Clinical and Genetic Characteristics of CKD Patients with High-Risk APOL1 Genotypes

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.

Automated summary

APOL1 genotype has significant effects on kidney disease development and progression, with various effect modifiers. High-risk APOL1 genotypes are associated with increased risk of kidney failure, faster eGFR decline rate, and younger age of kidney failure onset. Rare missense variants in the inflammasome pathway may act as genetic modifiers of APOL1 effect on kidney disease.