肠道菌群与多囊卵巢综合征的孟德尔随机化研究

Association between gut microbiota and polycystic ovary syndrome:a Mendelian randomization study

目的采用孟德尔随机化(MR)方法探究肠道菌群与多囊卵巢综合征(PCOS)的因果关联,为PCOS发病机制研究和防治策略制定提供依据。方法肠道菌群遗传资料来自一项涉及18340名研究对象的全基因组关联研究(GWAS)Meta分析;PCOS遗传资料来自2项欧洲人群的GWAS Meta分析,分别作为发现集和验证集。利用发现集数据进行双向MR分析,以逆方差加权法(IVW)为主要方法;敏感性分析采用加权中位数法、MR-Egger回归法和MR-PRESSO检验;利用验证集数据验证;并采用Meta分析对2个数据集的结果进行合并。结果正向MR分析结果显示,9种肠道菌群与PCOS存在统计学关联(均P<0.05),其中链球菌科(OR=1.442,95%CI:1.097~1.895)、放线菌属(OR=1.359,95%CI:1.036~1.784)、瘤胃球菌UCG 011(OR=0.755,95%CI:0.619~0.921)、塞利单胞菌属(OR=0.766,95%CI:0.657~0.893)、链球菌属(OR=1.496,95%CI:1.136~1.972)与PCOS的正向因果关联在敏感性分析中保持稳定。反向MR分析结果显示,上述5种肠道菌群与PCOS不存在反向因果关联(均P>0.05)。验证集的MR分析结果显示,上述5种肠道菌群与PCOS不存在统计学关联(均P>0.05)。Meta分析结果显示,放线菌属(OR=1.226,95%CI:1.010~1.503)、链球菌属(OR=1.266,95%CI:1.042~1.542)与PCOS存在统计学关联(均P<0.05)。结论肠道菌群中的链球菌属、放线菌属与PCOS风险升高有关。

Objective To investigate the causal relationship between gut microbiota and polycystic ovary syndrome(PCOS)using a Mendelian randomization(MR)study,so as to provide insights into the pathogenesis of PCOS and the formulation of prevention and treatment strategies.Methods The genetic data on gut microbiota was derived from a meta-analysis of genome-wide association studies(GWAS)involving 18340 participants.The genetic data on PCOS was sourced from two GWAS meta-analyses in European populations,serving as the discovery set and the validation set,respectively.A two-sample MR analysis was conducted using the discovery set,with the inverse variance weighted(IVW)method as the primary approach.Sensitivity analyses employed the weighted median method,MR-Egger regression,and the MR-PRESSO test.The validation set was utilized for verification,and a meta-analysis was performed to combine the results from the two datasets.Results Forward MR analysis results showed that nine types of gut microbiota were statistically associated with PCOS(all P<0.05).Specifically,the association of family Streptococcaceae(OR=1.442,95%CI:1.097-1.895),genus Actinomyces(OR=1.359,95%CI:1.036-1.784),genus Ruminococcaceae UCG 011(OR=0.755,95%CI:0.619-0.921),genus Sellimonas(OR=0.766,95%CI:0.657-0.893)and genus Streptococcus with PCOS(OR=1.496,95%CI:1.136-1.972)remained consistent in the sensitivity analysis.Reverse MR analysis showed no evidence for the causal association between PCOS and the aforementioned five types of gut microbiota(all P>0.05).The MR analysis results of the validation set showed that there was no statistical association between the aforementioned five types of gut microbiota and PCOS(all P>0.05).However,the associations remained significant for genus Actinomyces(OR=1.226,95%CI:1.010-1.503)and genus Streptococcus(OR=1.266,95%CI:1.042-1.452)in the meta-analysis(both P<0.05).Conclusion This study provides the evidence that genus Actinomyces and genus Streptococcus are causally associated with PCOS.