New Admixture Patterns Trigger Gene-Environment Mismatch between APOL1 Risk Alleles and Chronic Kidney Disease Disparities

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New Admixture Patterns Trigger Gene-Environment Mismatch between APOL1 Risk Alleles and Chronic Kidney Disease Disparities


Fatimah LC Jackson1,2*, Nicholas Guthrie1,4, Raven Flowers1,2, Shireen Shah1,3, Vick Mahase1,2, Hasan Jackson1, and Quad Grid Human Analytics Research Team1

1QuadGrid Data Lab, Bethesda, MD

Howard University, Washington, DC

3 University of Virginia, Charlotte, VA

4George Washington University, Washington, DC

*Corresponding author: Fatimah LC Jackson, Quad Grid Data Lab, Bethesda, MD

Citation: Jackson FLC, Guthrie N, Flowers R, Shah S, Mahase V, Jackson H. (2023) New Admixture Patterns Trigger Gene-Environment Mismatch between APOL1 Risk Alleles and Chronic Kidney Disease Disparities. Adv Clin Med Res. 4(4):1-23.

Received: August 14,  2023 | Published: September 14, 2023

Copyright© 2023 genesis pub by Jackson FLC, et al. CC BY-NC-ND 4.0 DEED. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International License., This allows others distribute, remix, tweak, and build upon the work, even commercially, as long as they credit the authors for the original creation.



The underlying evolutionary genetics of African Americans in North America increases their risk for chronic kidney disease and accounts, in part, for the significant health disparity observed. In this paper we suggest that a gene-environment mismatch is responsible for the high frequency of chronic kidney disease among many African Americans and that this mismatch is augmented by gene-gene interactions that enhance the pathology proliferates in a specific environmental setting of high infectious disease (specifically trypanosomiasis) and then loses its evolutionary advantage when the population is abruptly transferred to a new environment (North America) lacking these specific selective constraints. The inordinately high frequencies of chronic kidney diseases in this evolutionarily new environment are a direct result of a mismatch between the group’s background genetics, adaptations to their environments of origin, and the recent migratory transition to the Americas with new selective constraints coupled with the interactions of the original genetic adaptations with other nearby genetic and non-genetic traits. From historic demographic perspectives, the high level of kidney disease in African Americans is also a consequence of the robust interregional African-African genetic admixtures associated with ancestral relocations to the Americas and the resulting mating patterns that (intentionally) merged geographical groups of Africans who had been previously separated. Consequently, the potential developed for the compound double heterozygotes for the APOL1 genetic variants G1 and G2 with an increased risk for CKD has become elevated among the transatlantic African Diaspora populations.


 African Americans; G1/G2 compound double heterozygote; Selection dynamics; Microevolutionary shifts.

Lay Summary

Centuries of unique interregional African-African genetic admixtures in the Americas have set the stage for the increased contact between Africans with ancestries from different regions of the continent and the increased incidence of producing compound heterozygote’s for APOL1. This phenotype is associated with damage to the kidney.


Chronic kidney disease (CKD) is a global health problem [1]. CKD mortality almost doubled between 1990 and 2010, and by the end of 2013, over three million people were undergoing renal replacement therapy (RRT) worldwide, two and a half million were on hemodialysis or peritoneal dialysis, and close to 700,000 had received a kidney transplant. These numbers are predicted to continue to rise as the worldwide prevalence of CKD increases at a rate of 6% per year. Chronic kidney disease (CKD) is a national public health problem [2] that afflicts a broad cross-section of individuals in our society that has become recognized globally as an important cause of premature morbidity and mortality. However, it is particularly endemic among persons of historically recent African descent. In the United States, African Americans (AAs) are only 13% of the US population but are 32% of the  CKD-dialysis population [3,6]. An earlier onset of hemodialysis initiation for CKD is correlated with genetic variation in the APOL1 gene [62].


