Deciphering the Effect of High-Density Lipoprotein Cholesterol on Renal Function: a Mendelian Randomization Study

Abstract Background The causal relationship between high-density lipoprotein cholesterol (HDL) and cardiovascular protection remains unresolved. Mounting evidence now points towards a link between lipid levels, including HDL, and renal function. However, previous epidemiological and animal studies provide a mixed picture. This study investigates the causal interplay between HDL and renal function by leveraging the specific and substantial increase in HDL achieved with cholesteryl ester transfer protein (CETP) inhibition. Method and Results Two-sample and multivariable Mendelian randomization (MR) methods were used to explore the causal impact of HDL through genetically-proxied CETP inhibition on serum cystatin C-estimated glomerular filtration rate (eGFRcys). Secondary analyses delved into other renal markers and systolic blood pressure (SBP). Summary-based Mendelian Randomization (SMR) and genetic colocalisation analyses were used to evaluate the probability of shared causal variants within a 100Kb window of the gene. Genetically-proxied CETP inhibition, using HDL level as a biomarker, was linked to lower eGFRcys (effect size per 1 SD increase in HDL, −0.008, 95% CI −0.011 to - 0.005; p = 1.38 × 10 −06 ) and reduced chronic kidney disease (CKD) risk (OR 0.895 [0.838, 0.956]; p = 0.001). The HDL-eGFRcys relationship persisted after adjusting for low-density lipoprotein cholesterol (LDL) and SBP in multivariable MR, but the association with CKD risk attenuated. Decreased CETP expression in blood was associated with lower eGFRcys (effect size per 1-SD, −0.008 [−0.016, −0.001]; p SMR = 0.029), a reduced CKD risk (OR, 0.85 [0.74, 0.98]; p SMR = 0.03), and lower SBP (−0.71 [−1.177, −0.244]; p SMR = 0.003). Colocalisation results indicated low posterior probabilities for both shared and distinct causal variants between CETP gene expression and eGFRcys. Conclusion MR analyses support a causal inverse relationship between HDL and eGFRcys that is independent of SBP. The results warrant further studies to validate the nuanced roles of HDL and LDL on renal function.