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American Journal of Kidney Diseases

HDL Cholesterol, LDL Cholesterol, and Triglycerides as Risk Factors for CKD: A Mendelian Randomization Study

  • Author Footnotes
    ∗ M.B.L. and S.T. contributed equally to this work.
    Matthew B. Lanktree
    Correspondence
    Address for Correspondence: Matthew B. Lanktree, MD, PhD, St. Joseph’s Healthcare Hamilton, Division of Nephrology, 50 Charlton Ave E, Hamilton, Ontario, Canada L8N 4A6.
    Footnotes
    ∗ M.B.L. and S.T. contributed equally to this work.
    Affiliations
    Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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  • Author Footnotes
    ∗ M.B.L. and S.T. contributed equally to this work.
    Sébastien Thériault
    Footnotes
    ∗ M.B.L. and S.T. contributed equally to this work.
    Affiliations
    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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  • Michael Walsh
    Affiliations
    Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada

    Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada

    Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada
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  • Guillaume Paré
    Affiliations
    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada

    Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada
    Search for articles by this author
  • Author Footnotes
    ∗ M.B.L. and S.T. contributed equally to this work.

      Background

      High-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride concentrations are heritable risk factors for vascular disease, but their role in the progression of chronic kidney disease (CKD) is unclear.

      Study Design

      2-sample Mendelian randomization analysis of data derived from the largest published lipid and CKD studies.

      Setting & Participants

      Effect of independent genetic variants significantly associated with lipid concentrations was obtained from the Global Lipids Genetics Consortium (n = 188,577), and the effect of these same variants on estimated glomerular filtration rate (eGFR), CKD (defined as eGFR < 60 mL/min/1.73 m2), and albuminuria was obtained from the CKD Genetics Consortium (n = 133,814).

      Factor

      Using conventional, multivariable, and Egger Mendelian randomization approaches, we assessed the causal association between genetically determined lipid concentrations and kidney traits.

      Outcome

      eGFR, dichotomous eGFR < 60 mL/min/1.73 m2, and albuminuria.

      Results

      In multivariable analysis, a 17-mg/dL higher HDL cholesterol concentration was associated with an 0.8% higher eGFR (95% CI, 0.4%-1.3%; P = 0.004) and lower risk for eGFR < 60 mL/min/1.73 m2 (OR, 0.85; 95% CI, 0.77-0.93; P < 0.001), while Egger analysis showed no evidence of pleiotropy. There was no evidence for a causal relationship between LDL cholesterol concentration and any kidney disease measure. Genetically higher triglyceride concentrations appeared associated with higher eGFRs, but this finding was driven by a single pleiotropic variant in the glucokinase regulator gene (GCKR). After exclusion, genetically higher triglyceride concentration was not associated with any kidney trait.

      Limitations

      Individual patient–level phenotype and genotype information were unavailable.

      Conclusions

      2-sample Mendelian randomization analysis of data from the largest lipid and CKD cohorts supports genetically higher HDL cholesterol concentration as causally associated with better kidney function. There was no association between genetically altered LDL cholesterol or triglyceride concentration and kidney function. Further analysis of CKD outcomes in HDL cholesterol intervention trials is warranted.

      Index Words

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      Linked Article

      • Challenges in Interpreting Multivariable Mendelian Randomization: Might “Good Cholesterol” Be Good After All?
        American Journal of Kidney DiseasesVol. 71Issue 2
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          Understanding the causal basis of disease is important so that we approach disease prevention and treatment using a valid etiologic framework. Blood lipids play an important role in the shuttling of nutrients (in the form of triglycerides and fatty acids) and cholesterol from the diet to the peripheral tissues. Certain types of blood lipids (eg, low-density lipoprotein cholesterol [LDL-C] and probably triglycerides [TG]) are atherogenic and lead to higher risks for coronary heart disease (CHD).1-6 The role of high-density lipoprotein cholesterol (HDL-C) to date has been more elusive.
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