Dataset Information

APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis.

ABSTRACT: The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endothelial-specific expression of RV APOL1 and in vitro studies demonstrated that RV APOL1 interfered with mitophagy, leading to cytosolic release of mitochondrial DNA and activation of the inflammasome (NLRP3) and the cytosolic nucleotide sensing pathways (STING). Genetic deletion or pharmacological inhibition of NLRP3 and STING protected mice from RV APOL1-induced permeability defects and proinflammatory endothelial changes in sepsis. Our studies identify the inflammasome and STING pathways as potential targets to reduce APOL1-associated health disparities in sepsis and COVID-19.

SUBMITTER: Wu J

PROVIDER: S-EPMC9338439 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis.

Wu Junnan J Ma Ziyuan Z Raman Archana A Beckerman Pazit P Dhillon Poonam P Mukhi Dhanunjay D Palmer Matthew M Chen Hua Chang HC Cohen Cassiane Robinson CR Dunn Thomas T Reilly John J Meyer Nuala N Shashaty Michael M Arany Zoltan Z Haskó György G Laudanski Krzysztof K Hung Adriana A Susztak Katalin K

Immunity 20211012 11

The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endo ...[more]

PMID: 34715018

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Project description:ImportancePrimary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.ObjectivesTo perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, settings, and participantsA 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.ExposuresGenetic variants associated with primary open-angle glaucoma.Main outcomes and measuresPresence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data.ResultsA total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and relevanceIn this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

Project description:AbstractWhile increased obesity prevalence among persons of African ancestry (AAs) compared to persons of European ancestry (EAs) is linked to social, environmental and behavioral factors, there are no gene variants that are common and significantly associated with obesity in AA populations. We sought to explore the association between ancestry specific renal risk variants in the apolipoprotein L1 (APOL1) gene with obesity related traits in AAs.We conducted a genotype-phenotype association study from 3 electronic medical record linked cohorts (BioMe Biobank, BioVU, nuGENE); randomized controlled trials (genetic testing to understand and address renal disease disparities) and prospective cohort study (Jackson Heart Study). We analyzed association of APOL1 renal risk variants with cross-sectional measures of obesity (average body mass index (BMI), and proportion of overweight and obesity) and with measures of body composition (in Jackson Heart Study).We had data on 11,930 self-reported AA adults. Across cohorts, mean age was from 42 to 49 years and percentage female from 58% to 75.3%. Individuals who have 2 APOL1 risk alleles (14% of AAs) have 30% higher obesity odds compared to others (recessive model adjusted odds ratio 1.30; 95% confidence interval 1.16-1.41; P = 2.75 × 10-6). An additive model better fit the association, in which each allele (47% of AAs) increases obesity odds by 1.13-fold (adjusted odds ratio 1.13; 95% confidence interval 1.07-1.19; P = 3.07 × 10-6) and increases BMI by 0.36 kg/m2 (∼1 kg, for 1.7 m height; P = 2 × 10-4). APOL1 alleles are not associated with refined body composition traits overall but are significantly associated with fat free mass index in women [0.30 kg/m2 increment per allele; P = .03].Thus, renal risk variants in the APOL1 gene, found in nearly half of AAs, are associated with BMI and obesity in an additive manner. These variants could, either on their own or interacting with environmental factors, explain a proportion of ethnic disparities in obesity.

Project description:ImportanceCoronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates.ObjectiveIndividuals with African ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We tested the hypothesis that the APOL1 high-risk group is associated with a higher-risk of COVID-19-associated AKI and death.Design, setting, and participantsThis retrospective cohort study included 990 participants with African ancestry enrolled in the Million Veteran Program who were hospitalized with COVID-19 between March 2020 and January 2021 with available genetic information.ExposuresThe primary exposure was having 2 APOL1 risk variants (RV) (APOL1 high-risk group), compared with having 1 or 0 risk variants (APOL1 low-risk group).Main outcomes and measuresThe primary outcome was AKI. The secondary outcomes were stages of AKI severity and death. Multivariable logistic regression analyses adjusted for preexisting comorbidities, medications, and inpatient AKI risk factors; 10 principal components of ancestry were performed to study these associations. We performed a subgroup analysis in individuals with normal kidney function prior to hospitalization (estimated glomerular filtration rate ≥60 mL/min/1.73 m2).ResultsOf the 990 participants with African ancestry, 905 (91.4%) were male with a median (IQR) age of 68 (60-73) years. Overall, 392 (39.6%) patients developed AKI, 141 (14%) developed stages 2 or 3 AKI, 28 (3%) required dialysis, and 122 (12.3%) died. One hundred twenty-five (12.6%) of the participants were in the APOL1 high-risk group. Patients categorized as APOL1 high-risk group had significantly higher odds of AKI (adjusted odds ratio [OR], 1.95; 95% CI, 1.27-3.02; P = .002), higher AKI severity stages (OR, 2.03; 95% CI, 1.37-2.99; P < .001), and death (OR, 2.15; 95% CI, 1.22-3.72; P = .007). The association with AKI persisted in the subgroup with normal kidney function (OR, 1.93; 95% CI, 1.15-3.26; P = .01). Data analysis was conducted between February 2021 and April 2021.Conclusions and relevanceIn this cohort study of veterans with African ancestry hospitalized with COVID-19 infection, APOL1 kidney risk variants were associated with higher odds of AKI, AKI severity, and death, even among individuals with prior normal kidney function.

Dataset Information

APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis.

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APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis.

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