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

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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Background: The causal nature of the observed associations between serum lipids and apolipoproteins and kidney function are unclear.

Subjects and Methods: Using two-sample and multivariable Mendelian randomization (MR), we examined the causal effects of serum lipids and apolipoproteins on kidney function, indicated by glomerular filtration rate estimated using creatinine (eGFRcrea) or cystatin C (eGFRcys), and 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 (GWASs).

Results: There 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.

Conclusion: Our MR estimates suggest that serum lipid and apolipoproteins 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.
Original languageEnglish
Pages (from-to)1569-1579
Number of pages11
JournalInternational Journal of Epidemiology
Issue number5
Early online date21 Jun 2021
Publication statusPublished - 10 Nov 2021

Bibliographical note

Funding Information:
Dr Zhang is supported by the Vice-Chancellor fellowship and Dr Sanderson was supported by Medical Research Council (MC_UU_00011/1) during the study. Professors Davey Smith and Gaunt work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1and4) and have received research funding from GlaxoSmithKline and Biogen

Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.


  • lipids
  • eGFR
  • Mendelian randomization
  • urinary albumen to creatinine ratio
  • apolipoproteins
  • kidney


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