To test our hypothesis that APOL1 allelic status is associated with CKD susceptibility, contributes to the current health disparity in kidney disease, and that the population frequency of the compound  double heterozygote G1/G2 has been enhanced by recent microevolutionary events among Africans of  the transatlantic Diaspora (i.e., Legacy African Americans), we consulted the existing scientific and  historic literatures and, on the basis of these data, developed a model of the interactions of  evolutionarily-important circumstances within their historical contexts and contemporary health  disparities in a vulnerable, case-appropriate population. Data was solicited from the following sources:

  • PubMed (,
  • CDC Africa (http://africacdc.home;
  • WHO fact sheet on human African trypanosomiasis (,
  • Trypansomes Database (,
  • Trypanosome_brucei- Ensembl Genome 53 (,
  • Empires of West Africa Database (,
  • African History Sourcebook (,
  • USRDS data (,,
  • (,,
  •, and the
  • Trans-Atlantic Slave Trade Database (

No date limits were imposed upon the search for clinical and parasitological data; however, for the purpose of this study, our historical data was restricted to 1500 to 1900 CE. Our effort was to be comprehensive and inclusive, but temporally more recent references were given preference in our model construction and analysis. Our analysis did not include data from the Intra-American Slave Trade Database as these were not available at the time of our analyses.


Of the numerous genes that have been associated with increased risk for chronic kidney disease, the APOL1 gene is among the most significant. The APOL1 gene codes for a high-density lipoprotein which binds to apolipoprotein A-I. Apolipoprotein A-I is an abundant plasma protein and is the major apoprotein of HDL. It forms most of the cholesteryl esters in plasma and promotes efflux of cholesterol from cells. This apolipoprotein L family member plays a role in lipid exchange and transport throughout the body, as well reversing the pattern of cholesterol transport from peripheral cells to the liver [4]. G1 and G2 are genetic variations in the APOL1 gene with G0 being the wild-type variant [5]. G1 is the major APOL1 risk allele for hypertension induced CKD in Central Africa, [56] a major site of source populations for Africans of the Atlantic Diaspora to the Americas. The APOL1 gene is a member of a family of six genes (APOL1, APOL2, APOL3, APOL4, APOL5 and APOL6), that are all located in close proximity on chromosome 22. Twenty-four different transcript variants encoding different isoforms have been found for this gene as of May 2023, representing coding sequence variants, synonymous variants, and missense variants (see 4). The APOL1 kidney risk variants are in the terminal exon of APOL1 within the SRA-binding domain on chromosome 22. (Table 1) summarizes the annotations for a few of the more common variants, indicating the linked mutational changes and associated phenotypes.

Table 1: Summary of specific major phenotypic effects in commonly encountered mutational changes in APOL1. Data accessed from [44-47]. Explanatory Box 1 provides more detail on the APOL1 variants associated with Trypanosoma brucei spp.

While an array of predisposing socioeconomic, political, genetic, and environmental conditions can initiate chronic kidney disease, APOL1-associated kidney disease is thought to account for a substantial proportion of CKD in AAs [7]. Population-based studies showed that APOL1 high-risk variant alleles were associated with an increased risk of CKD, [7] a 5.7-fold (95% CI 3.6–8.9) greater odds of incident albuminuria, [9] lower age of dialysis initiation, greater risk of incident hypertension, diabetes, but not acute kidney injury (AKI), hospitalizations, and mortality compared to European Americans [12]. The African American (AA) population has a total lifetime risk of ~0.8% (1 in 125) to develop focal segmental glomerulosclerosis (FSGS). A particular type of kidney lesion called focal segmental glomerulosclerosis (FSGS) causes a disease in which scar tissue develops on the glomeruli, The glomeruli are the small parts of the kidneys that filter waste from the blood. The G1 and G2 alleles of APOL1 increase this risk of scarification. The aggregate frequency of either of these two alleles in AAs is about 35% (1 in 3 individuals). For those persons with zero risk alleles, the risk of developing FSGS is 0.2%; for persons with 1 risk allele, it is 0.3%; and for persons with 2 risk alleles, it is 4.25% [13]. While it was known that the APOL1 genetic variants exert a protective action against African sleep sickness, the unexpected finding was that these, APOL1 variants also cause kidney disease [14]. It is not yet known if the risk for kidney disease is greater in the compound double heterozygote (Gi/G2) than in individuals with either the G1/G1 or G2/G2 phenotypes.

