APOL1 Nephropathy: A Population Genetics and Evolutionary Medicine Detective Story

doi:10.1016/j.semnephrol.2017.07.002

Seminars in Nephrology

Volume 37, Issue 6, November 2017, Pages 490-507

https://doi.org/10.1016/j.semnephrol.2017.07.002 Get rights and content

Summary: Common DNA sequence variants rarely have a high-risk association with a common disease. When such associations do occur, evolutionary forces must be sought, such as in the association of apolipoprotein L1 (APOL1) gene risk variants with nondiabetic kidney diseases in populations of African ancestry. The variants originated in West Africa and provided pathogenic resistance in the heterozygous state that led to high allele frequencies owing to an adaptive evolutionary selective sweep. However, the homozygous state is disadvantageous and is associated with a markedly increased risk of a spectrum of kidney diseases encompassing hypertension-attributed kidney disease, focal segmental glomerulosclerosis, human immunodeficiency virus nephropathy, sickle cell nephropathy, and progressive lupus nephritis. This scientific success story emerged with the help of the tools developed over the past 2 decades in human genome sequencing and population genomic databases. In this introductory article to a timely issue dedicated to illuminating progress in this area, we describe this unique population genetics and evolutionary medicine detective story. We emphasize the paradox of the inheritance mode, the missing heritability, and unresolved associations, including cardiovascular risk and diabetic nephropathy. We also highlight how genetic epidemiology elucidates mechanisms and how the principles of evolution can be used to unravel conserved pathways affected by APOL1 that may lead to novel therapies. The APOL1 gene provides a compelling example of a common variant association with common forms of nondiabetic kidney disease occurring in a continental population isolate with subsequent global admixture. Scientific collaboration using multiple experimental model systems and approaches should further clarify pathomechanisms further, leading to novel therapies.

Section snippets

The Discovery of African Kidney Risk Genetic Loci by Admixture Linkage Disequilibrium Mapping

Two overall approaches can be used to discover disease-causing genetic loci: family based disease gene discovery, which was conducted previously using linkage and now is performed by whole-exome and whole-genome sequencing¹⁸; and population-based disease gene discovery, among which the most widely used methodology is genome-wide association studies (GWAS).19, 20 Family based discovery has failed to identify genes that explain the overall heritable component of the disparity in CKD in

Pathogen Resistance Provokes a Selective Sweep, Propelling APOL1 Variants to High Allele Frequencies

For most common heritable diseases with non-Mendelian inheritance, the genetic contribution represents the summation of the infinitesimal contribution of many common variants, each with a small effect size, scattered across the genome.³⁹ In general, there is an inverse relationship between the deleterious mutant allele frequency and the effect size. Common variants generally have weak effects with a low odds ratio (OR), usually well below 1.2, signifying a 20% increased incidence of the disease

Supportive Evidence for the Causality of APOL1 G1 and G2 Risk Alleles

The admixture LD analyses conducted in 2008 that erroneously identified MYH9 as the locus bearing the African ancestry kidney disease risk variants was nevertheless a key advance supporting the association of a single genetic locus with major ancestry disparity in kidney disease and identified the relevant genomic region of chromosome 22.21, 22 Given the initial misattribution to MYH9 and the presence of approximately 30 genes adjacent to APOL1 in the admixture LD interval, addressing whether

Missing Heritability Provokes the Search for Additional Variants in Chromosome 22

Although statistical evidence strongly supports a causal role for APOL1 G1 and G2 in kidney disease, approximately 30% of African Americans with primary sporadic focal segmental glomerulosclerosis (FSGS) or HIVAN do not carry an APOL1 kidney risk genotype.³⁵ African Americans without the high-risk APOL1 genotypes still remain at a greater risk for ESKD than European Americans, suggesting unidentified kidney disease risk variants.92, 93, 94, 95

Limou et al⁵⁶ sequenced all APOL1 exons in African

The Paradox of the Recessive Mode of Inheritance and Gain-of-Function Injury

The close proximity of the G1 and G2 alleles results in a low likelihood of recombination between the two alleles. Hence, the G1 and G2 alleles appear to be mutually exclusive. Therefore, in the absence of copy number variation (CNV), an individual can carry no more than two copies of G1, two copies of G2, or one copy of each (Fig. 3). Almost all studies have shown an equivalent CKD association of individuals carrying two copies of G1, two copies of G2, or one copy of each.33, 34, 35, 42

Cohorts

How Can We Explain the Variable and Incomplete Penetrance of APOL1 Kidney Risk Variants?

