The risk of chronic kidney disease (CKD) is four times greater for Black Americans compared to Americans of European ancestry. Variants in the apolipoprotein L1 gene (APOL1), found exclusively in Africans and people of African descent, are associated with higher risk of CKD and focal segmental glomerulosclerosis (FSGS) in Black people. The G1 and G2 variants have been identified as risk factors, and individuals who are homozygous or compound heterozygous for the G1 and G2 risk variants are at an increased risk for CKD from hypertension, kidney diseases such as FSGS, and human immunodeficiency virus-associated nephropathy.
However, few data exist regarding the genetic epidemiology of CKD and the clinical association of APOL1 variants with CKD in West Africans. To address this gap, R. A. Gbadegesin, MD, MBBS, and colleagues conducted a case-control study of participants from Ghana and Nigeria to determine the association of APOL1 risk variants and genotypes with CKD, including the type and severity of disease and the effect modification by clinical factors.
The study included 8,355 participants ages 1-74 years with CKD stages 2-5 (n=4,712), biopsy-proven glomerular disease (n=866), or no kidney disease (n=2,777). Participants with CKD had an estimated glomerular filtration rate (eGFR) of less than 90 mL/min/1.73 m2 of body surface area according to the Chronic Kidney Disease Epidemiology Collaboration equation, a urinary albumin-to-creatinine ratio (UACR) of at least 30.0 (with albumin measured in milligrams and creatinine measured in grams), or both. Participants without kidney disease had an eGFR of at least 90 mL/min/1.73 m2 and a UACR of less than 30.0.
The researchers used custom TaqMan assays (Applied Biosystems) to genotype APOL1 kidney risk variants G1 and G2. Nonrisk APOL1 alleles were designated as G0. Participants could have G1/G1, G2/G2, G1/G2, G0/G1, G0/G2, or G0/G0 genotypes. Kidney biopsies were conducted when eGFR was 15 mL/min/1.73 m2 or less and UACR was greater than 50.0.
The authors analyzed the association of CKD with APOL1 variants among participants with high-risk genotypes (two APOL1 risk alleles) and those with low-risk genotypes (fewer than two APOL1 risk alleles) by fitting logistic-regression models that controlled for covariates, including clinical site, age, and sex.
Among all participants, 43.0% carried monoallelic APOL1 variants and 29.7% carried biallelic variants. The G1 variant was more predominant (40.7%) than the G2 variant (13.9%). The proportion of participants with two APOL1 risk alleles was higher among those with CKD than those who did not have CKD (31.6% vs 25.7%).
The odds ratio for CKD among APOL1 high-risk carriers compared to low-risk carriers was 1.25 (95% CI, 1.11-1.40) after adjusting for age, sex, HIV status, diabetes status, mean arterial pressure, clinical site, tobacco use, and ethnic group. Compared to the G0/G0 genotype, the odds of having CKD were 1.37 times as high (95% CI, 1.16-1.61) with the G1/G1 genotype, 2.05 times as high (95% CI, 1.35-3.13) with the G2/G2 genotype, and 1.34 times as high (95% CI, 1.12-1.61) with the G1/G2 genotype. The adjusted odds ratio (aOR) for CKD increased with CKD stage among biallelic APOL1 carriers, from 1.20 (95% CI, 1.04-1.38) for stage 2, to 1.32 (95% CI, 1.12-1.56) for stage 3, and 1.37 (95% CI, 1.18-1.59) for stage 4-5.
The researchers assessed the effect on disease risk of having one APOL1 risk allele. To do this, they compared the odds of CKD among participants with a single risk allele (genotype G0/G1 or G0/G2) with the odds among those with no risk alleles (genotype G0/G0). They found that the odds of having CKD were higher in participants with G0/G1 or G0/G2 than in those with the G0/G0 genotype (aOR, 1.18; 95% CI, 1.04-1.33).
Among the 866 participants who had kidney biopsies (with glomerulopathy), four major histologic patterns were found: minimal change disease (34.6%; n=300), FSGS (24.7%; n=214), lupus nephritis (11.7%; n=101), and membranous nephropathy (10.2%; n=88). Other conditions were identified in 161 (18.6%) participants.
Participants with the high-risk APOL1 genotypes had 84% greater odds of FSGS than low-risk carriers (aOR, 1.84; 95% CI, 1.30-2.61), but their odds for minimal change disease, lupus nephritis, and membranous nephropathy did not increase. The odds of FSGS increased when one risk allele was present compared to no risk alleles (aOR, 1.61; 95% CI, 1.04-2.48).
The authors acknowledge several limitations to their study. The moderate association between APOL1 high-risk genotypes and CKD could be due to the heterogeneity of CKD. The researchers were unable to perform genotyping for the recently reported APOL1 N264K (rs73885316) G2 disease-associated modifier and did not screen for monogenic kidney diseases by whole-genome sequencing. Participants came from two West African countries, so the results may not be generalizable to other regions of Africa.
The authors summarized, “In this large study of the prevalence and association of high-risk APOL1 genotypes with CKD in persons in West Africa, a region that contributed substantially to the ancestry of Black Americans, almost one third of those tested carried a high-risk APOL1 genotype. Both monoallelic (G0/G1 and G0/G2) and biallelic (G1/G1, G2/G2, and G1/G2) risk variants increased the odds of CKD.”
Source: The New England Journal of Medicine.
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