遗传预测的胆结石与胆道肿瘤关联的分子流行病学研究

Biliary tract cancers are a group of rare but highly lethal malignancies. Gallstones are the major risk factor for biliary tract cancer, but whether this association is causal remains unclear due to underpowered studies and presence of confounding factors. Because genes are assigned randomly during mitosis and this process is generally independent of confounding factors, the observed associations between gallstones and biliary tract cancers is likely to be causal if the genetic factors of gallstones are also significantly associated with biliary tract cancers. We have now collected a large sample of cases with biliary tract cancer and controls, as well as cases with gallstone disease, which makes it possible to systematically evaluate the association of genetically determined gallstones with biliary tract cancers. Here, we propose to conduct replication and fine-mapping analyses for gallstone disease susceptibility loci initially identified in populations of European ancestry using cases with gallstone disease and controls recruited from China. Next, we will test for associations between gallstone disease susceptibility loci and biliary tract cancers using cases with biliary tract cancer and controls recruited from China and South Korea. Lastly, we will perform a two-sample Mendelian randomization analysis to investigate the relationship between genetically determined gallstones and biliary tract cancers using a genetic score comprising variants in gallstone disease susceptibility loci as an instrument. Findings from this project will not only advance our understanding of the etiology that gallstones cause biliary tract cancers but also provide new insight into the prevention and treatment of these highly lethal cancers.

胆道肿瘤是一组罕见却高度致死的恶性肿瘤，胆结石是胆道肿瘤的主要危险因素。由于样本量不足的限制以及混杂因素的干扰，现有研究无法阐明二者之间的关联是否为直接的因果关联。因为基因在有丝分裂时随机分配且不受混杂因素的干扰，如果胆结石的遗传因素同时也和胆道肿瘤显著关联，那么二者之间的关联很可能是直接的因果关联。项目组前期建立大样本胆结石病例、胆道肿瘤病例和对照组人群，使得系统评估遗传预测的胆结石与胆道肿瘤关联成为可能。为此，本项目拟使用胆结石病例和对照来验证并精细定位欧洲人群鉴定的胆结石易感位点。其次使用胆道肿瘤病例和对照来测试胆结石易感位点与胆道肿瘤之间的关联。最后使用胆结石易感位点所构建的遗传分数作为工具变量，开展独立样本孟德尔随机化分析，调查遗传预测的胆结石与胆道肿瘤之间的关系。本项目的研究结果不仅有助于促进深入理解胆结石导致胆道肿瘤发生的病因学基础，而且有望为胆道肿瘤的防治提供新视点。

胆道肿瘤是一组高度致死的恶性肿瘤，包括胆囊癌、胆管癌和壶腹癌等，胆结石是胆道肿瘤发生的主要危险因素。因混杂因素的干扰，现有研究无法阐明二者之间的流行病学关联是否为直接的因果关联。因为基因在有丝分裂时随机分配且不受混杂因素的干扰，如果胆结石的遗传因素同时也和胆道肿瘤显著关联，那么二者之间的关联很可能是直接的因果关联。项目组共纳入约5000例胆结石病例、6600例胆道系统肿瘤病例和8000例对照组人群，系统评估遗传预测的胆结石与胆道肿瘤关联。因新型冠状病毒肺炎疫情的影响，本项目的实验进度无法按照预期进度进行，因此目前的研究结果无法阐明胆结石与胆道肿瘤之间的流行病学关联是否为直接的因果关联。项目组将在2021年样本量的基础上完成实验并分析数据，以促进深层次理解胆结石与胆道肿瘤之间的关联及胆结石引起胆道肿瘤发生的潜在病因学基础。