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 Åsvold

doi:10.1093/ije/dyab014

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

Int J Epidemiol. 2021 Nov 10;50(5):1569-1579. doi: 10.1093/ije/dyab014.

Authors

Humaira Rasheed^{1

2

3}, Jie Zheng², Jessica Rees⁴, Eleanor Sanderson², Laurent Thomas^{1

5}, Tom G Richardson², Si Fang², Ole-Jørgen Bekkevold¹, Endre Bakken Stovner¹, Maiken Elvestad Gabrielsen¹, Anne Heidi Skogholt¹, Solfrid Romundstad^{5

6}, Ben Brumpton^{1

2

7}, Stein Hallan^{5

8}, Cristen Willer⁹, Stephen Burgess^{4

10}, Kristian Hveem¹, George Davey Smith^{2

11}, Tom R Gaunt^{2

11}, Bjørn Olav Åsvold^{1

12}

Affiliations

¹ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
² MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³ Department of Chemistry, University of Engineering and Technology, Lahore, Pakistan.
⁴ Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, UK.
⁵ Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
⁶ Department of Internal Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
⁷ Department of Thoracic Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁸ Department of Nephrology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁹ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁰ MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
¹¹ NIHR Bristol Biomedical Research Centre, University of Bristol, Bristol, UK.
¹² Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Abstract

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

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). 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.

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 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.

Keywords: Lipids; Mendelian randomization; apolipoproteins; eGFR; kidney; urinary albumin-to-creatinine ratio.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apolipoproteins / genetics
Genome-Wide Association Study*
Humans
Kidney
Lipids
Mendelian Randomization Analysis*
Random Allocation
Triglycerides

Substances

Apolipoproteins
Lipids
Triglycerides

Abstract

Publication types

MeSH terms

Substances

Grants and funding