In the United States, a third of people on dialysis for kidney failure are African American, yet this population comprises only 13% of the US population.1 The incidence of end stage renal disease (ESRD) is 3.5 times greater in African Americans compared to European Americans.1 The reasons for this discrepancy are multifactorial, but a large component can be attributed to genetics. Specifically, the APOL1 gene on chromosome 22 is strongly associated with development of hypertensive-associated nephropathy in African Americans.2
APOL1 is an apoprotein that circulates in the blood as a component of high-density lipoprotein (HDL) and plays a role in innate immunity.3 Two alleles of this gene, G1 and G2, drastically increase the risk of development and rapid progression of ESRD. Case control studies demonstrate that two copies of the alleles (either two of G1, two of G2, or one of each) result in a seven- to tenfold increased risk of hypertension-associated chronic kidney disease (CKD).2 Notably, this effect is more modest in two longitudinal cohort studies of CKD, with a hazard ratio between 1.88 and 2.22 (primary outcome: doubling of creatinine or developing ESRD).2 The APOL1 effect also works synergistically with other risk factors for kidney injury. For example, patients with two APOL1 risk variants and concurrent HIV infection have a 30-fold risk of developing HIV associated nephropathy.2
The two risk variants of APOL1 are thought to contribute to kidney injury through several mechanisms. In vitro, they cause podocyte swelling, reduce cellular viability, and increase permeability of lysosomal membranes.2 In vivo, transgenic mice expressing either the G1 or G2 risk variant have increased protein kinase R activation, increased interferon response, and decreased protein synthesis, resulting in decreased cell viability.4
Although the two APOL1 risk variants cause kidney injury, they are highly prevalent in the African-American population. The allele frequencies of G1 and G2 in this population are 23% and 14%, respectively.3 One out of 7-8 African Americans has two copies of these alleles and is thus at increased risk of developing ESRD. This begs the question: why would such a harmful gene persist at such high a prevalence? It follows evolutionary principles that harmful alleles found at high frequencies most likely confer an unknown evolutionary advantage.
Prevalence of G1 and G2 alleles is highest in West Africa, where certain subspecies of trypanosomes are found. Trypanosomes are extracellular hemoflagellate parasites carried by the tsetse fly (Glossinidae glossina).5 Human trypanosomal infection results in African sleeping sickness, which is nearly 100% fatal if untreated. Humans are naturally immune to infection from two trypanosome subspecies, Trypanosoma evansi and Trypanosoma brucei brucei, due to the APOL1 protein. APOL1 is taken up by these trypanosomes and forms a chloride ion channel within the parasite’s lysosomal membrane. Chloride influx results in osmotic swelling of the lysosome until it is lysed, killing the trypanosome.6
Two other sub-species of trypanosomes, T brucei rhodensiense and T brucei gambiense, have developed resistance to this innate immunity and are able to infect humans. T b rhodensiense accomplishes this using a protein called serum resistance-associated protein (SRA), which inactivates APOL1.5 In response to this resistance, some populations in West Africa evolved modified APOL1 proteins. The G1 and G2 alleles resulted from two different mutations that altered the SRA binding site. The resultant APOL1 protein prevents SRA binding and causes T b rhodensiense lysis.2 Thus, anyone with a copy of the G1 or G2 variant is immune to T b rhodensiense infection and has a survival advantage.
Positive selection for an adaptive allele, such as the APOL1 risk variants, can be quantified through many different forms of analyses. The first is the integrated haplotype homozygosity (iHH), which compares the variation of DNA sequences in the selected allele locus compared to the rest of the genome. Among the Yoruba population in West Africa, the G1 and G2 alleles exhibit less variation in sequence than the rest of the genome (iHH scores of 5 and 2.6 respectively), showing positive selection at this locus.7 Evidence for positive selection is also seen when comparing the Yoruba people to a genetically similar tribe in East Africa, the Luhya of Kenya. In the million genes sequenced, the largest difference in frequency between the two populations was of the G1 risk variant (38% vs 5%).8 In the Yoruba population, whose distribution historically overlapped with that of T b rhodensiense, the G1 allele rapidly increased in frequency because its carriers were less likely to die from trypanosomal infection.
Even though the signal for positive selection is stronger for G1 than G2, the latter is better at staving off T b rhodensiense infection.3 It is thought that although G2 is more effective at preventing T b rhodensiense infection, it is less effective against other pathogens. Indeed, when infected with the other resistant trypanosome, T b gambiense, carriers of the G1 allele are less symptomatic than G2 carriers.3 Presumably, people with both G1 and G2 alleles would have the strongest immunity to trypanosomal infection but would also be most at risk for hypertensive-associated nephropathy. Thus, the frequencies of each of the alleles–G1, G2 and wild-type– represent a balance between different selection pressures acting on different populations.
Evolution can often provide insight into why a disease exists or why it affects certain populations and spares others. What is less obvious, however, is how this knowledge informs current management of disease. With prevalence of the APOL1 risk variants so high in the African American population (12-14%), would genome sequencing this demographic be of benefit? Perhaps these patients require lower blood pressure targets in order to prevent ESRD. Or perhaps more aggressive treatment should be limited to those at greatest risk: people with two APOL1 risk variants and concurrent HIV infection. Future drugs may even attempt to target the APOL1 protein for the treatment or prevention of hypertensive nephropathy, with the possibility that any manipulation of the protein might increase risk of trypanosome infection in endemic areas. It is clear that understanding the evolutionary history of this disease illuminates potential paths and pitfalls for future therapy.
Laura McLaughlin is a 2nd year medical student at NYU Robert I. Grossman School of Medicine
Peer reviewed by Shivam Joshi, MD, department of medicine, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
- United States Renal Data System. 2018 USRDS annual data report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2018. https://www.usrds.org/2018/view/Default.aspx
- Kruzel-Davila E, Wasser WG, Aviram S, Skorecki K. APOL1 nephropathy: from gene to mechanisms of kidney injury. Nephrol Dial Transplant. 2016;31(3):349-58. https://academic.oup.com/ndt/article/31/3/349/2459931
- Friedman DJ. A brief history of APOL1: a gene evolving. Seminars in Nephrology. 2017;37(6):508-513. https://www.seminarsinnephrology.org/article/S0270-9295(17)30069-4/abstract
- Okamoto K, Rausch JW, Wakashin H, et al. APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R. Communications Biology. 2018;1(118):1-12. https://www.nature.com/articles/s42003-018-0188-2/
- Vanhollebeke B, Truc P, Poelvoorde P, et al. Human Trypanosoma evansi infection linked to a lack of apolipoprotein L-I. N Engl J Med. 2006;355:2752-2756. https://www.nejm.org/doi/full/10.1056/nejmoa063265
- Pérez-Morga D, Vanhollebeke B, Paturiaux-Hanocq F, et al. Apolipoprotein L-I promotes trypanosome lysis by forming pores in lysosomal membranes. Science. 2005; 309(5733):469-472. http://science.sciencemag.org/content/309/5733/469
- Genovese G, Friedman D, Ross MJ, et al. Association of trypanolytic APOL1 variants with kidney disease in African Americans. Science. 2010;329(5993):841-845. http://science.sciencemag.org/content/329/5993/841
- Thomson R, Genovese G, Canon C, et al. Evolution of the primate trypanolytic factor APOL1. Proc Natl Acad Sci USA. 2014;111(20):E2130-9. https://www.pnas.org/content/111/20/E2130