Kidney Res Clin Pract.
2023 Jul;42(4):460-472. 10.23876/j.krcp.22.237.
Genetic variations in HMGCR and PCSK9 and kidney function: a Mendelian randomization study
- Park S
1 - Kim SG2
- Lee S3,4
- Kim Y5
- Cho S6
- Kim K7
- Kim YC2
- Han SS2,8
- Lee H2
- Lee JP4,8,9
- Joo KW2,4,8
- Lim CS4,8,9
- Kim YS1,2,4,8
- Kim DK2,4,8
- Affiliations
-
- 1Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- 2Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
- 3Department of Internal Medicine, Uijeongbu Eulji University Medical Center, Uijeongbu, Republic of Korea
- 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- 5Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
- 6Department of Internal Medicine, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong, Republic of Korea
- 7Transdisciplinary Department of Medicine & Advanced Technology, Seoul National University Hospital, Seoul, Republic of Korea
- 8Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Republic of Korea
- 9Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
- KMID: 2547117
- DOI: http://doi.org/10.23876/j.krcp.22.237
Abstract
- Background
The genetically predicted lipid-lowering effect of HMGCR or PCSK9 variant can be used to assess drug proxy effects on kidney function.
Methods
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.
Results
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.
Conclusion
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.
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