两样本孟德尔随机化方法对甲状腺功能减退症与肠道菌群因果关系研究

Exploring the causal relationship between hypothyroidism and intestinal microbiota based on two-sam Mendelian randomization method

目的 通过孟德尔随机化研究(Mendelian randomization, MR)分析肠道菌群和甲状腺功能减退症之间的因果关系。方法 从MiBioGen数据库下载人类肠道菌群数据集,保留196个已知菌群(9个门、16个纲、20个目、32个科和119个属)用作暴露因素,工具变量为与暴露因素强相关且相互独立的单核苷酸多态性(single nucleotide polymorphism, SNP)。从全基因组关联研究数据库下载包含30 155例患者和379 986例对照的甲状腺功能减退症数据集用作结局变量。分别采用逆方差加权(IVW)法、加权中位数(WM)法、MR-Egger检验进行两样本MR分析,以优势比(odds ratio, OR)评估肠道菌群与甲状腺功能减退症的因果关联;利用留一法进行敏感性分析,采用MR-Egger截距测试和MR-PRESSO全局检验来检测水平多效性,Cochran Q检测异质性。结果 共发现196个肠道微生物群类中有6菌类与甲状腺功能减退症发病风险有因果关联(P<0.05),共纳入分析SNP152个。IVW分析结果显示慢球菌纲[OR=1.003,95%置信区间(confidence interval, CI)(1.001,1.005),P<0.05]、巴氏杆菌科[OR=1.003,95%CI(1.001,1.006),P=0.005]、斯莱克菌属[OR=1.002,95%CI(1.000,1.005),P=0.0048]和脱硫弧菌目[OR=1.003,95%CI(1.002,1.006),P=0.0349]、放线菌门[OR=1.004,95%CI(1.002,1.006),P=0.0385]、与甲状腺功能减退症呈正相关;消化球菌科[OR=0.995,95%CI(0.992,0.998),P=0.0031]与甲状腺功能减退症呈负相关。此外,留一法敏感性分析结果稳定,MR-Egger截距测试和MR-PRESSO全局检验无水平多效性,Cochran Q检验不存在异质性。结论 肠道菌群和甲状腺功能减退症之间存在因果关系,慢球菌纲、放线菌门、巴氏杆菌科、斯莱克菌属和脱硫弧菌目可增加甲状腺功能减退症发病风险,消化球菌科可降低甲状腺功能减退症发病风险。

Objective To analyze the causal relationship between intestinal flora and hypothyroidism through Mendelian randomization(MR)study.Methods The human intestinal flora data set was downloaded from the MiBioGen database,and 196 known flora(9 phyla,16 classes,20 orders,32 families and 119 genera)were retained as exposure factors,and those related to exposure were screened out.Single nucleotide polymorphism(SNP)with strongly correlated and independent factors is used as an effective instrumental variable.A hypothyroidism data set containing 30155 patients and 379986 controls was downloaded from the Genome-Wide Association Study Database and used as outcome variables.Two-sample MR analysis was performed using the inverse variance weighting(IVW)method,the weighted median(WM)method,and the MR-Egger test,respectively,and the odds ratio(odds ratio,OR)was used to evaluate the causality between intestinal flora and hypothyroidism.Association;sensitivity analysis was performed using the leave-one-out method,MR-Egger intercept test and MR-PRESSO global test were used to detect horizontal pleiotropy,and Cochran Q was used to detect heterogeneity.Results A total of 6 out of 196 intestinal microbiota categories were found to be causally associated with the risk of hypothyroidism(P<0.05),and a total of 152 SNPs were included in the analysis.IVW analysis results showed that Brad ycoccus[OR=1.003,95%confidence interval(CI)(1.001,1.005),P<0.05],Pasteurellaceae[OR=1.003,95%CI(1.001,1.006),P=0.005],Schleckella[OR=1.002,95%CI(1.000,1.005),P=0.0048]and Desulfovibrioles[OR=1.003,95%CI(1.002,1.006),P=0.0349],Actinobacteria[OR=1.004,95%CI(1.002,1.006),P=0.0385],positively correlated with hypothyroidism;Peptococcusaceae[OR=0.995,95%CI(0.992,0.998),P=0.0031] was negatively correlated with hypothyroidism.In addition,the results of the leaveone-out sensitivity analysis were stable,there was no horizontal pleiotropy in the MR-Egger intercept test and the MRPRESSO global test,and there was no heterogeneity in the Cochran Q test.Conclusion There is a causal relationship between intestinal flora and hypothyroidism.The class Bradycoccus,Actinobacteria,Pasteurellaceae,Schleckella and Desulfovibrioles can increase the risk of hypothyroidism.Peptococcus family May reduce the risk of hypothyroidism.