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Clinical and Genetic Characteristics of CKD Patients with High-Risk APOL1 Genotypes
Mark D Elliott1,2,3,4, Maddalena Marasa1,2, Enrico Cocchi1,2,5
1Division of Nephrology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY.
Insights
High-risk APOL1 genotypes significantly increase kidney failure risk and eGFR decline. Rare inflammasome pathway variants may modify APOL1
Area of Science:
- Nephrology
- Genetics
- Genomics
Background:
- APOL1 gene variants are a major risk factor for kidney disease.
- Clinical outcomes vary significantly among individuals with high-risk APOL1 genotypes, suggesting the presence of genetic modifiers.
Purpose of the Study:
- To investigate the impact of APOL1 high-risk genotypes on kidney disease progression.
- To identify genetic modifiers that influence the APOL1 gene's effect on kidney disease.
Main Methods:
- Assessed kidney failure risk and estimated glomerular filtration rate (eGFR) decline in CKD patients with high-risk versus low-risk APOL1 genotypes.
- Utilized exome sequencing and exome-wide association studies to identify genetic modifiers.
- Performed gene-based and gene set-based collapsing analyses to evaluate modifier effects.
Main Results:
- High-risk APOL1 genotypes were associated with a 1.58-fold increased risk of kidney failure and a faster eGFR decline (6.55 vs. 3.63 ml/min/1.73 m²/yr).
- Specific high-risk genotypes, like G1/G1, showed the highest risk. Patients with high-risk genotypes had a lower incidence of monogenic kidney diseases (2.5% vs. 6.7%).
- Rare missense variants in the inflammasome pathway were enriched in individuals with high-risk APOL1 genotypes and CKD (OR=1.90).
Conclusions:
- High-risk APOL1 genotypes are linked to accelerated kidney disease progression and increased kidney failure risk.
- A graded risk exists among specific high-risk APOL1 genotypes.
- Rare variants in the inflammasome pathway may function as genetic modifiers, contributing to the clinical heterogeneity observed in APOL1-associated kidney disease.
Significance Statement:
APOL1 high-risk genotypes confer a significant risk of kidney disease, but variability in patient outcomes suggests the presence of modifiers of the APOL1 effect. We show that a diverse population of CKD patients with high-risk APOL1 genotypes have an increased lifetime risk of kidney failure and higher eGFR decline rates, with a graded risk among specific high-risk genotypes. CKD patients with high-risk APOL1 genotypes have a lower diagnostic yield for monogenic kidney disease. Exome sequencing revealed enrichment of rare missense variants within the inflammasome pathway modifying the effect of APOL1 risk genotypes, which may explain some clinical heterogeneity.
Background:
APOL1 genotype has significant effects on kidney disease development and progression that vary among specific causes of kidney disease, suggesting the presence of effect modifiers.
Methods:
We assessed the risk of kidney failure and the eGFR decline rate in patients with CKD carrying high-risk ( N =239) and genetically matched low-risk ( N =1187) APOL1 genotypes. Exome sequencing revealed monogenic kidney diseases. Exome-wide association studies and gene-based and gene set-based collapsing analyses evaluated genetic modifiers of the effect of APOL1 genotype on CKD.
Results:
Compared with genetic ancestry-matched patients with CKD with low-risk APOL1 genotypes, those with high-risk APOL1 genotypes had a higher risk of kidney failure (Hazard Ratio [HR]=1.58), a higher decline in eGFR (6.55 versus 3.63 ml/min/1.73 m 2 /yr), and were younger at time of kidney failure (45.1 versus 53.6 years), with the G1/G1 genotype demonstrating the highest risk. The rate for monogenic kidney disorders was lower among patients with CKD with high-risk APOL1 genotypes (2.5%) compared with those with low-risk genotypes (6.7%). Gene set analysis identified an enrichment of rare missense variants in the inflammasome pathway in individuals with high-risk APOL1 genotypes and CKD (odds ratio=1.90).
Conclusions:
In this genetically matched cohort, high-risk APOL1 genotypes were associated with an increased risk of kidney failure and eGFR decline rate, with a graded risk between specific high-risk genotypes and a lower rate of monogenic kidney disease. Rare missense variants in the inflammasome pathway may act as genetic modifiers of APOL1 effect on kidney disease.
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