Only subsets of individuals who carry two APOL1 risk alleles develop kidney disease. The lifetime risk for kidney disease in individuals with HIV infection, in the absence of antiviral therapy, is estimated to exceed 50%, whereas the lifetime risk for FSGS is 4%.35, 47 Even among individuals with two APOL1 risk alleles, the progression of CKD is variable. Despite the faster estimated glomerular filtration rate (eGFR) decrease in African Americans with high-risk APOL1 status compared with

APOL1 Risk Alleles are Associated with a Broad Spectrum of Kidney Disease

The description of APOL1 variants was launched with case-control studies of kidney disease in patients with nondiabetic ESKD, FSGS, HIVAN, and hypertension-attributed nephropathy,33, 34, 35, 42, 46, 47, 51, 122 and continued with population-based studies and longitudinal CKD cohorts showing a higher incidence of albuminuria and kidney disease with a more progressive course of accelerated kidney function decline.37, 43, 44, 45, 48, 49 Analysis of the APOL1 genotype in the Coronary Artery Risk

Unresolved Genetic Epidemiologic Associations

In contrast to the consistently increased risk with a plethora of kidney diseases in individuals with the APOL1 risk genotypes, the exploration of two other associations has not yet arrived at a consensus and clearly is worthy of further consideration and investigation. These associations are the purported association with diabetic nephropathy and the increased risk of cardiovascular disease.

Lessons from Transplantation Studies: Mechanisms and Beyond

APOL1 has a signal peptide and is secreted into the circulation from a predominant hepatic site of origin¹⁴³ in the form of two TLF complexes. One fundamental question concerning the mechanism of APOL1-mediated kidney disease is whether the risk is caused by circulating or endogenous APOL1. APOL1 blood levels do not correlate with the risk of kidney disease.144, 145 Clues regarding the biological action of circulating versus endogenous APOL1 may be gleaned from published studies of kidney

Clinical APOL1 Genotyping

A major practical question in the era of precision medicine is who presently can benefit from APOL1 genotyping at a time when a specific mechanism of kidney disease association, prevention, or therapy has not been developed. Although it is premature to make definitive evidence-based recommendations, several different clinical scenarios warrant consideration.

What are the Implications of Our Understanding of the Mechanisms Underlying APOL1-Mediated Kidney Disease?

A comprehensive update of APOL1 cellular injury mechanisms is beyond the scope of this introductory article. Several studies have explored APOL1 cellular injury in in vitro and in vivo models and suggested gain-of-function injury, but a complete picture remains to be fully elucidated.57, 76, 84, 104, 105, 106, 107, 108, 109 Recent studies using a variety of model systems including yeast, fly, mouse, to human cells in culture, however, have converged on mechanisms wherein APOL1 interferes with

Potential Therapeutic Strategies and Novel Drug Discovery

Potential therapeutic directions for APOL1-associated nephropathy include the following: mitigating the second hit in individuals with a high genotypic risk (eg, HIV infection as well as other viruses or newly discovered deleterious environmental factors), and inhibiting the injury pathway mediated by APOL1. APOL1 constitutes a classic application of precision medicine because it appears to be dispensable for human health except under circumstances of specific pathogen attack. Therefore, direct

Concluding Remarks

The sequencing of the human genome and the subsequent development of genomic databases have led to the identification of common variants that successfully explain the basis of common polygenic inherited diseases suggestive of key biologic pathways underlying disease.¹⁶⁶ In individuals at risk for nondiabetic kidney disease based on African ancestry, the majority of that risk can be explained by two variants in the APOL1 gene. Further advances already have led to the development of cellular and

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Cited by (33)