Genetics and epidemiology of APOL1 risk alleles in african americans and correlation with CKD

In genomics, a genome-wide association study (GWAS), us frequently used to link a set of genetic variants in different individuals with a disease condition. GWAS has revealed that a substantial fraction of the previously unexplained disparity in the incidence of end-stage renal disease between African Americans and European Americans can be explained by differences in the frequencies of the 2 alleles APOL1, G1 and G2. The APOL1 G1 allele consists of 2 missense mutational variants in very high linkage disequilibrium (APOL1 p. S342G, rs73885319[A;G]; APOL1 p.I384M, rs60910145[G:T]) or (rs71785313(-;TTATAA), rs71785313(D;I)), and the G2 allele is a 2–amino acid deletion (APOL1 p.delN388/Y389, rs60910145).

Although the effects of APOL1 risk variants on kidney disease in continental Africans is understudied (60), in admixed South Africans, it has been reported that, the frequency of the risk alleles of G1: rs73885319, G2: rs60910145 and G1:rs71785313 were respectively, 3.6%, 3.4%, and 5.8%, resulting in a 1.01% frequency of the APOL1 two-risk allele phenotypes (G1:G1 or G1:G2 or G2:G2). The presence of the two-risk alleles increased serum creatinine in South Africans with a corresponding reduction in eGFR (either MDRD or CKD-EPI based) [66]. In the United States, 30%−35% of AAs carry at least one APOL1 risk allele [61]. Between 13-14% of African Americans carry two APOL1 risk alleles, accounting for the high CKD burden in this population [32]. The compound double heterozygote genotype with alleles G1/G2 of the APOL1 gene, together increases the risk for kidney disease about 6-fold. The combination is considered pathogenic and of potential clinical significance both to the individual as well as for kidney transplantation considerations. 12-13% of African Americans carry the compound double heterozygote G1/G2 (31). Case control studies among African Americans with non-diabetic kidney disease showed that those individuals with two APOL1 high risk variants (G1/G1, G2/G2), or compound heterozygotes (G1/G2), are at a 10.5-fold (95% Confidence Intervals (CI) 6.0–18.4) greater risk of biopsy-proven focal segmental glomerulosclerosis (FSGS)-associated ESRD, 7.3-fold greater risk of hypertensive ESRD (95% CI 5.6–9.5), and 29-fold greater risk of HIV associated nephropathy (HIVAN) ESRD when compared to African Americans with only one or no copies of the APOL1 alleles. The risk of development of chronic kidney disease (CKD) is already 3–5 fold higher in the African American population. This increased risk is partly attributed to these two African ancestral genetic variants in the C-terminal domain of the APOL1 gene on chromosome 22 [33] and having the double heterozygote phenotype only amplifies this risk. African Americans carrying two APOL1 risk alleles have increased risk of myocardial infarction (odds ratio of 1.8) and mortality and having two APOL1 risk alleles increases the risk for peripheral vascular disease (determined non-invasively by ankle-brachial index) [34]. These compound double heterozygotes are at a 1.5- to 2.5-fold increased risk of chronic kidney disease [5]. Their chronic kidney disease risk appears to be triggered by either hypertension, type 2 diabetes, or HIV.

Background on the parasite

Trypanosomes are unicellular parasites that live in the blood plasma, the lymph and other tissues of vertebrate hosts including humans. These flagellate protozoans can cause a variety of diseases including fatal sleeping sickness. The trypanosomes cause serious economic losses and impose a severe public health burden. In West and Central Africa, the T. b. ambience parasite typically causes a chronic disease profile, while the zoonotic T. b. Rhodesians sub-species, located in Eastern and Southern Africa sylvatic reserves, results in a more rapidly progressing, acute infection. T. b. gambiense accounts for over 95% of infections [15]. In humans and other primates [16], APOL1 variants evolved as an innate resistance factor against trypanosomes and, possibly, other pathogens in Africa.

Figure 1: Depicts the relationship between the parasite, wild and domesticated ungulate species, and the evolutionary pressure on the APOL1 variants G1 and G2.

Figure 2: Shows the current geographical ranges for Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense.