他汀类药物与骨密度:一项药物靶向孟德尔随机化分析

Relationship between statin drugs and bone density:a drug target-mediated Mendelian randomization study

背景:观察性研究表明他汀类药物可能对骨密度具有保护作用,这使其成为潜在的骨质疏松症治疗药物之一。目的:通过孟德尔随机化方法来评估药物靶点介导的脂质表型与骨密度之间的因果关系。方法:从IEU Open GWAS数据库获取了与他汀类药物相关的单核苷酸多态性以及骨密度相关数据。主要分析方法是逆方差加权法,同时也使用了加权中位数法、简单中位数法、加权中值方法和MR-Egger回归法。使用β值和95%CI来评估他汀类药物与骨密度之间的因果关系;另外,进行敏感性分析以验证结果的可靠性,使用Cochran’s Q检验来评估异质性,使用MR-Egger截距检验是否存在水平多效性。使用留一法分析确定是否有单个或多个单核苷酸多态性影响了结果。结果与结论:他汀类药物作用靶点——3-羟基-3-甲基戊二酰辅酶A还原酶介导的低密度脂蛋白胆固醇与足跟定量超声骨密度(β=-0.086,95%CI:-0.117至-0.055,P=5.42×10^(-8))和全身骨密度(β=-0.193,95%CI:-0.288至-0.098,P=7.35×10^(-5))呈显著相关。该研究结果支持了他汀类药物对骨密度的保护作用。这些发现不仅加深了对胆固醇相关基因和骨骼健康关系的理解,还揭示了改善骨密度的潜在治疗靶点。

BACKGROUND:Observational studies have suggested that statin drugs may have a protective effect on bone density,making them a potential treatment option for osteoporosis.OBJECTIVE:To evaluate the causal relationship between drug target-mediated lipid phenotypes and bone mineral density(BMD)using Mendelian randomization methods.METHODS:We obtained single nucleotide polymorphismsrelated to statin drugs and BMD data from the IEU Open GWAS database.The primary analysis method was the inverse variance weighted method,and we also used weighted median,simple median,weighted mode,and MR-Egger regression.We used β values and 95% confidence intervals(CI)to assess the causal relationship between statin drugs and BMD.Additionally,we conducted sensitivity analyses to validate the results,assessed heterogeneity using Cochran’s Q test,examined for horizontal pleiotropy using the MR-Egger intercept test,and performed leaveone-out analyses to determine if individual or multiplesingle nucleotide polymorphism influenced the results.RESULTS AND CONCLUSION:There was a significant association between the statin target of action,3-hydroxy-3-methyl glutaryl coenzyme A reductasemediated low-density lipoprotein cholesterol,and heel bone BMD(β=-0.086,95%CI:-0.117 to-0.055,P=5.42×10^(-8))and whole-body BMD(β=-0.193,95%CI:-0.288 to -0.098,P=7.35×10^(-5)).The findings of this study support the protective effect of statin drugs on BMD.These findings not only deepen our understanding of the relationship between cholesterol-related genes and bone health but also reveal potential therapeutic targets for improving BMD.