Endoplasmic reticulum-translocation is essential for APOL1 cellular toxicity
2022, iScience
Two variants at the APOL1 gene, encoding apolipoprotein L1, account for more than 70% of the increased risk for chronic kidney disease in individuals of African ancestry. While the initiating event for APOL1 risk variant cell injury remains to be clarified, we explored the possibility of blocking APOL1 toxicity at a more upstream level. We demonstrate that deletion of the first six amino acids of exon 4 abrogates APOL1 cytotoxicity by impairing APOL1 translocation to the lumen of ER and splicing of the signal peptide. Likewise, in orthologous systems, APOL1 lethality was partially abrogated in yeast strains and flies with reduced dosage of genes encoding ER translocon proteins. An inhibitor of ER to Golgi trafficking reduced lethality as well. We suggest that targeting the MSALFL sequence or exon 4 skipping may serve as potential therapeutic approaches to mitigate the risk of CKD caused by APOL1 renal risk variants.
Evolutionary medicine-Apolipoprotein L1 in human health and disease
2021, New Horizons in Evolution
Population genetic tools have led to the discovery of two variants located in the apolipoprotein gene that explain the increased chronic kidney disease (CKD) risk in individuals of African Ancestry. These variants (designated G1 and G2 as distinct from ancestral alleles. Collectively designated as G0) originated in West Africa and have risen to high allele frequency due to their ability to confer protection from subspecies of Trypanosoma. While pathogen resistance is conferred in the heterozygous state, the homozygous state can lead to CKD. Thereby, APOL1 gene variants provide an unique and compelling example for common variants with large effect sizes leading to common forms of nondiabetic kidney disease. Herein, we describe the Trypanosoma—APOL1 evolutionary arms race, explaining the high frequencies of APOL1 renal risk variants. We elaborate on the different protection conferred by each of these two variants and highlight the specific evolutionary pressures that have driven their high allele frequency in Africa, namely, the protective effect of G1 allele in T. b. gambiense infection and the dual contrasting effects of G2 allele on T. b. gambiense (deleterious) and rhodesiense (protective) infection, explaining the high allele frequency of APOL1 G1 compared to G2 in west Africa. We emphasize the recessive mode of inheritance paradox and suggest several theories that reconcile with the dispensability of APOL1 for kidney development and health in human and most nonhuman primates and with the gain-of-function injury that has been demonstrated in several in vivo and in vitro models. The discovery of APOL1 provides an exciting example for evolutionary medicine that has by now already been translated to personalized medicine in individuals suffering from CKD. Various platform for high-throughput screening for drug discovery and antisense oligonucleotide technologies are being developed to alter APOL1 toxicity and expression. Hopefully, these will be translated to therapies that could precisely mitigate CKD risk in individuals at genotypic risk.
Genetics and ESKD Disparities in African Americans
2019, American Journal of Kidney Diseases
Citation Excerpt :
APOL1 protein derives from a family of 6 apolipoproteins that are relatively conserved in both primates and humans.32 APOL1 is believed to have developed relatively recently and is found to cluster on chromosome 22.33 The APOL1 gene arose approximately 30 million years ago and is present in humans and some nonhuman primates.34
African Americans have a 2- to 4-fold greater incidence of end-stage kidney disease (ESKD) than whites, which has long raised the possibility of a genetic cause for this disparity. Recent advances in genetic studies have shown a causal association of polymorphisms at the apolipoprotein L1 gene (APOL1) with the markedly increased risk for the nondiabetic component of the overall disparity in ESKD in African Americans. Although APOL1-associated kidney disease is thought to account for a substantial proportion of ESKD in African Americans, not all the increased risk for ESKD is accounted for, and a complete cataloging of disparities in genetic causes of ESKD eludes our current understanding of genetic-associated kidney disease. Genetic testing aids the screening, diagnosis, prognosis, and treatment of diseases with a genetic basis. Widespread use of genetic testing in clinical practice is limited by the small number of actionable genetic variants, limited health literacy of providers and patients, and underlying complex ethical, legal, and social issues. This perspective reviews racial and ethnic differences associated with genetic diseases and the development of ESKD in African Americans and discusses potential uncertainties associated with our current understanding of penetrance of genetically linked kidney disease and population-attributable risk percent.
Apolipoprotein L1, Cardiovascular Disease and Hypertension: More Questions than Answers
2019, Cardiology Clinics
Citation Excerpt :
The Apolipoprotein L1 (APOL1) gene, located on the short arm of chromosome 22, is only found in humans and closely related primate species.1
