■先前的观察性研究报道了循环脂质和降脂药物与男性不育(MIF)之间的可能关联,以及循环维生素D的中介作用。由于偏见等问题,反向因果关系,和残余混杂,从这些研究中推断因果关系可能具有挑战性。因此,本研究旨在通过孟德尔随机化(MR)分析探讨循环脂质和降脂药物对MIF的影响,并评估维生素D的中介作用。
■与脂质性状相关的遗传变异和脂质修饰靶标的降脂作用来自全球脂质遗传学联盟全基因组关联研究。MIF的汇总统计数据来自FinnGen第9版。利用相关组织的定量表达特征位点数据,获取与基因表达水平相关的遗传变异,进一步探讨这些靶基因表达水平与MIF风险的关系。两步MR分析用于探索维生素D的中介作用。多敏感性分析方法(共定位分析,Egger截距测试,Cochrane的Q测试,多效性残差和离群值(MR-PRESSO),和留一法)用于证明我们结果的可靠性。
■在我们的研究中,我们观察到四种降脂药靶点的脂质修饰与MIF风险相关,LDLR激活剂(相当于LDL-C降低1-SD)(OR=1.94,95%CI1.14-3.28,FDR=0.040),LPL激活剂(相当于TG降低1-SD)(OR=1.86,95%CI1.25-2.76,FDR=0.022),CETP抑制剂(相当于HDL-C的1-SD增加)(OR=1.28,95%CI1.07-1.53,FDR=0.035)与MIF的高风险相关。HMGCR抑制剂(相当于LDL-C降低1-SD)与MIF风险降低相关(OR=0.38,95%CI0.17-0.83,FDR=0.39)。三个靶点的调脂作用部分由血清维生素D水平介导。调解为0.035(LDLR激活剂),0.012(LPL活化剂),和0.030(CETP抑制剂),调解率为5.34%(LDLR激活剂),1.94%(LPL活化剂),和12.2%(CETP抑制剂),分别。此外,没有证据表明其他6种降脂药物的脂质特性和脂质修饰作用与MIF风险相关.多重敏感性分析方法显示,由多效性或遗传混杂引起的偏见的证据微不足道。
■这项研究不支持脂质性状(LDL-C,HDL-C,TG,Apo-A1和Apo-B)是MIF的致病危险因素。它强调LPL,LDLR,CETP,和HMGCR是改善男性生育力的有希望的药物靶标。
UNASSIGNED: Previous observational studies have reported a possible association between circulating lipids and lipid-lowering drugs and male infertility (MIF), as well as the mediating role of circulating vitamin D. Then, due to issues such as bias, reverse causality, and residual confounding, inferring causal relationships from these studies may be challenging. Therefore, this study aims to explore the effects of circulating lipids and lipid-lowering drugs on MIF through Mendelian randomization (MR) analysis and evaluate the mediating role of vitamin D.
UNASSIGNED: Genetic variations related to lipid traits and the lipid-lowering effect of lipid modification targets are extracted from the Global Alliance for Lipid Genetics Genome-Wide Association Study. The summary statistics for MIF are from the FinnGen 9th edition. Using quantitative expression feature loci data from relevant organizations to obtain genetic variations related to gene expression level, further to explore the relationship between these target gene expression levels and MIF risk. Two-step MR analysis is used to explore the mediating role of vitamin D. Multiple sensitivity analysis methods (co-localization analysis, Egger intercept test, Cochrane\'s Q test, pleiotropy residuals and outliers (MR-PRESSO), and the leave-one-out method) are used to demonstrate the reliability of our results.
UNASSIGNED: In our study, we observed that lipid modification of four lipid-lowering drug targets was associated with MIF risk, the LDLR activator (equivalent to a 1-SD decrease in LDL-C) (OR=1.94, 95% CI 1.14-3.28, FDR=0.040), LPL activator (equivalent to a 1-SD decrease in TG) (OR=1.86, 95% CI 1.25-2.76, FDR=0.022), and CETP inhibitor (equivalent to a 1-SD increase in HDL-C) (OR=1.28, 95% CI 1.07-1.53, FDR=0.035) were associated with a higher risk of MIF. The HMGCR inhibitor (equivalent to a 1-SD decrease in LDL-C) was associated with a lower risk of MIF (OR=0.38, 95% CI 0.17-0.83, FDR=0.39). Lipid-modifying effects of three targets were partially mediated by serum vitamin D levels. Mediation was 0.035 (LDLR activator), 0.012 (LPL activator), and 0.030 (CETP inhibitor), with mediation ratios of 5.34% (LDLR activator), 1.94% (LPL activator), and 12.2% (CETP inhibitor), respectively. In addition, there was no evidence that lipid properties and lipid modification effects of six other lipid-lowering drug targets were associated with MIF risk. Multiple sensitivity analysis methods revealed insignificant evidence of bias arising from pleiotropy or genetic confounding.
UNASSIGNED: This study did not support lipid traits (LDL-C, HDL-C, TG, Apo-A1, and Apo-B) as pathogenic risk factors for MIF. It emphasized that LPL, LDLR, CETP, and HMGCR were promising drug targets for improving male fertility.