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
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)
Evolutionary medicine-Apolipoprotein L1 in human health and disease
2021, New Horizons in EvolutionGenetics and ESKD Disparities in African Americans
2019, American Journal of Kidney DiseasesCitation 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
Apolipoprotein L1, Cardiovascular Disease and Hypertension: More Questions than Answers
2019, Cardiology ClinicsCitation 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 DiseaseCitation 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.
HIVAN associated tubular pathology with reference to ER stress, mitochondrial changes, and autophagy
2019, Experimental and Molecular PathologyCitation 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).
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