Common Mechanisms of Viral Injury to the Kidney
2019, Advances in Chronic Kidney Disease
Citation Excerpt :
It has been estimated that HIV-1–infected individuals with the at-risk APOL1 genotype (and not receiving antiviral treatment) have a 50% lifetime risk for developing HIVAN.39 Although APOL1 is believed to have evolved as part of our innate immune system to primarily combat parasitic infections,40 several in vitro studies provide evidence that APOL1 also may be a host restriction factor for HIV-1.41,42 Host restriction factors are intracellular proteins with functions that disable some aspect of the viral life cycle and prevents the virus from replicating and establishing a chronic infection.
Viral infections in an immunocompetent host can cause both acute and chronic kidney diseases, either by direct damage to the infected kidney cells or as a consequence of systemic immune responses that impact the kidneys' function. Viruses have evolved mechanisms to hijack signaling pathways of the infected cell, including the mammalian target of rapamycin pathway to support viral replication, and to evade antiviral immune responses such as those mediated by miR-155 via microRNA mimetics expressed by the virus. At both the cellular and systemic levels, the host has also evolved mechanisms to counter the viral subversion strategies in the evolutionary battle for mutual survival. In the era of genomic medicine, understanding individual genetic variations that lead to differences in susceptibilities to infection and variabilities in immune responses may open new avenues for treatment, such as the recently described functions of apolipoprotein L1 risk alleles in HIV-associated nephropathy. In addition, state-of-the-art high-throughput sequencing methods have discovered new viruses as the cause for chronic diseases not previously attributed to an infection. The potential application of these methods to idiopathic kidney diseases may reveal similar occult infections by unknown viruses. Precision medicine objectives to optimize host-directed and pathogen-directed therapies for kidney diseases associated with infectious causes will only be achieved through detailed understanding of genetic susceptibility associated with immune responses and viral tropism.
HIVAN associated tubular pathology with reference to ER stress, mitochondrial changes, and autophagy
2019, Experimental and Molecular Pathology
Citation Excerpt :
In healthy kidney tubular epithelial cells, it is noted that ApoL1 is strongly expressed and is induced by cytokines such as tumor necrosis factor-alpha (TNF-a) and interferon-gamma (IFN-y), both of which are proinflammatory cytokines upregulated in HIV cells, suggesting that autophagy promotes disease through ApoL1. Furthermore, as ApoL1 is very involved with autophagic mechanisms, disruption of this gene through genetic variants and mutations potentially inducing cytotoxicity and kidney injury (Ray and Hu, 2011; Kruzel-Davila et al., 2017). Specifically, research has confirmed that the G1 and G2 mutation of the ApoL1 gene greatly increases susceptibility to HIVAN, although only present in the African American population (Kruzel-Davila et al., 2017).
Human immunodeficiency virus associated nephropathy (HIVAN) is a unique form of a renal parenchymal disorder. This disease and its characteristics can be accredited to incorporation of DNA and mRNA of human immunodeficiency virus type 1 into the renal parenchymal cells. A proper understanding of the intricacies of HIVAN and the underlying mechanisms associated with renal function and disorders is vital for the potential development of a reliable treatment for HIVAN.
Specifically, the renal tubule segment of the kidney is characterized by its transport capabilities and its ability to reabsorb water and salts into the blood. However, the segment is also known for certain disorders, such as renal tubular epithelial cell infection and microcyst formation, which are also closely linked to HIVAN.
Furthermore, certain organelles, like the endoplasmic reticulum (ER), mitochondria, and lysosome, are vital for certain underlying mechanisms in kidney cells. A paradigm of the importance of said organelles can be seen in documented cases of HIVAN where the renal disorder results increased ER stress due to HIV viral propagation. This balance can be restored through the synthesis of secretory proteins, but, in return, the secretion requires more energy; therefore, there is a noticeable increase in mitochondrial stress. The increased ER changes and mitochondrial stress will greatly upregulate the process of autophagy, which involves the cell's lysosomes. In conjunction, we found that ER stress and mitochondrial changes are associated in the Tg26 animal model of HIVAN.
The aim of our review is to consolidate current knowledge of important mechanisms in HIVAN, specifically related to the renal tubules' association with ER stress, mitochondrial changes and autophagy. Although the specific regulatory mechanism detailing the cross-talk between the various organelles is unknown in HIVAN, the continued research in this field may potentially shed light on a possible improved treatment for HIVAN.

