Kidney Disease in the Caribbean-APOL1 Risk Alleles and Emerging Environmental Stressors.
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SUBMITTER: Myrie J
PROVIDER: S-EPMC11284400 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
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Kidney Disease in the Caribbean-APOL1 Risk Alleles and Emerging Environmental Stressors.
Myrie Joseph J Soyibo Adedamola A Friedman David D Anand Shuchi S Fisher Lori-Ann LA
Kidney international reports 20240507 7
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Project description:BACKGROUNDTwo coding alleles within the APOL1 gene, G1 and G2, found almost exclusively in individuals genetically similar to West African populations, contribute substantially to the pathogenesis of chronic kidney disease (CKD). The APOL gene cluster on chromosome 22 contains a total of 6 APOL genes that have arisen as a result of gene duplication.METHODSUsing a genome-first approach in the Penn Medicine BioBank, we identified 62 protein-altering variants in the 6 APOL genes with a minor allele frequency of >0.1% in a population of participants genetically similar to African reference populations and performed population-specific phenome-wide association studies.RESULTSWe identified rs1108978, a stop-gain variant in APOL3 (p.Q58*), to be significantly associated with increased CKD risk, even after conditioning on APOL1 G1/G2 carrier status. These findings were replicated in the Veterans Affairs Million Veteran Program and the All of Us Research Program. APOL3 p.Q58* was also significantly associated with a number of quantitative traits linked to CKD, including decreased kidney volume. This truncating variant contributed the most risk for CKD in patients monoallelic for APOL1 G1/G2, suggesting an epistatic interaction and a potential protective effect of wild-type APOL3 against APOL1-induced kidney disease.CONCLUSIONThis study demonstrates the utility of targeting population-specific variants in a genome-first approach, even in the context of well-studied gene-disease relationships.FUNDINGNational Heart, Lung, and Blood Institute (F30HL172382, R01HL169378, R01HL169458), Doris Duke Foundation (grant 2023-2024), National Institute of Biomedical Imaging and Bioengineering (P41EB029460), and National Center for Advancing Translational Sciences (UL1-TR-001878).
| S-EPMC11466179 | biostudies-literature
Project description:People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1 We performed an admixture mapping study to identify genetic modifiers of APOL1-associated kidney disease. Individuals with two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the UBD (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the UBD locus correlates with lower levels of UBD expression. In cell-based experiments, the disease-associated APOL1 alleles (known as G1 and G2) lead to increased abundance of UBD mRNA but to decreased levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both UBD and APOL1, which interact in a functionally important manner. UBD appears to mitigate APOL1-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in UBD and UBD expression appear to modify the APOL1-associated kidney phenotype.
| S-EPMC5879665 | biostudies-literature
Project description:BackgroundHuman African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken candidate gene association studies (CGAS) in a Ugandan Tbr and a Tbg HAT endemic area, to determine whether polymorphisms in IL10, IL8, IL4, HLAG, TNFA, TNX4LB, IL6, IFNG, MIF, APOL1, HLAA, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH have a role in HAT.Methodology and resultsWe included 238 and 202 participants from the Busoga Tbr and Northwest Uganda Tbg endemic areas respectively. Single Nucleotide Polymorphism (SNP) genotype data were analysed in the CGAS. The study was powered to find odds ratios > 2 but association testing of the SNPs with HAT yielded no positive associations i.e. none significant after correction for multiple testing. However there was strong evidence for no association with Tbr HAT and APOL1 G2 of the size previously reported in the Kabermaido district of Uganda.Conclusions/significanceA recent study in the Soroti and Kaberamaido focus in Central Uganda found that the APOL1 G2 allele was strongly associated with protection against Tbr HAT (odds ratio = 0.2, 95% CI: 0.07 to 0.48, p = 0.0001). However, in our study no effect of G2 on Tbr HAT was found, despite being well powered to find a similar sized effect (OR = 0.9281, 95% CI: 0.482 to 1.788, p = 0.8035). It is possible that the G2 allele is protective from Tbr in the Soroti/Kabermaido focus but not in the Iganga district of Busoga, which differ in ethnicity and infection history. Mechanisms underlying HAT infection outcome and virulence are complex and might differ between populations, and likely involve several host, parasite or even environmental factors.
