Genetic variations in HMGCR and PCSK9 and kidney function: a Mendelian randomization study

• Published in: Kidney research and clinical practice Vol. 42; no. 4; pp. 460 - 472
• Main Authors: Park, Sehoon, Kim, Seong Geun, Lee, Soojin, Kim, Yaerim, Cho, Semin, Kim, Kwangsoo, Kim, Yong Chul, Han, Seung Seok, Lee, Hajeong, Lee, Jung Pyo, Joo, Kwon Wook, Lim, Chun Soo, Kim, Yon Su, Kim, Dong Ki
• Format: Journal Article
• Language: English
• Published: Korea (South) The Korean Society of Nephrology 01.07.2023; 대한신장학회
• Subjects: chronic kidney disease; dyslipidaemia; mendelian randomization; Original; statin; 내과학; Chronic kidney disease; Dyslipidaemia; Mendelian randomization; Statin
• ISSN: 2211-9132; 2211-9140
• DOI: 10.23876/j.krcp.22.237

The genetically predicted lipid-lowering effect of HMGCR or PCSK9 variant can be used to assess drug proxy effects on kidney function. Mendelian randomization (MR) analysis-identified HMGCR and PCSK9 genetic variants were used to predict the low-density lipoprotein (LDL) cholesterol-lowering effects of medications targeting related molecules. Primary summary-level outcome data for log-estimated glomerular filtration rate (eGFR; creatinine) were provided by the CKDGen Consortium (n = 1,004,040 European) from a meta-analysis of CKDGen and UK Biobank data. We also conducted a separate investigation of summary-level data from CKDGen (n = 567,460, log-eGFR [creatinine]) and UK Biobank (n = 436,581, log-eGFR [cystatin C]) samples. Summary-level MRs using an inverse variance weighted method and pleiotropy-robust methods were performed. Summary-level MR analysis indicated that the LDL-lowering effect predicted genetically by HMGCR variants (50-mg/dL decrease) was significantly associated with a decrease in eGFR (-1.67%; 95% confidence interval [CI], -2.20% to -1.13%). Similar significance was found in results from the pleiotropy-robust MR methods when the CKDGen and UK Biobank data were analyzed separately. However, the LDL-lowering effect predicted genetically by PCSK9 variants was significantly associated with an increase in eGFR (+1.17%; 95% CI, 0.10%-2.25%). The results were similarly supported by the weighted median method and in each CKDGen and UK Biobank dataset, but the significance obtained by MR-Egger regression was attenuated. Genetically predicted HMG-CoA reductase inhibition was associated with low eGFR, while genetically predicted PCSK9 inhibition was associated with high eGFR. Clinicians should consider that the direct effect of different types of lipid-lowering medication on kidney function can vary.