调脂药物靶点与高血压肾病风险:一项药物靶向孟德尔随机化分析

Lipid-lowering drugs targets and the risk of hypertensive nephropathy:A drug-target Mendelian randomization analysis

目的评估调脂药物靶点所介导的脂质表型(HMGCR、PCSK9和NPC1L1)与高血压肾病风险之间潜在的因果相关性。方法使用来自欧洲人群公开可获得的全基因组关联研究(GWAS)汇总数据进行孟德尔随机化(MR)分析。采用与低密度脂蛋白胆固醇(LDL-C)相关的遗传变异,根据选定的调脂药物靶基因筛选工具变量,使用逆方差加权法作为主要MR分析方法,并进行敏感性分析确保结果的稳健性。结果基因预测的LDL-C水平与较高的高血压肾病风险相关(OR=1.19,95%CI:1.03~1.38,P=0.021)。较高的HMGCR介导的LDL-C水平与高血压肾病风险存在正向因果相关性(OR=4.08,95%CI:2.86~5.81;P<0.001)。然而,PCSK9和NPC1L1介导的LDL-C水平与高血压肾病风险无相关性。Cochran Q检验、MR-PRESSO检测和MR-Egger截距测试显示工具变量之间不存在异质性或水平多效性。结论HMGCR介导的LDL-C与高血压肾病的发病风险存在因果相关性,针对HMGCR基因的他汀类药物在高血压肾病的防治中可能具有潜在益处。

Objective To assess the potential causal relationship between lipid phenotypes mediated by lipid-lowering drug targets(HMGCR,PCSK9 and NPC1L1)and the risk of hypertensive nephropathy.Methods Mendelian randomization(MR)analysis was conducted using summary data from publicly available European ancestry genome-wide association studies(GWAS).Genetic variants associated with low-density lipoprotein cholesterol(LDL-C)were used as instrumental variables based on selected lipid-lowering drug target genes screening tools.Inverse variance weighting was selected as the main MR analysis method,with sensitivity analyses conducted to ensure the robustness of the results.Results Genetically predicted LDL-C levels were associated with a higher risk of hypertensive nephropathy(OR=1.19,95%CI:1.03~1.38,P=0.021).Higher LDL-C levels mediated by HMGCR were positively causally related to increased risk of hypertensive nephropathy(OR=4.08,95%CI:2.86~5.81;P<0.001).However,LDL-C levels mediated by PCSK9 and NPC1L1 showed no significant association with the risk of hypertensive nephropathy.Cochran’s Q test,MR-PRESSO,and MR-Egger intercept tests showed no heterogeneity or horizontal pleiotropy among instrumental variables.Conclusions The findings of this study support the causal relationship between LDL-C mediated by HMGCR and increased risk of hypertensive nephropathy,suggesting potential benefits of statin therapy for hypertensive nephropathy.