Clinical Information

The APOL1 gene encodes apolipoprotein L-1, a serum apolipoprotein bound to high-density lipoprotein (HDL) particles. Two alleles, commonly called G1 and G2, have been associated with increased risk for development or progression of nondiabetic chronic kidney diseases (CKD), including HIV-associated nephropathy (HIVAN) and focal segmental glomerulosclerosis (FSGS) with collapsing features.(1-4)

The APOL1 (NM_001136540.1) G1 allele is a haplotype consisting of 2 missense variants: c.1024A>G (p.Ser342Gly) and c.1152T>G (p.Ile384Met). The G2 allele is comprised of a 6 base pair deletion that results in the deletion of 2 amino acids: c.1164_1169del (p.Asn388_Tyr389del). The G1 and G2 alleles are thought to be in complete linkage disequilibrium, meaning when both the G1 and G2 alleles are detected, they are on opposite chromosomes.(1) The risk for chronic kidney disease is only increased when 2 risk alleles are present (ie, genotypes G1/G1, G2/G2, or G1/G2), following an autosomal recessive pattern of inheritance.(1) Individuals with 2 risk alleles and nondiabetic CKD can be described as having APOL1-associated nephropathy. Individuals with one risk allele or no risk alleles do not appear to be at an increased risk for APOL1-associated nephropathy.

The G1 and G2 risk alleles are enriched in individuals of African ancestry. Population studies show that in individuals of African descent, the G1 and G2 alleles occur at a frequency of 20% to 22.5% and 13% to 15%, respectively.(5-6) Importantly, it is estimated that 10% to 15% of individuals of African descent have 2 risk alleles.(5-6) The high frequency of the G1 and G2 alleles in this population is likely due to the protective effect these alleles confer against Trypanosoma brucei ganbiense and Trypanosoma brucei rhodesiense, which are parasites that causes trypanosomiasis, a disease endemic to Africa.(1) The G1 and G2 alleles are extremely rare or absent in individuals not of recent African descent (eg, European and Asian descent).(1,5) For this reason, increased risk associated with the G1 and G2 alleles has only been stratified in populations of recent African ancestry, and it remains unclear if similar risk effects associated with these APOL1 risk genotypes are applicable to individuals without African ancestry.

Currently, there are no guidelines for clinical management of individuals with APOL1 risk genotypes and there are no specific treatments for APOL1-associated nephropathy.(7) However, several clinical trials are underway studying potential treatments.(8) Additionally, there currently is limited guidance on genetic testing strategies for APOL1 risk genotypes.(9) One consensus statement suggests APOL1 genotyping should be considered "in all patients of African ancestry with kidney disease and in any patient with kidney disease and a family member with a confirmed APOL1 high-risk genotype."(7)

Evidence exists that the donor APOL1 genotype may impact both donor and recipient outcomes of kidney allografts. Previous studies have shown that donor kidneys from individuals with 2 risk alleles were more likely to fail after transplantation when compared to donor kidneys from individuals with one or no risk alleles.(10-11) Another study suggests that living donors with two risk alleles may be at an increased risk for reduced kidney function following kidney donation.(12) Recent literature suggests that recipients with 2 APOL1 high risk alleles may have lower graft survival one year after transplantation; however, additional research is required.(13-14) A prospective, large scale study to assess kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes is currently ongoing.(15) Based on presently available data, guidelines advise that an individual's APOL1 genotype alone should not determine eligibility for donation or receipt of kidney allografts.(16)