Association of APOL1 gene variants with Chronic Kidney Disease

In a previous post, I described chronic kidney disease (CKD) which is a long-term condition characterized by the gradual loss of kidney function over time. The kidneys, vital for filtering waste and excess fluids from the blood, play a critical role in maintaining the body’s balance. When kidney function diminishes, waste products and fluids build up in the body, leading to a wide array of health problems. CKD is classified into five stages based on the estimated glomerular filtration rate (eGFR), which measures how well the kidneys are functioning. Early stages may be asymptomatic, but symptoms become prominent as the disease progresses, particularly in stages 4 and 5.

Chronic kidney disease (CKD) affects individuals of African ancestry, both children and adults, at a significantly higher rate than other populations. Black Americans have a four times greater risk of developing CKD compared to Americans of European ancestry. Traditional clinical and environmental factors do not fully account for this increased risk in Black populations, suggesting a genetic component.

The heritability of chronic kidney disease (CKD), i.e. how much of the disease trait can be attributed to genetics compared to environment, varies depending on the population studied and the specific measure of kidney function used. Estimates of CKD heritability from twin studies generally range from 30% to 50%, whereas more recent molecular heritability estimates are lower (~5–10%). Regardless, there are specific genetic variants that contribute to the higher rate of CKD among populations of African ancestry. In particular, DNA variants in the APOL1 gene can explain a significant portion of the difference in CKD risk between populations of African and European ancestry. 

APOL1 is a multi-faceted gene. One of its primary functions is as a component of HDL in cholesterol transport. It also has a role in innate immunity, as we will discuss below, helping to combat foreign invaders such as Trypanosoma brucei, a group of parasites that cause African trypanosomiasis (sleeping sickness) by acting as a pore-forming toxin that ruptures the parasitic cells.

Two of the most prevalent APOL1 risk variants are G1 and G2. G1 contains two single nucleotide changes which result in two amino acid substitutions. G2 is a short deletion of two amino acids. Studies suggest that the G2 mutation causes a more severe kidney phenotype. While the wild-type G0 allele effectively protects against most trypanosomes, some specific strains (e.g. T. brucei rhodesiense) have evolved a way to resist wild-type APOL1. The G1 and G2 mutations overcome this resistance, providing humans with better protection against the parasite, and helping to explain why these mutant alleles persist in the population. This is an example of balancing selection in which there is natural selection for and against the variants.

The G1 and G2 risk variants are strongly associated with a particular type of CKD, focal segmental glomerulosclerosis (FSGS). Focal segmental glomerulosclerosis is a kidney disorder characterized by scarring (sclerosis) in parts of some glomeruli, the tiny filtering units of the kidney. which is focal (only some glomeruli are affected), segmental (only a portion of the affected glomeruli shows scarring), and involves glomerulosclerosis (hardening or scarring of the glomeruli).

A new study published in The New England Journal of Medicine (NEJM) was conducted in West Africans to assess the association between APOL1 risk variants and CKD, as well as their relationship with the type and severity of CKD. It was a case-control study which included individuals from Ghana and Nigeria. The case group consisted of those with CKD stages 2 through 5 or biopsy-proven glomerular disease. The control group was those with no kidney disease but otherwise similar to the case individuals. There were 8355 participants of which 5578 were cases and 2777 were controls.

Each person was genotyped at the APOL1 locus, and among all participants 43.0% possessed one risk allele (monoallelic), 29.7% possessed two risk alleles (biallelic), with the remainder being homozygous (two copies) for the G0 wild-type (non-mutant) allele. Overall, the G1 variant was found much more frequently (40.7%) than the G2 variant (13.9%).

Individuals with one APOL1 risk allele (G0/G1 or G0/G2) had 1.18 times the odds of having CKD compared to those with no risk alleles (G0/G0) after adjusting for multiple factors (age, sex, blood pressure, HIV status, diabetes, clinical site, tobacco use, and ethnicity). Those with two risk alleles had an even higher odds of CKD depending on the allele:

• G1/G1: 1.37 times higher odds of CKD.
• G2/G2: 2.05 times higher odds of CKD.
• G1/G2: 1.34 times higher odds of CKD.

These results showed a dose-response relationship, meaning the odds of CKD increased with the number of APOL1 risk alleles (0, 1, or 2), providing further evidence of the causal relationship between the genetic variants and CKD.

Furthermore, among the high-risk carriers possessing two risk alleles compared to low-risk (0 or 1 allele), the adjusted odds ratio of having CKD increased with the severity of CKD stage: Stage 2 aOR = 1.20,  Stage 3 aOR = 1.32, and Stage 4/5 aOR = 1.37 (Figure 1). Thus, having two risk alleles increases the probability of more severe later stage CKD.

Finally, High-risk APOL1 carriers had 84% higher odds of having FSGS compared to low-risk carriers (adjusted odds ratio = 1.84). Having one risk allele versus no risk alleles resulted in 1.61 time higher odds of FSGS. Again a smaller risk, but still significant. This is a strong and significant association between the APOL1 gene variants and this particular type of CKD.

In summary, the paper demonstrates a significant association between APOL1 risk variants (both one and two copies) and increased risk of CKD and, particularly, FSGS in this West African population. The risk increases with the number of risk alleles, and the association with FSGS is notably strong.

However, in the section on possible limitations of the work, the authors also note that the association between APOL1 high-risk genotypes and CKD is moderate, and perhaps not as high as one might expect from the increased incidence of CKD among people of African ancestry. They explain this moderate association "may be due to the heterogeneity of CKD," and point out the stronger association with FSGS. Alternatively, as mentioned above, the molecular heritability estimates suggest that environmental factors may contribute more strongly to CKD than genetic factors.

Figure 1. "Association of APOL1 Risk Alleles and Genotypes with CKD According to Disease Stage and Type." The data were adjusted for the following covariates: age, sex, BMI, mean arterial pressure, HIV status, diabetes status, clinical site, tobacco use, and language group (from Table 3 of Gbadegesin et al. NEJM, 2025).