白介素6通路与胆道肿瘤关联的分子流行病学研究

Biliary tract cancers are rare malignant cancers originating from biliary epithelial cells. Epidemiological studies have found that high serum levels of interleukin 6 (IL6) and its receptors (IL6R) are potential risk factors for biliary tract cancers. However, whether this relationship is causal remains unclear due to the interference of confounding factors. In our previous study, we found that IL6R genetic variation was significantly associated with biliary tract cancers. Based on observational evidence and previous findings, we hypothesize that there is a direct causal relationship between IL6 pathway and the incidence of biliary tract cancers. Therefore, we aim to test the hypothesis based on a large sample of biliary tract cancer cases and controls through the following molecular epidemiological studies: (1) to investigate the association between IL6 and IL6R serum levels and biliary tract cancers in Chinese population; (2) to validate the susceptibility loci of IL6 pathway identified in European population among Chinese population; (3) to test the association between the validated IL6 pathway susceptibility loci and biliary tract cancers in cases and controls; (4) to determine the relationship between genetically predicted IL6 pathway and biliary tract cancers through Mendelian randomization study using IL6 pathway susceptibility loci as an instrument. Because the levels of IL6 and IL6R are controllable, findings from this project are expected to provide new insight into for the prevention and treatment of biliary tract cancers.

胆道肿瘤是起源于胆道上皮细胞的罕见恶性肿瘤，流行病学研究发现高血清白介素6及其受体水平是胆道肿瘤发病的潜在危险因素。然而因混杂因素的干扰，目前无法确定二者是否存在因果关系。课题组的小样本研究发现，白介素6受体遗传变异与胆道肿瘤显著关联。基于观察性证据及课题组前期发现，本项目假设白介素6通路与胆道肿瘤发病之间的流行病学关联为直接的因果关联。为此，课题组以前期建立的大样本胆道肿瘤病例及对照组人群为基础，开展分子流行病学研究：⑴在中国人群中调查白介素6及其受体水平与胆道肿瘤的关联；⑵在中国人群中重复验证欧洲人群中鉴定的白介素6通路易感位点；⑶在胆道肿瘤病例及对照中测试白介素6通路易感位点与胆道肿瘤的关联；⑷使用白介素6通路易感位点构建工具变量，开展孟德尔随机化研究，测试遗传预测的白介素6通路与胆道肿瘤之间的关系。因白介素6及其受体水平是可控因素，本项目研究结果有望为胆道肿瘤的防治提供新视点。

胆道肿瘤是一类起源于胆道上皮细胞的恶性肿瘤，研究其病因有重要意义，有望通过干预高危人群达到预防或降低胆道肿瘤的发生。在本课题中，课题组经过3年时间，圆满完成了课题计划的预期任务。完成的主要研究内容包括：（1）血清IL6水平与胆道肿瘤的两样本孟德尔随机化研究，结果显示遗传预测的IL6水平与胆道肿瘤之间无关联（P=0.571）；（2）系统综述及meta分析评估了胆道肿瘤关联的环境因素及遗传因素，共纳入414项研究，评估BTC风险与30个主要环境因素和15个遗传变异之间的关系。结果提示20个环境因素【吸烟和饮酒、13种疾病史、3种感染、初潮年龄较高（>13）和生殖数量高（>3）】著增加了胆道肿瘤风险，而4个因素（女性、饮用咖啡和茶以及阿司匹林的使用）显著降低了胆道肿瘤风险。在遗传因素方面，4个基因的7个变异与胆道肿瘤的发生风险增加显著相关，而两个变异与胆道肿瘤发生风险降低相关。（3）IL6R基因多态性与疾病的关联，发现IL-6R基因多态性与心血管及炎症性疾病相关联。（4）组织芯片多色免疫荧光染色及组织定量分析IL6通路分子水平与胆管癌预后之间的关联，结果有待进一步分析。我们的研究有助于加深对胆道肿瘤发生机制的理解，并为高危人群的疾病筛查和预防提供思路。相关研究结果发表在Frontiers in Immunology、Frontiers in Oncology、Liver International等杂志。