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

doi:10.1093/ije/dyab014

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

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Abstract

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 language	English
Pages (from-to)	1569-1579
Number of pages	11
Journal	International Journal of Epidemiology
Volume	50
Issue number	5
Early online date	21 Jun 2021
DOIs	https://doi.org/10.1093/ije/dyab014
Publication status	Published - 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.

Keywords

lipids
eGFR
Mendelian randomization
urinary albumen to creatinine ratio
apolipoproteins
kidney

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Rasheed, H., Zheng, J., Rees, J., Sanderson, E., Thomas, L., Richardson, T. G., Fang, S., Bekkevold, O-J., Stovner, E. B., Gabrielsen, M. E., Skogholt, A. H., Romundstad, S., Brumpton, B., Hallan, S., Willer, C., Burgess, S., Hveem, K., Davey Smith, G., Gaunt, T. R., & Asvold, B. O. (2021). The causal effects of serum lipids and apolipoproteins on kidney function: multivariable and bidirectional Mendelian randomization analyses. International Journal of Epidemiology, 50(5), 1569-1579. https://doi.org/10.1093/ije/dyab014

@article{e337084f16eb4f8eb30822181df957ad,

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

abstract = "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 Tr{\o}ndelag 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. ",

keywords = "lipids, eGFR, Mendelian randomization, urinary albumen to creatinine ratio, apolipoproteins, kidney",

author = "Humaira Rasheed and Jie Zheng and Jessica Rees and Eleanor Sanderson and Laurent Thomas and Richardson, {Tom G} and Si Fang and Ole-J{\o}rgen Bekkevold and Stovner, {Endre Bakken} and Gabrielsen, {Maiken Elvestad} and Skogholt, {Anne Heidi} and Solfrid Romundstad and Ben Brumpton and Stein Hallan and Cristen Willer and Stephen Burgess and Kristian Hveem and {Davey Smith}, George and Gaunt, {Tom R} and Asvold, {Bj{\o}rn Olav}",

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: {\textcopyright} 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.",

year = "2021",

month = nov,

day = "10",

doi = "10.1093/ije/dyab014",

language = "English",

volume = "50",

pages = "1569--1579",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

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}

Rasheed, H, Zheng, J, Rees, J, Sanderson, E, Thomas, L, Richardson, TG, Fang, S, Bekkevold, O-J, Stovner, EB, Gabrielsen, ME, Skogholt, AH, Romundstad, S, Brumpton, B, Hallan, S, Willer, C, Burgess, S, Hveem, K, Davey Smith, G , Gaunt, TR & Asvold, BO 2021, 'The causal effects of serum lipids and apolipoproteins on kidney function: multivariable and bidirectional Mendelian randomization analyses', International Journal of Epidemiology, vol. 50, no. 5, pp. 1569-1579. https://doi.org/10.1093/ije/dyab014

TY - JOUR

T1 - The causal effects of serum lipids and apolipoproteins on kidney function

T2 - multivariable and bidirectional Mendelian randomization analyses

AU - Rasheed, Humaira

AU - Zheng, Jie

AU - Rees, Jessica

AU - Sanderson, Eleanor

AU - Thomas, Laurent

AU - Richardson, Tom G

AU - Fang, Si

AU - Bekkevold, Ole-Jørgen

AU - Stovner, Endre Bakken

AU - Gabrielsen, Maiken Elvestad

AU - Skogholt, Anne Heidi

AU - Romundstad, Solfrid

AU - Brumpton, Ben

AU - Hallan, Stein

AU - Willer, Cristen

AU - Burgess, Stephen

AU - Hveem, Kristian

AU - Davey Smith, George

AU - Gaunt, Tom R

AU - Asvold, Bjørn Olav

N1 - 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.

PY - 2021/11/10

Y1 - 2021/11/10

N2 - 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.

AB - 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.

KW - lipids

KW - eGFR

KW - Mendelian randomization

KW - urinary albumen to creatinine ratio

KW - apolipoproteins

KW - kidney

U2 - 10.1093/ije/dyab014

DO - 10.1093/ije/dyab014

M3 - Article (Academic Journal)

C2 - 34151951

VL - 50

SP - 1569

EP - 1579

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

SN - 0300-5771

IS - 5

ER -

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

Abstract

Bibliographical note

Keywords

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