Centre for Cancer Epidemiology, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.
Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.
Cancer Epidemiol Biomarkers Prev. 2021 Feb;30(2):396-403. doi: 10.1158/1055-9965.EPI-20-0919. Epub 2020 Nov 13.
Past history of gallstones is associated with increased risk of gallbladder cancer in observational studies. We conducted complementary observational and Mendelian randomization (MR) analyses to determine whether history of gallstones is causally related to development of gallbladder cancer in an Indian population.
To investigate associations between history of gallstones and gallbladder cancer, we used questionnaire and imaging data from a gallbladder cancer case-control study conducted at Tata Memorial Hospital, Mumbai, Maharashtra, India (cases = 1,170; controls = 2,525). We then used 26 genetic variants identified in a genome-wide association study of 27,174 gallstone cases and 736,838 controls of European ancestry in an MR approach to assess causality. The association of these genetic variants with both gallstones and gallbladder cancer was examined in the gallbladder cancer case-control study. Various complementary MR approaches were used to evaluate the robustness of our results in the presence of pleiotropy and heterogeneity, and to consider the suitability of the selected SNPs as genetic instruments for gallstones in an Indian population.
We found a strong observational association between gallstones and gallbladder cancer using self-reported history of gallstones [OR = 4.5; 95% confidence interval (CI) = 3.5-5.8] and with objective measures of gallstone presence using imaging techniques (OR = 2.0; 95% CI = 1.5-2.7). We found consistent causal estimates across all MR techniques, with ORs for gallbladder cancer in the range of 1.3-1.6.
Our findings indicate a causal relationship between history of gallstones and increased risk of gallbladder cancer, albeit of a smaller magnitude than those found in observational analysis.
Our findings emphasize the importance of gallstone treatment for preventing gallbladder cancer in high-risk individuals.
在观察性研究中，胆囊结石病史与胆囊癌风险增加相关。我们进行了互补的观察性和孟德尔随机化（MR）分析，以确定在印度人群中，胆囊结石病史是否与胆囊癌的发生有因果关系。
为了研究胆囊结石病史与胆囊癌之间的关联，我们使用了在印度马哈拉施特拉邦孟买塔塔纪念医院进行的胆囊癌病例对照研究中的问卷调查和影像学数据（病例=1170；对照=2525）。然后，我们使用了在 27174 例胆囊结石病例和 736838 例欧洲血统对照的全基因组关联研究中确定的 26 个遗传变异，通过 MR 方法来评估因果关系。在胆囊癌病例对照研究中，我们检查了这些遗传变异与胆囊结石和胆囊癌的关联。我们使用了各种互补的 MR 方法来评估在存在多效性和异质性的情况下我们的结果的稳健性，并考虑所选 SNP 作为印度人群中胆囊结石的遗传工具的适宜性。
我们使用自我报告的胆囊结石病史（OR=4.5；95%置信区间[CI]：3.5-5.8）和使用影像学技术的胆囊结石存在的客观测量（OR=2.0；95%CI：1.5-2.7）发现了胆囊结石和胆囊癌之间的强烈观察性关联。我们发现所有 MR 技术的因果估计都一致，胆囊癌的 OR 值在 1.3-1.6 之间。
我们的研究结果表明，胆囊结石病史与胆囊癌风险增加之间存在因果关系，尽管其程度小于观察性分析中发现的程度。
我们的研究结果强调了在高危人群中治疗胆囊结石对于预防胆囊癌的重要性。
