Genetic variations in HMGCR and PCSK9 and kidney function: a Mendelian randomization study
- Author:
Sehoon PARK
1
;
Seong Geun KIM
;
Soojin LEE
;
Yaerim KIM
;
Semin CHO
;
Kwangsoo KIM
;
Yong Chul KIM
;
Seung Seok HAN
;
Hajeong LEE
;
Jung Pyo LEE
;
Kwon Wook JOO
;
Chun Soo LIM
;
Yon Su KIM
;
Dong Ki KIM
Author Information
- Publication Type:Original Article
- From:Kidney Research and Clinical Practice 2023;42(4):460-472
- CountryRepublic of Korea
- Language:English
-
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.