| S-EPMC5844566 | biostudies-literature
Project description:BackgroundExisting data suggest that human immunodeficiency virus (HIV)-infected African Americans carrying 2 copies of the APOL1 risk alleles have greater risk of kidney disease than noncarriers. We sought to determine whether HIV RNA suppression mitigates APOL1-related kidney function decline among African Americans enrolled in the Multicenter AIDS Cohort Study.MethodsWe genotyped HIV-infected men for the G1 and G2 risk alleles and ancestry informative markers. Mixed-effects models were used to estimate the annual rate of estimated glomerular filtration rate (eGFR) decline, comparing men carrying 2 (high-risk) vs 0-1 risk allele (low-risk). Effect modification by HIV suppression status (defined as HIV type 1 RNA level <400 copies/mL for >90% of follow-up time) was evaluated using interaction terms and stratified analyses.ResultsOf the 333 African American men included in this study, 54 (16%) carried the APOL1 high-risk genotype. Among HIV-infected men with unsuppressed viral loads, those with the high-risk genotype had a 2.42 mL/minute/1.73 m(2) (95% confidence interval [CI], -3.52 to -1.32) faster annual eGFR decline than men with the low-risk genotype. This association was independent of age, comorbid conditions, baseline eGFR, ancestry, and HIV-related factors. In contrast, the rate of decline was similar by APOL1 genotype among men with sustained viral suppression (-0.16 mL/minute/1.73 m(2)/year; 95% CI, -.59 to .27; P for interaction <.001).ConclusionsUnsuppressed HIV-infected African Americans with the APOL1 high-risk genotype experience an accelerated rate of kidney function decline; HIV suppression with antiretroviral therapy may reduce these deleterious renal effects.
| S-EPMC4318914 | biostudies-literature
Project description:BackgroundAmong patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.MethodsIn two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline.ResultsIn the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons).ConclusionsRenal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
| S-EPMC3969022 | biostudies-literature
Project description:Background and objectivesapo L1 (APOL1) nephropathy risk alleles are associated with CKD in blacks. Although APOL1 has innate immune functions, little is known about the association of APOL1 genotypes with risk of infectious outcomes, such as sepsis. The objective of this study was to examine the associations of APOL1 nephropathy risk alleles with risk of sepsis in black adults.Design, setting, participants, & measurementsWe assessed the association of APOL1 risk alleles with incident sepsis in 10,366 black participants of the Reasons for Geographic and Racial Differences in Stroke study enrolled between 2003 and 2007 with follow-up through December 31, 2012. In Cox models adjusted for demographics, comorbid conditions, and principal components ancestry, we examined the association of APOL1 risk alleles with incident sepsis using recessive (comparing zero or one versus two risk alleles), dominant (zero versus one or two risk alleles), and additive genetic models. We also examined models stratified by diabetes and CKD status.ResultsA total of 1320 (13%) participants had two APOL1 risk alleles, 4719 (46%) had one risk allele, and 4327 (42%) participants had zero risk alleles. A total of 306 sepsis events occurred over a median 6.5 years (interquartile range, 4.5-8.1). There were no statistically significant associations of APOL1 genotype with sepsis risk under recessive genetic models. APOL1 genotypes were associated with sepsis risk under dominant (hazard ratio, 1.55; 95% confidence interval, 1.13 to 2.11) and additive (hazard ratio per variant allele copy, 1.25; 95% confidence interval, 1.02 to 1.53) genetic models adjusted for covariates and ancestry. These associations did not vary by diabetes or CKD status (P interaction>0.10 for both).ConclusionsIn community-dwelling black adults, carriage of APOL1 nephropathy risk alleles are common and associated with higher risk of sepsis.
