二甲双胍治疗与结核病发病的两样本孟德尔随机化分析

Randomization analysis of metformin treatment and the onset of tuberculosis with two-sample Mendelian randomization

目的:以孟德尔随机化方法探讨二甲双胍治疗与结核病发病之间的关系。方法:以二甲双胍治疗作为暴露变量、以结核病发病作为结局变量搜索MR Base在线数据库(http://app.mrbase.org),使用一组公开可用的全基因组关联研究(GWAS)对数据进行汇总,并采用逆方差加权(IVW)、加权中位数和MR-Egger回归分析两个样本(二甲双胍治疗样本:462933例,病例组:11552例,对照组:451381例;结核病发病样本:212453例,病例组:549例,对照组:211904例)的孟德尔随机化关联性,采用Cochran’s Q统计量和I2统计量评价单核苷酸多态性(SNP)之间的异质性。采用“留一法”敏感性分析和漏斗图验证结果的可靠性。结果:从GWAS中筛选出40个在全基因组水平上与二甲双胍治疗显著相关的独立的SNP作为工具变量,168个与结核病发病显著相关的独立的SNP。逆方差加权分析显示,二甲双胍治疗与结核病发病之间存在显著的正相关性(P=0.022);MR-Egger回归分析发现,定向多效性不太可能影响结果(截距=-0.043,P=0.394),没有证据表明二甲双胍治疗与结核病发病之间存在直接关联性(P=0.150);但加权中位数方法分析支持二甲双胍治疗与结核病发病之间存在正相关性(P=0.010)。逆方差加权和MR-Egger分析均未发现异质性(Q=46.890,I2=0.168,P=0.175;Q=45.990,I2=0.174,P=0.181),增加了孟德尔随机化分析估计的可靠性。“留一法”敏感性分析发现,孟德尔随机化整体估计结果稳定,没有出现显著偏差,结果具有可靠性。漏斗图也未显示不对称,不存在定向多效性,支持结果的稳健可靠。结论:经异质性和敏感性检验,通过逆方差加权、加权中位数和MR-Egger回归3种分析方法获得的孟德尔随机化结果支持二甲双胍治疗与结核病发病风险之间的正相关性。

Objective:To explore the correlation between metformin treatment and the onset of tuberculosis(TB)by Mendelian randomization(MR).Methods:We searched the MR Base database(http://app.mrbase.org)using metformin treatment as the exposure variable and TB incidence as the outcome variable.A set of publicly available genome-wide association studies(GWAS)were used to summarize the data.Mendelian randomization causal association analysis was performed using inverse variance weighting(IVW),weighted median,and MR-Egger regression analysis on two samples(462933 cases of metformin treatment,including 11552 cases and 451381 controls;212453 cases of TB,including 549 cases and 211904 controls).Cochran’s Q statistic and I 2 statistic were used to evaluate heterogeneity among single-nucleotide polymorphisms(SNPs).The“leave-one-out-method”sensitivity analysis and funnel plot were used to verify the reliability of the results.Results:Forty independent SNPs significantly associated with metformin treatment at the genome-wide level were selected as instrumental variables from GWAS,and 168 independent SNPs significantly associated with TB were selected.Inverse variance-weighted analysis showed a significant positive correlation between metformin treatment and TB incidence(P=0.022).MR-Egger regression analysis found that directional pleiotropy was unlikely to affect the results(intercept=-0.043,P=0.394),there was no evidence of a direct correlation between metformin treatment and TB incidence(P=0.150).However,the weighted median method analysis supported a positive correlation between metformin treatment and TB incidence(P=0.010).No heterogeneity was found in the inverse variance-weighted and MR-Egger analyses(Q=46.890,I 2=0.168,P=0.175;Q=45.990,I 2=0.174,P=0.181),increasing the reliability of the Mendelian randomization analysis estimates.The“leave-one-out-method”sensitivity analysis found that the overall Mendelian randomization estimates were stable,with no significant bias,and the results were reliable.The funnel plot also did not show asymmetry,indicating no directional pleiotropy and supporting the robustness and reliability of the results.Conclusion:After heterogeneity and sensitivity testing,the Mendelian randomization results obtained through inverse variance weighting,weighted median,and MR-Egger regression analysis support a positive correlation between metformin treatment and TB onset.