Lian Zhiwen, Liang Zijie, Chen Qiyan, Xie Chao, Kong Yaozhong
Division of Nephrology, The First People's Hospital of Foshan, Foshan, Guangdong, China.
Ren Fail. 2025 Dec;47(1):2491657. doi: 10.1080/0886022X.2025.2491657. Epub 2025 Apr 27.
Evidence regarding the causal relationship between lipid-lowering drugs and cystic kidney disease, including polycystic kidney disease (PKD), was limited. This study aimed to evaluate the causal relationship between lipid phenotypes mediated by lipid-lowering drug targets-3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR), proprotein convertase subtilisin/kexin type-9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1)-and the risk of cystic kidney disease and PKD.
Genetic variants encoding lipid-lowering drug targets-HMGCR, PCSK9, and NPC1L1-from published genome-wide association study (GWAS) statistics were collected to perform drug target Mendelian randomization (MR) analysis. Summary statistics for the GWAS of cystic kidney disease and PKD were obtained from the FinnGen consortium and the European Bioinformatics Institute. Inverse variance weighting (IVW) was used as the primary MR analysis method, with sensitivity analyses conducted to ensure the robustness of the results.
Increased gene expression of HMGCR was associated with an elevated risk of cystic kidney disease (IVW-MR: odds ratio [OR] = 3.05, 95% confidence interval [CI] = 1.19-7.84, = 0.02) and PKD (IVW-MR: OR = 2.13, 95% CI = 1.01-4.46; = 0.045). There was no evidence of causal effects of PCSK9 and NPC1L1 targets on cystic kidney disease and PKD. Cochran's Q test, MR-PRESSO, and MR-Egger intercept tests showed no heterogeneity or horizontal pleiotropy among the instrumental variables.
This study supported that increased HMGCR expression was associated with an increased risk of cystic kidney disease and PKD, suggesting potential benefits of statin therapy for cystic kidney disease and PKD. Further research is necessary to elucidate specific mechanisms and potential therapeutic applications of HMGCR inhibitors.
关于降脂药物与囊性肾病（包括多囊肾病，PKD）之间因果关系的证据有限。本研究旨在评估由降脂药物靶点——3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）、前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）和尼曼-匹克C1样1蛋白（NPC1L1）介导的脂质表型与囊性肾病和PKD风险之间的因果关系。
从已发表的全基因组关联研究（GWAS）统计数据中收集编码降脂药物靶点HMGCR、PCSK9和NPC1L1的基因变异，以进行药物靶点孟德尔随机化（MR）分析。囊性肾病和PKD的GWAS汇总统计数据来自芬兰基因联盟和欧洲生物信息学研究所。采用逆方差加权（IVW）作为主要的MR分析方法，并进行敏感性分析以确保结果的稳健性。
HMGCR基因表达增加与囊性肾病风险升高相关（IVW-MR：优势比[OR]=3.05，95%置信区间[CI]=1.19-7.84，P=0.02）和PKD（IVW-MR：OR=2.13，95%CI=1.01-4.46；P=0.045）。没有证据表明PCSK9和NPC1L1靶点对囊性肾病和PKD有因果效应。Cochran's Q检验、MR-PRESSO和MR-Egger截距检验显示工具变量之间没有异质性或水平多效性。
本研究支持HMGCR表达增加与囊性肾病和PKD风险增加相关，提示他汀类药物治疗囊性肾病和PKD可能有益。有必要进一步研究以阐明HMGCR抑制剂的具体机制和潜在治疗应用。
