Absence of APOL1 Risk Variants Protects against HIV-Associated Nephropathy in the Ethiopian Population

Abstract

Background: Susceptibility to end-stage kidney disease (ESKD) among HIV-infected Americans of African ancestral heritage has been attributed to APOL1 genetic variation. We determined the frequency of the APOL1 G1 and G2 risk variants together with the prevalence of HIV-associated nephropathy (HIVAN) among individuals of Ethiopian ancestry to determine whether the kidney disease genetic risk is PanAfrican or restricted to West Africa, and can explain the previously reported low risk of HIVAN among Ethiopians. Methods: We studied a cohort of 338 HIV-infected individuals of Ethiopian ancestry treated in one Israeli and one Ethiopian center. We sought clinical evidence for HIVAN (serum creatinine >1.4 mg/dl or proteinuria >30 mg/dl in a spot urine sample). Genetic analyses included the genotyping of the APOL1 G1 and G2 variants, and a panel of 33 genomic ancestry-informative markers. Statistical analysis compared clinical and genetic indices for HIV-infected individuals of Ethiopian ancestry and overall Ethiopians to those reported for HIV-infected African-Americans, overall African-Americans, West Africans and non-Africans. Findings: Three (0.8%) of 338 HIV-infected patients of Ethiopian ancestry showed clinical criteria compatible with renal impairment. Two of these 3 patients also have severe poorly controlled diabetes mellitus. The third nondiabetic patient underwent renal biopsy which ruled out HIVAN. This absence of clinically apparent HIVAN was significantly different from that reported for African-Americans. The APOL1 G1 and G2 risk variants were found, respectively, in 0 and 2 (heterozygote state) of the 338 HIV-infected individuals. Global ancestry and the frequencies of the APOL1 G1 and G2 variants are not statistically different from their frequencies in the general Ethiopian population, but are significantly and dramatically lower than those observed among HIV-infected African-Americans, African-Americans and West Africans. Interpretation: The coinciding absence of HIVAN and the APOL1 risk variants among HIV-infected individuals of Ethiopian ancestry support a Western rather than Pan-African ancestry risk for ESKD, and can readily explain the lack of HIVAN among individuals of Ethiopian ancestry.

APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability

“…This suggests that genetic susceptibility is combined with a nongenetic second, which transforms risk to disease causation. This is especially prominent in the case of HIVAN, wherein in the absence of APOL1 genetic susceptibility HIVAN is rare to absent, and in the presence of APOL1 genetic susceptibility, poor control of HIV viral load leads to HIVAN with a very high likelihood (3,11). To examine the pathobiological underpinnings of this second-hit formulation, we evaluated the effect of G0, G1, and G2 versions of APOL1 in the presence of AHFs such as H 2 O 2 , hypoxia, TNF-␣, puromycin aminonucleoside, and HIV.…”

Gene–Gene and Gene–Environment Interactions in Apolipoprotein L1 Gene-Associated Nephropathy

“…In contrast, HIV-infected individuals whose APOL1 genotype status is nonrisk at both parental alleles are protected from this form of CKD, even when systemic viral replication is not controlled, although they may develop HIV immune complex nephropathy, a disorder unrelated to APOL1. A striking example of the effect of APOL1-mediated risk for HIVAN is seen in the HIV-infected Ethiopian population (57). Whether residing in Ethiopia or emigrating to Israel, Ethiopians seemed to be protected from HIVAN when contrasted to Africans residing in the western and southern regions of the continent.…”

High Population Frequencies of APOL1 Risk Variants Are Associated with Increased Prevalence of Non-Diabetic Chronic Kidney Disease in the Igbo People from South-Eastern Nigeria

“…The finding of both a zero frequency of the APOL1 G1 and G2 risk alleles, together with complete absence of HIV nephropathy in HIV-infected Ethiopians, helped to distinguish the APOL1 locus from neighboring loci as most likely harboring the functional risk variants [12,13,14]. The absence of APOL1 kidney disease risk variants also correlates with the low rate of non-diabetic ESKD in Israeli Ethiopians [12].…”