降脂药物与两种骨骼疾病的因果关联:一项跨种族药物靶点孟德尔随机化分析

Causal associations of lipid-lowering drugs with skeletal diseases: a transethnic drug-target Mendelian randomization analysis

摘要

目的 采用药物靶点孟德尔随机化方法,评估他汀类药物、胆固醇吸收抑制剂、前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin/kexin type 9, PCSK9)抑制剂、ATP-柠檬酸裂解酶(ATP citrate lyase, ACL)抑制剂和血管生成素样蛋白3(angiopoietin-like 3, ANGPTL3)抑制剂5类降脂药物与骨质疏松及骨关节炎发病风险的因果关联。 方法 利用公开发布的全基因组关联研究汇总数据,以5类降脂药物为暴露因素,骨质疏松和骨关节炎为结局变量,采用逆方差加权法为主、辅以7种补充方法进行药物靶点孟德尔随机化分析;采用错误发现率(false discovery rate, FDR)法校正多重比较,并通过异质性检验、多效性检验及留一法评估结果的稳健性。 结果 PCSK9抑制剂的使用与骨质疏松风险增加呈正向因果关联,在欧洲人群(OR=1.169,95%CI:1.025~1.332,P_FDR=0.040)和东亚人群(OR=1.370,95%CI:1.115~1.683, P_FDR=0.008)中均有统计学意义;PCSK9抑制剂的使用与骨关节炎风险增加亦呈正向关联(OR=1.183,95%CI:1.102~1.271, P_FDR=1.46×10^-5)。他汀类药物的使用与骨关节炎的因果关联呈现人群异质性:在欧洲人群中呈正向关联(OR=1.128,95%CI:1.01~1.259, P_FDR=0.040),在东亚人群中呈负向关联(OR=0.440,95%CI:0.253~0.765, P_FDR=0.010)。胆固醇吸收抑制剂的使用与欧洲人群骨关节炎风险降低存在因果关联(OR=0.723,95%CI:0.544~0.962,P_FDR=0.043)。 结论 PCSK9抑制剂的使用可增加欧亚人群的骨质疏松发病风险,而他汀类药物对骨关节炎的影响存在种族特异性,提示降脂药物的骨骼安全性评价需考虑靶点差异与人群异质性。

Abstract

Objective To assess the causal associations of five lipid-lowering drug classes—statins, cholesterol absorption inhibitors, proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors, ATP citrate lyase(ACL)inhibitors, and angiopoietin-like 3(ANGPTL3)inhibitors—with the risk of osteoporosis and osteoarthritis using a drug-target Mendelian randomization approach. Methods Summary statistics from publicly available genome-wide association studies were used. Five lipid-lowering drug classes were considered as exposures, and osteoporosis and osteoarthritis as outcomes. Drug-target Mendelian randomization analyses were conducted using inverse-variance weighting as the primary method, supplemented by seven additional methods. The false discovery rate(FDR)method was applied to correct for multiple comparisons. Heterogeneity tests, pleiotropy tests, and leave-one-out analyses were performed to assess robustness. Results PCSK9 inhibitor use showed a positive causal association with increased osteoporosis risk in both European(OR=1.169, 95%CI: 1.025-1.332, P_FDR=0.040)and East Asian populations(OR=1.370, 95%CI: 1.115-1.683, P_FDR=0.008). PCSK9 inhibitor use was also positively associated with osteoarthritis risk in the European population(OR=1.183, 95%CI: 1.102-1.271, P_FDR=1.46×10^-5). The causal association between statin use and osteoarthritis exhibited population heterogeneity: a positive association in the European population(OR=1.128, 95%CI: 1.01-1.259, P_FDR=0.040)and a negative association in the East Asian population(OR=0.440, 95%CI: 0.253-0.765, P_FDR=0.010). Cholesterol absorption inhibitor use was causally associated with reduced osteoarthritis risk in the European population(OR=0.723, 95%CI: 0.544-0.962, P_FDR=0.043). Conclusion PCSK9 inhibitor use increases the risk of osteoporosis in both European and East Asian populations, while the effect of statins on osteoarthritis is population-specific. These findings suggest that skeletal safety evaluation of lipid-lowering drugs should consider target specificity and population heterogeneity.

关键词

孟德尔随机化 / 前蛋白转化酶枯草溶菌素9抑制剂 / 他汀类药物 / 骨质疏松 / 骨关节炎

Key words

Mendelian randomization / Proprotein convertase subtilisin/kexin type 9 inhibitors / Statins / Osteoporosis / Osteoarthritis

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基金资助

国家自然科学基金(82173624)

国家自然科学基金(82373686)

山东省自然科学基金(ZR2019ZD02)