| S-EPMC6895473 | biostudies-literature
Project description:IntroductionCoding variants in apolipoprotein L-1 (APOL1) are associated with an increased risk of end-stage kidney disease (ESRD) in African American individuals under a recessive model of inheritance. The effect of the APOL1 risk alleles on kidney disease has been observed in studies in African American and African populations. Despite the 130 million individuals of recent African ancestry in South America, the impact of APOL1 has not been explored.MethodsIn this case-control study, we tested APOL1 genotype in 106 Brazilian HD (hemodialysis) patients with African ancestry and compared risk allele frequency with 106 healthy first-degree relatives. The association of risk alleles and ESRD was calculated with a linear mixed model and was adjusted for relatedness and additional confounders. In a broader survey, the age of dialysis initiation and APOL1 variants were analyzed in 274 HD patients.ResultsTwo APOL1 risk alleles were 10 times more common in patients with ESRD than in controls (9.4% vs. 0.9%; odds ratio [OR]: 10.95, SE = 1.49, P = 0.0017). Carriers of 2 risk alleles initiated dialysis 12 years earlier than patients with zero risk alleles.ConclusionThe APOL1 risk variants were less frequent in dialysis patients of African ancestry in Brazil than in the United States. Nonetheless, carriers of 2 risk variants had 10-fold higher odds of ESRD. Age of dialysis initiation was markedly lower in 2-risk allele carriers, suggesting a more aggressive disease phenotype. The Brazilian population represents an opportunity to identify different sets of genetic modifiers or environmental triggers that might be present in more extensively studied populations.
| S-EPMC6611925 | biostudies-literature
Project description:A third of African Americans with sporadic focal segmental glomerulosclerosis (FSGS) or HIV-associated nephropathy (HIVAN) do not carry APOL1 renal risk genotypes. This raises the possibility that other APOL1 variants may contribute to kidney disease. To address this question, we sequenced all APOL1 exons in 1437 Americans of African and European descent, including 464 patients with biopsy-proven FSGS/HIVAN. Testing for association with 33 common and rare variants with FSGS/HIVAN revealed no association independent of strong recessive G1 and G2 effects. Seeking additional variants that might have been under selection by pathogens and could represent candidates for kidney disease risk, we also sequenced an additional 1112 individuals representing 53 global populations. Except for G1 and G2, none of the 7 common codon-altering variants showed evidence of selection or could restore lysis against trypanosomes causing human African trypanosomiasis. Thus, only APOL1 G1 and G2 confer renal risk, and other common and rare APOL1 missense variants, including the archaic G3 haplotype, do not contribute to sporadic FSGS and HIVAN in the US population. Hence, in most potential clinical or screening applications, our study suggests that sequencing APOL1 exons is unlikely to bring additional information compared to genotyping only APOL1 G1 and G2 risk alleles.
| S-EPMC4591109 | biostudies-literature
Project description:In patients of African ancestry, genetic variants in APOL1, which encodes apolipoprotein L1, associate with the nondiabetic kidney diseases, focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy (HIVAN), and hypertensive nephropathy. Understanding the renal localization of APOL1 may provide clues that will ultimately help elucidate the mechanisms by which APOL1 variants promote nephropathy. Here, we used immunohistology to examine APOL1 localization in normal human kidney sections and in biopsies demonstrating either FSGS (n = 8) or HIVAN (n = 2). Within normal glomeruli, APOL1 only localized to podocytes. Compared with normal glomeruli, fewer cells stained for APOL1 in FSGS and HIVAN glomeruli, even when expression of the podocyte markers GLEPP1 and synaptopodin appeared normal. APOL1 localized to proximal tubular epithelia in normal kidneys, FSGS, and HIVAN. We detected APOL1 in the arteriolar endothelium of normal and diseased kidney sections. Unexpectedly, in both FSGS and HIVAN but not normal kidneys, the media of medium artery and arterioles contained a subset of α-smooth muscle actin-positive cells that stained for APOL1. Comparing the renal distribution of APOL1 in nondiabetic kidney disease to normal kidney suggests that a previously unrecognized arteriopathy may contribute to disease pathogenesis in patients of African ancestry.
| S-EPMC3231786 | biostudies-literature