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

Area of Science:

• Genetics
• Nephrology
• Pharmacology

Background:

• Genetic variants in HMGCR and PCSK9 can serve as proxies for drug effects on kidney function.
• Understanding these genetic links is crucial for assessing medication impacts.

Purpose of the Study:

• To investigate the association between genetically predicted lipid-lowering effects of HMGCR and PCSK9 variants and kidney function (eGFR).
• To differentiate the effects of HMGCR and PCSK9 inhibition on estimated glomerular filtration rate.

Main Methods:

• Mendelian randomization (MR) analysis using summary-level data from large European cohorts (CKDGen, UK Biobank).
• Utilized HMGCR and PCSK9 genetic variants to predict low-density lipoprotein (LDL) cholesterol reduction.
• Employed inverse variance weighted and pleiotropy-robust methods to analyze log-estimated glomerular filtration rate (eGFR).

Main Results:

• Genetically predicted HMGCR inhibition (LDL reduction) was significantly associated with a decrease in eGFR (-1.67%).
• Genetically predicted PCSK9 inhibition (LDL reduction) was significantly associated with an increase in eGFR (+1.17%).
• Results were consistent across different MR methods and datasets, including analyses of eGFR based on creatinine and cystatin C.

Conclusions:

• HMG-CoA reductase inhibition, predicted genetically, shows an association with reduced kidney function (lower eGFR).
• PCSK9 inhibition, predicted genetically, demonstrates an association with improved kidney function (higher eGFR).
• Clinicians should recognize that different lipid-lowering medications may have distinct effects on kidney function.