The causal effects of serum lipids and apolipoproteins on kidney function: multivariable and bidirectional Mendelian-randomization analyses.

Humaira Rasheed ,Cristen J Willer ,Ole-Jørgen Bekkevold ,Kristian Hveem ,J K H Rees ,Stein Hallan ,Anne Heidi Skogholt ,Laurent F Thomas ,Solfrid Romundstad ,George Davey Smith ,Endre Bakken Stovner ,Shiqiang Fang ,Jie Zheng ,Eleanor Sanderson ,Tom R Gaunt ,Stephen Burgess ,Maiken Elvestad Gabrielsen ,Ben Brumpton ,Tom G Richardson ,Bjørn Olav Åsvold

doi:10.1093/ije/dyab014

Abstract

BackgroundThe causal nature of the observed associations between serum lipids and apolipoproteins and kidney function are unclear.MethodsUsing two-sample and multivariable Mendelian randomization (MR), we examined the causal effects of serum lipids and apolipoproteins on kidney function, indicated by the glomerular-filtration rate estimated using creatinine (eGFRcrea) or cystatin C (eGFRcys) and the urinary albumin-to-creatinine ratio (UACR). We obtained lipid- and apolipoprotein-associated genetic variants from the Global Lipids Genetics Consortium (n = 331 368) and UK Biobank (n = 441 016), respectively, and kidney-function markers from the Trøndelag Health Study (HUNT; n = 69 736) and UK Biobank (n = 464 207). The reverse causal direction was examined using variants associated with kidney-function markers selected from recent genome-wide association studies.ResultsThere were no strong associations between genetically predicted lipid and apolipoprotein levels with kidney-function markers. Some, but inconsistent, evidence suggested a weak association of higher genetically predicted atherogenic lipid levels [indicated by low-density lipoprotein cholesterol (LDL-C), triglycerides and apolipoprotein B] with increased eGFR and UACR. For high-density lipoprotein cholesterol (HDL-C), results differed between eGFRcrea and eGFRcys, but neither analysis suggested substantial effects. We found no clear evidence of a reverse causal effect of eGFR on lipid or apolipoprotein traits, but higher UACR was associated with higher LDL-C, triglyceride and apolipoprotein B levels.ConclusionOur MR estimates suggest that serum lipid and apolipoprotein levels do not cause substantial changes in kidney function. A possible weak effect of higher atherogenic lipids on increased eGFR and UACR warrants further investigation. Processes leading to higher UACR may lead to more atherogenic lipid levels.

Highlights

The increasing prevalence of chronic kidney disease (CKD) has become an important public-health concern.[1]
We found no clear evidence of a reverse causal effect of eGFR on lipid or apolipoprotein traits, but higher urinary albumin-to-creatinine ratio (UACR) was associated with higher low-density lipoprotein cholesterol (LDL-C), triglyceride and apolipoprotein B levels
The observational associations and phenotypic and genotypic correlation of serum lipids and apolipoproteins with kidneyfunction markers in HUNT and UK Biobank (UKBB) are presented in Supplementary Figures 2 and 3, available as Supplementary data at IJE online, respectively

Summary

Introduction

The increasing prevalence of chronic kidney disease (CKD) has become an important public-health concern.[1]. Methods: Using two-sample and multivariable Mendelian randomization (MR), we examined the causal effects of serum lipids and apolipoproteins on kidney function, indicated by the glomerular-filtration rate estimated using creatinine (eGFRcrea) or cystatin C (eGFRcys) and the urinary albumin-to-creatinine ratio (UACR). But inconsistent, evidence suggested a weak association of higher genetically predicted atherogenic lipid levels [indicated by lowdensity lipoprotein cholesterol (LDL-C), triglycerides and apolipoprotein B] with increased eGFR and UACR. We found no clear evidence of a reverse causal effect of eGFR on lipid or apolipoprotein traits, but higher UACR was associated with higher LDL-C, triglyceride and apolipoprotein B levels. Processes leading to higher UACR may lead to more atherogenic lipid levels

Methods

Results

Conclusion