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APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis.
Wu, Junnan; Ma, Ziyuan; Raman, Archana; Beckerman, Pazit; Dhillon, Poonam; Mukhi, Dhanunjay; Palmer, Matthew; Chen, Hua Chang; Cohen, Cassiane Robinson; Dunn, Thomas; Reilly, John; Meyer, Nuala; Shashaty, Michael; Arany, Zoltan; Haskó, György; Laudanski, Krzysztof; Hung, Adriana; Susztak, Katalin.
  • Wu J; Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Departme
  • Ma Z; Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • Raman A; Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • Beckerman P; Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • Dhillon P; Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • Mukhi D; Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • Palmer M; Department of Pathology and Laboratory Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Chen HC; Division of Nephrology & Hypertension, Tennessee Valley Healthcare System, Nashville Campus and Vanderbilt University Medical Centre, Nashville, TN, USA; Division of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Cohen CR; Division of Nephrology & Hypertension, Tennessee Valley Healthcare System, Nashville Campus and Vanderbilt University Medical Centre, Nashville, TN, USA; Division of Nephrology & Hypertension, Vanderbilt Precision Nephrology Program, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Dunn T; Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Reilly J; Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Meyer N; Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Shashaty M; Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Clinical Epidemiology and Bios
  • Arany Z; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Haskó G; Department of Anesthesiology, Columbia University, New York, NY 10032, USA.
  • Laudanski K; Department of Anesthesiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Hung A; Division of Nephrology & Hypertension, Tennessee Valley Healthcare System, Nashville Campus and Vanderbilt University Medical Centre, Nashville, TN, USA; Division of Nephrology & Hypertension, Vanderbilt Precision Nephrology Program, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Susztak K; Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electron
Immunity ; 54(11): 2632-2649.e6, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1549842
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sepsis / Genetic Predisposition to Disease / Black People / Apolipoprotein L1 / COVID-19 Type of study: Observational study / Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Immunity Journal subject: Allergy and Immunology Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sepsis / Genetic Predisposition to Disease / Black People / Apolipoprotein L1 / COVID-19 Type of study: Observational study / Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Immunity Journal subject: Allergy and Immunology Year: 2021 Document Type: Article