孟德尔随机化研究揭示脂质和脂蛋白参数与男性生殖的遗传学关联

Mendelian randomization study reveals genetic associations of lipid and lipoprotein parameters with male reproduction

摘要:

目的 采用单变量、多变量、双向孟德尔随机化(MR)研究233种循环代谢生物标志物与男性不育症、畸形精子症之间的因果关系。方法 基于大规模全基因组关联研究汇总数据，选择与233种循环代谢生物标志物强相关性的单核苷酸多态性(SNP)作为工具变量。采用逆方差加权、加权中位数、MR-Egger加权回归、加权模式和简单模式方法研究暴露与结局的因果关系，并进行敏感性分析以验证结果的稳健性。结果 根据逆方差加权(IVW)的结果，认为高密度脂蛋白(HDL)甘油三酯含量[OR:1.24, 95%CI(1.00,1.51),P:0.031]和大HDL甘油三酯与总脂质的比值[OR:1.26, 95%CI(1.00,1.55),P:0.035]与男性不育症的风险升高存在因果关系，中HDL总胆固醇含量[OR:0.79, 95%CI(0.60,0.99),P:0.037]和中HDL胆固醇酯含量[OR:0.78, 95%CI(0.60,0.97),P:0.023]与男性不育症的风险降低存在因果关系；中HDL总胆固醇含量[OR:1.22, 95%CI(1.01,1.47),P:0.042]与畸形精子症的风险升高存在因果关系，极低密度脂蛋白(VLDL)的平均直径(OR:0.84,95%CI(0.71,0.99),P:0.039)与畸形精子症的风险降低存在因果关系。多变量孟德尔随机化(MR)分析结果证实，大HDL甘油三酯与总脂质的比值[OR:1.97,95%CI(1.20,3.22),P:0.007]是男性不育症的独立危险因素。反向MR分析否定反向因果关系的存在。敏感性分析未发现异质性和多效性。结论 大HDL甘油三酯含量和甘油三酯与总脂质的比值是男性不育症的危险因素，中HDL总胆固醇以及胆固醇酯含量是男性不育症的保护因素。中HDL的总胆固醇含量是畸形精子症的危险因素，VLDL的平均直径是畸形精子症的保护因素。调节脂质和脂蛋白代谢是改善男性生殖的重要手段。

Abstract:

Objective Toinvestigatethecausalrelationshipsbetween233circulatingmetabolicbiomarkersandmale infertility,as well as teratozoospermia,using univariate, multivariate,and bidirectional Mendelian randomization approaches.Methods Leveragingsummarystatisticsfromlarge-scalegenome-wideassociationstudies (GWAS),single nucleotidepolymorphisms (SNPs)strongly associated with 233 circulating metabolic biomarkers were selected as instrumentalvariable(IV).Thecausalrelationshipbetweenexposureandoutcomewasinvestigatedusingmethodssuchas inversevarianceweighting (IVW),weightedmedian (WM),MR-Eggerweightedregression,weightedmode,andsimple mode.Sensitivityanalyseswerealsoconductedtoverifytherobustnessoftheresults.Results AccordingtotheIVWresults, therewasacausalrelationshipbetweenelevatedlevelsoftriglyceridesinlargehigh-densitylipoprotein (HDL)particles (OR:1.24,95% CI:1.00-1.51,P:0.031)andtheratiooftriglyceridestototallipidsinlargeHDL(OR:1.26,95% CI: 1.0-1.55,P:0.035)withanincreasedriskofmaleinfertility.Conversely,totalcholesterolcontentin medium HDL particles(OR:0.79,95% CI:0.60-0.99,P:0.037)andcholesterolestercontentinmedium HDL (OR:0.78,95% CI: 0.60-0.97,P:0.023)showedacausalrelationshipwithadecreasedriskofmaleinfertility.Totalcholesterolcontentin medium HDL (OR:1.22,95% CI:1.01-1.47,P:0.042) wascausally associated with anincreased risk of teratozoospermia,whiletheaveragediameterofvery-low-densitylipoprotein (VLDL)particles (OR:0.84,95% CI: 0.71-0.99,P:0.039)wascausallyassociatedwithadecreasedriskofteratozoospermia.MultivariateMRanalysisconfirmed thattheratiooftriglyceridestototallipidsinlargeHDL (OR:1.97,95% CI:1.20-3.22,P:0.007)wasanindependent riskfactorfor maleinfertility.One-samplereverse MR analysisnegatedtheexistenceofreversecausality.Sensitivity analysesrevealednoheterogeneityorpleiotropy.Conclusion Triglyceridecontentandtheratiooftriglyceridestototallipids inlargeHDLparticlesareriskfactorsformaleinfertility,whiletotalcholesterolandcholesterolestercontentin medium HDLparticlesareprotectivefactors.Totalcholesterolcontentinmedium HDLisariskfactorforteratozoospermia,while theaveragediameterofVLDLparticlesisaprotectivefactor.Modulatinglipidandlipoproteinmetabolismisanimportant meanstoimprovemalereproductivehealth.