两样本孟德尔随机化研究肥胖与男性不育症的因果关系

Causal relationship between obesity and male infertility:A two⁃sample Mendelian randomization study

目的:通过孟德尔随机化(MR)研究阐明肥胖与男性不育症(MI)之间的因果关系。方法:进行双样本MR分析,以评估遗传预测的体质量指数(BMI)与MI风险的因果关联。暴露因子为BMI(n;病例组;=99998,n;对照组;=12746)。MI的遗传信息来自一项全基因组关联研究(GWAS),该研究包含73479例欧洲人。在单变量孟德尔随机化研究(UVMR)分析中,将逆方差加权法(IVW)作为主要方法,MR-Egger回归模型和加权中值估计模型作为因果推断的补充方法。其次,运用多种敏感性分析方法来验证MR结果的稳健性,包括Cochran's Q检验、MR-Egger截距检验、MR-PRESSO、留一法检验和漏斗图。为了评估BMI对MI风险的直接因果效应,进行多变量孟德尔随机化研究(MVMR)。结果:UVMR发现遗传预测BMI与MI风险增加之间存在因果关系(OR:1.237,95%CI:1.090~1.404,P=0.001)。敏感性分析发现,目前的研究几乎不存在偏倚(P>0.05)。在调整2型糖尿病、饮酒和吸烟等危险因素后,MVMR进一步证实遗传预测的BMI对MI风险增加有直接影响(P均<0.05)。结论:两样本MR研究表明,遗传预测的BMI可能与MI风险增加之间存在因果关系。未来的研究可基于这一发现,进一步探讨肥胖与MI两者之间因果关系的具体机制,为预防和治疗提供新途径。

Objective:To clarify the causal relationship between obesity and male infertility through Mendelian randomization(MR)study.Methods:We assessed the causal effect of genetically predicted body mass index(BMI)on the risk of male infertility via a two⁃sample MR analysis,with the BMIs of 99998 cases and 12746 controls as the exposure factor and genetic information on male infertility obtained from a genome⁃wide association study of 73479 Europeans.In the univariable MR(UVMR)analysis of the causal relationship,we mainly used inverse variance weighting(IVW),with MR⁃Egger regression and weighted median filtering as the supplementary methods.Sensitivity analyses including the Cochran's Q test,Egger intercept test,MR⁃PRESSO,leave⁃one⁃out analysis and funnel plot were performed to verify the robustness of the MR results.To evaluate the direct causal effects of BMI on MI risk,mult⁃ivariable MR(MVMR)was performed.Results:UVMR indicated a causal relationship between genetically predicted BMI and an in⁃creased risk of male infertility(OR:1.237,95%CI:1.090-1.404,P=0.001).Sensitivity analysis revealed little evidence of bias in the current study(P>0.05).With such risk factors as type 2 diabetes,alcohol consumption and smoking adjusted,MVMR confirmed a direct causal effect of genetically predicted BMI on the risk of male infertility(P<0.05).Conclusion:Genetically pre⁃dicted BMI may be associated with an increased risk of male infertility.Further studies are expected to explore the underlying mecha⁃nisms of this association and provide some new strategies for the prevention and treatment of BMI⁃related male infertility.