茶摄入量与消化系统恶性肿瘤的因果关联：两样本孟德尔随机化研究

Causal association between tea intake and digestive system malignancies： a two-sample Mendelian randomization study

摘要:

目的 采用两样本的孟德尔随机化（two-sample mendelian randomization，TSMR）分析方法，探讨茶摄入量与消化系统恶性肿瘤之间的因果关联。方法 在欧洲人群的全基因组关联研究（genome-wide association study，GWAS）中选择与暴露因素茶摄入量密切相关的单核苷酸多态性（single nucleotide polymorphisms，SNP）作为工具变量。英国生物库联合会（United Kingdom Biobank，UKB）提供了消化系统肿瘤的汇总统计数据作为结局变量，其中包括食道癌、胃癌、小肠癌、结肠癌、直肠癌、肝癌及肝内胆管癌。采用逆方差加权（inverse-variance weighted，IVW）作为主要分析方法，并进行了异质性检验、多效性分析以及敏感性分析以评价研究的可靠性。结果 本研究在全基因组显著性水平（P<5×10^-8）上，共纳入32个独立与茶摄入量相关的SNPs作为工具变量。IVW分析方法显示，茶摄入量与发生肝癌或肝内胆管癌的风险增加相关（OR=1.0019，95%CI=1.0003~1.0035，P=0.020），而茶摄入量与其他消化系统肿瘤的发生在统计学上没有明显联系。研究结果均不受多效性、异质性的影响，敏感性分析验证了结果的可靠性。结论 这项孟德尔随机研究表明，饮茶可能是增加肝癌和肝内胆管癌风险的一个危险因素，但目前仍需更大样本量的GWAS数据进行进一步的孟德尔随机化研究来验证这种关系。

Abstract:

Objective To investigate the possible causal association between tea intake and digestive system malignancies by using the two-sample Mendelian randomization method.Methods In the genome-wide association studies（GWAS） of the European population，the single nucleotide polymorphisms（SNPs） that are strongly associated with the exposure factor of tea intake were selected as instrumental variables. The summary statistics of digestive system tumors provided by The United Kingdom Biobank were used as outcome variables，including esophageal cancer，gastric cancer，small intestine cancer，colon cancer，rectal cancer，liver cancer，and intrahepatic cholangiocarcinoma. Inverse-variance weighting（IVW） was used as the primary analytic method，and a series of analyses were performed to evaluate the reliability of the study，including heterogeneity test，pleiotropic analysis，and sensitivity analysis.Results At the genome-wide significance level（P<5×10^-8），32 independent SNPs associated with tea intake were included as instrumental variables. The IVW analysis showed that tea intake was associated with an increased risk of liver cancer or intrahepatic cholangiocarcinoma（odds ratio=1.0019，95%CI=1.0003-1.0035，P=0.020），while there was no significant association between tea intake and the development of other digestive system tumors. The research findings were not affected by pleiotropy or heterogeneity，and the sensitivity analysis verified the reliability of results.Conclusion This Mendelian randomization study shows that tea intake might be a risk factor for the increased risk of liver cancer and intrahepatic cholangiocarcinoma；however，further Mendelian randomization studies with larger sample sizes of GWAS data are still needed to verify such association.