APOL1 Monoallelic and Biallelic genotypes and CKD, Proteinuria and FSGS in African Americans from the Vanderbilt...

African Americans are at increased risk for chronic kidney disease (CKD) in part due to Apolipoprotein L1 gene (APOL1) high-risk genotypes. Recently, a study from West Africa reported an association between monoallelic genotypes and risk of CKD and focal segmental glomerulosclerosis (FSGS). We here study the association of biallelic and monoallelic genotypes with CKD, proteinuria, and FSGS in participants in a hospital-based cohort in the Southeastern United States.

We conducted a case-control study of African Ancestry participants from the Vanderbilt University Medical Center Biobank (n=23, 857). The primary outcome was CKD defined as: persistent GFR < 60 ml/min, end stage kidney disease (ESKD), biopsy-proven FSGS or urine protein-to-creatinine ratio of >700 mg/g or albumin-to-creatinine ratio of >420 mg/g. Secondary outcomes were proteinuria and FSGS outcomes separately. The primary exposure was APOL1 monoallelic genotype (1 copy of a risk allele versus none). APOL1 biallelic genotypes was studied as a secondary exposure. Sequential logistic regression models were performed adjusting for potential confounders.

Among 23,857 participants, 5,784 had CKD, 1,533 had proteinuria, and 80 had biopsy-proven FSGS, 44.5% had one risk allele (monoallelic) and 13.6% had two risk alleles (biallelic). Biallelic carriers had higher odds of CKD than those with one or no risk alleles (adjusted odds ratio ( aOR ), 1.72; 95% confidence interval [CI], 1.57-1.89), proteinuria aOR = 2.02 (95% CI, 1.77-2.31), and FSGS aOR = 17.48 (95%CI 10.53-29.02). Monoallelic carriers (G0/G1 or G0/G2) had a small increase in odds of CKD ( aOR = 1.08, 95% CI 1.00-1.16, p=0.04), which was driven by the G0/G2 genotype ( aOR = 1.11, 95% CI 1.01-1.23, p=0.03). Monoallelic carriers (G0/G1 or G0/G2) had higher odds of proteinuria ( aOR = 1.23; 95% CI, 1.09-1.39) and G0/G1 had higher odds of FSGS (14 cases) ( aOR = 2.83; 95% CI, 1.18-6.79).

In our study, monoallelic APOL1 genotypes were associated with 23% higher odds of proteinuria and 3-fold higher odds of FSGS for G0/G1. A modest increase odd for CKD of 8%, which may reflect CKD phenotypic heterogeneity. Our study supports the observations from a West Africa cohort in a US based cohort and adds the association of APOL1 monoallelic genotypes with proteinuria.