸烟对膀胱癌风险的交互作用（P交互作用=5.04×10-3），携带T等位基因的吸烟者的风险增加至OR为3.96（Ptrend<0.001）。基因上,rs7087341显示等位基因特异性转录调控，位于由组蛋白标记突出显示的AKR1C2的DNA敏感区域。机械上,rs7087341A等位基因降低AKR1C2表达，在膀胱肿瘤中高表达，增强烟草致癌物的代谢，从而在膀胱肿瘤发生过程中增加了DNA加合物和活性氧的形成。这些发现为膀胱癌的遗传机制提供了新的见解。
