Association of Trypanolytic ApoL1 Variants with Kidney Disease in African Americans

TLDR

African Americans experience higher kidney disease rates, partly linked to the trypanolytic ApoL1 protein, whose evolutionary adaptation may contribute to this disparity. We found that two APOL1 variants strongly associate with FSGS and hypertension‑related ESKD in African Americans, are common in African populations but absent in Europeans, reside on positively selected haplotypes, and uniquely lyse Trypanosoma brucei rhodesiense.

Abstract

African Americans have higher rates of kidney disease than European Americans. Here, we show that, in African Americans, focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) are associated with two independent sequence variants in the APOL1 gene on chromosome 22 {FSGS odds ratio = 10.5 [95% confidence interval (CI) 6.0 to 18.4]; H-ESKD odds ratio = 7.3 (95% CI 5.6 to 9.5)}. The two APOL1 variants are common in African chromosomes but absent from European chromosomes, and both reside within haplotypes that harbor signatures of positive selection. ApoL1 (apolipoprotein L-1) is a serum factor that lyses trypanosomes. In vitro assays revealed that only the kidney disease-associated ApoL1 variants lysed Trypanosoma brucei rhodesiense. We speculate that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African Americans.