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HDL Cholesterol, LDL Cholesterol, and Triglycerides as Risk Factors for CKD: A Mendelian Randomization Study
Matthew B Lanktree1, Sébastien Thériault2, Michael Walsh3
1Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Insights
Higher high-density lipoprotein (HDL) cholesterol levels are causally linked to improved kidney function, according to Mendelian randomization. Low-density lipoprotein (LDL) cholesterol and triglycerides showed no significant association with chronic kidney disease (CKD) progression.
Area of Science:
- Nephrology
- Cardiovascular Genetics
- Metabolic Disorders
Background:
- Heritable lipid concentrations (HDL, LDL, triglycerides) are risk factors for vascular disease.
- The direct impact of these lipids on chronic kidney disease (CKD) progression remains unclear.
- Investigating the causal relationship between lipids and kidney function is crucial for understanding CKD pathogenesis.
Purpose of the Study:
- To determine the causal effect of genetically determined high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride concentrations on kidney function.
- To assess the association between these lipid profiles and key CKD indicators such as estimated glomerular filtration rate (eGFR), CKD diagnosis, and albuminuria.
Main Methods:
- Utilized a 2-sample Mendelian randomization (MR) approach, analyzing data from large-scale lipid (Global Lipids Genetics Consortium) and CKD (CKD Genetics Consortium) studies.
- Employed conventional, multivariable, and Egger MR methods to evaluate causal associations between genetic variants influencing lipid levels and kidney traits.
- Included genetic variants associated with lipid concentrations and their effects on eGFR, CKD, and albuminuria in a combined cohort of over 320,000 participants.
Main Results:
- Genetically higher HDL cholesterol concentrations were causally associated with improved kidney function, indicated by higher eGFR and reduced risk of CKD (eGFR<60mL/min/1.73m²).
- No causal relationship was found between genetically determined LDL cholesterol concentrations and kidney function or albuminuria.
- Initial associations between higher triglycerides and eGFR were attributed to a single pleiotropic variant, disappearing after its exclusion, indicating no causal link.
Conclusions:
- Genetically determined higher HDL cholesterol levels are causally associated with better kidney function, suggesting a protective role in CKD.
- Genetically influenced LDL cholesterol and triglyceride levels do not appear to have a direct causal impact on kidney function.
- Further investigation in clinical trials focusing on HDL cholesterol interventions for CKD outcomes is warranted.
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<60mL/min/1.73m2), 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<60mL/min/1.73m2, 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<60mL/min/1.73m2 (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.
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