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^☆: Financial disclosure and conflict of interest statements: none.

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APOL1 Nephropathy: A Population Genetics and Evolutionary Medicine Detective Story☆

Section snippets

The Discovery of African Kidney Risk Genetic Loci by Admixture Linkage Disequilibrium Mapping

Pathogen Resistance Provokes a Selective Sweep, Propelling APOL1 Variants to High Allele Frequencies

Supportive Evidence for the Causality of APOL1 G1 and G2 Risk Alleles

Missing Heritability Provokes the Search for Additional Variants in Chromosome 22

The Paradox of the Recessive Mode of Inheritance and Gain-of-Function Injury

How Can We Explain the Variable and Incomplete Penetrance of APOL1 Kidney Risk Variants?

APOL1 Risk Alleles are Associated with a Broad Spectrum of Kidney Disease

Unresolved Genetic Epidemiologic Associations

Lessons from Transplantation Studies: Mechanisms and Beyond

Clinical APOL1 Genotyping

What are the Implications of Our Understanding of the Mechanisms Underlying APOL1-Mediated Kidney Disease?

Potential Therapeutic Strategies and Novel Drug Discovery

Concluding Remarks

Kidney Int

Am J Kidney Dis

Am J Kidney Dis

Am J Hum Genet

Kidney Int

Semin Nephrol

Trans R Soc Trop Med Hyg

Kidney Int

Am J Hum Genet

Kidney Int

Am J Hum Genet

Genomics

J Biol Chem

Genomics

J Biol Chem

J Lipid Res

Kidney Int

J Invest Dermatol

Am J Hum Genet

Kidney Int

Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention

Circulation

Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization

N Engl J Med

Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis

Lancet

National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification

Ann Intern Med

USRDS 2010 annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States

Racial differences in the progression from chronic renal insufficiency to end-stage renal disease in the United States

J Am Soc Nephrol

Is there an epidemic of HIV infection in the US ESRD program?

J Am Soc Nephrol

Chronic kidney disease incidence, and progression to end-stage renal disease, in HIV-infected individuals: a tale of two races

J Infect Dis

Family history of end-stage renal disease among incident dialysis patients

J Am Soc Nephrol

End-stage renal disease in African-American and white men. 16-year MRFIT findings

JAMA

Excess risk of chronic kidney disease among African-American versus white subjects in the United States: a population-based study of potential explanatory factors

J Am Soc Nephrol

Race and end-stage renal disease. Socioeconomic status and access to health care as mediating factors

Arch Intern Med

Segregation, income disparities, and survival in hemodialysis patients

J Am Soc Nephrol

Familial aggregation of renal disease in a population-based case-control study

J Am Soc Nephrol

Family-based designs in the age of large-scale gene-association studies

Nat Rev Genet

Bringing genome-wide association findings into clinical use

Nat Rev Genet

Genomic approaches for understanding the genetics of complex disease

Genome Res

MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

Nat Genet

MYH9 is associated with nondiabetic end-stage renal disease in African Americans

Nat Genet

Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci

Proc Natl Acad Sci U S A

Mapping by admixture linkage disequilibrium in human populations: limits and guidelines

Am J Hum Genet

Mapping by admixture linkage disequilibrium: advances, limitations and guidelines

Nat Rev Genet

Admixture mapping of end stage kidney disease genetic susceptibility using estimated mutual information ancestry informative markers

BMC Med Genomics