Carmen Mikacenic1, Pavan Bhatraju2, Cassianne Robinson-Cohen3, Susanna Kosamo4, Alison E Fohner5, Victoria Dmyterko2, S Alice Long1, Karen Cerosaletti1, Carolyn S Calfee6, Michael A Matthay6, Keith R Walley7, James A Russell7, Jason D Christie8, Nuala J Meyer8, David C Christiani9, Mark M Wurfel2. 1. Translational Immunology, Benaroya Research Institute, Seattle, WA. 2. Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA. 3. Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN. 4. Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland. 5. Department of Epidemiology, Institute of Public Health Genetics, University of Washington, Seattle, WA. 6. Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California San Francisco, San Francisco, CA. 7. Department of Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada. 8. Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 9. Harvard University School of Public Health and Division of Pulmonary and Critical Care, Department of Epidemiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
Abstract
OBJECTIVES: Multiple organ failure in critically ill patients is associated with poor prognosis, but biomarkers contributory to pathogenesis are unknown. Previous studies support a role for Fas cell surface death receptor (Fas)-mediated apoptosis in organ dysfunction. Our objectives were to test for associations between soluble Fas and multiple organ failure, identify protein quantitative trait loci, and determine associations between genetic variants and multiple organ failure. DESIGN: Retrospective observational cohort study. SETTING: Four academic ICUs at U.S. hospitals. PATIENTS: Genetic analyses were completed in a discovery (n = 1,589) and validation set (n = 863). Fas gene expression and flow cytometry studies were completed in outpatient research participants (n = 250). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In discovery and validation sets of critically ill patients, we tested for associations between enrollment plasma soluble Fas concentrations and Sequential Organ Failure Assessment score on day 3. We conducted a genome-wide association study of plasma soluble Fas (discovery n = 1,042) and carried forward a single nucleotide variant in the FAS gene, rs982764, for validation (n = 863). We further tested whether the single nucleotide variant in FAS (rs982764) was associated with Sequential Organ Failure Assessment score, FAS transcriptional isoforms, and Fas cell surface expression. Higher plasma soluble Fas was associated with higher day 3 Sequential Organ Failure Assessment scores in both the discovery (β = 4.07; p < 0.001) and validation (β = 6.96; p < 0.001) sets. A single nucleotide variant in FAS (rs982764G) was associated with lower plasma soluble Fas concentrations and lower day 3 Sequential Organ Failure Assessment score in meta-analysis (-0.21; p = 0.02). Single nucleotide variant rs982764G was also associated with a lower relative expression of the transcript for soluble as opposed to transmembrane Fas and higher cell surface expression of Fas on CD4+ T cells. CONCLUSIONS: We found that single nucleotide variant rs982764G was associated with lower plasma soluble Fas concentrations in a discovery and validation population, and single nucleotide variant rs982764G was also associated with lower organ dysfunction on day 3. These findings support further study of the Fas pathway as a potential mediator of organ dysfunction in critically ill patients.
OBJECTIVES: Multiple organ failure in critically ill patients is associated with poor prognosis, but biomarkers contributory to pathogenesis are unknown. Previous studies support a role for Fas cell surface death receptor (Fas)-mediated apoptosis in organ dysfunction. Our objectives were to test for associations between soluble Fas and multiple organ failure, identify protein quantitative trait loci, and determine associations between genetic variants and multiple organ failure. DESIGN: Retrospective observational cohort study. SETTING: Four academic ICUs at U.S. hospitals. PATIENTS: Genetic analyses were completed in a discovery (n = 1,589) and validation set (n = 863). Fas gene expression and flow cytometry studies were completed in outpatient research participants (n = 250). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In discovery and validation sets of critically ill patients, we tested for associations between enrollment plasma soluble Fas concentrations and Sequential Organ Failure Assessment score on day 3. We conducted a genome-wide association study of plasma soluble Fas (discovery n = 1,042) and carried forward a single nucleotide variant in the FAS gene, rs982764, for validation (n = 863). We further tested whether the single nucleotide variant in FAS (rs982764) was associated with Sequential Organ Failure Assessment score, FAS transcriptional isoforms, and Fas cell surface expression. Higher plasma soluble Fas was associated with higher day 3 Sequential Organ Failure Assessment scores in both the discovery (β = 4.07; p < 0.001) and validation (β = 6.96; p < 0.001) sets. A single nucleotide variant in FAS (rs982764G) was associated with lower plasma soluble Fas concentrations and lower day 3 Sequential Organ Failure Assessment score in meta-analysis (-0.21; p = 0.02). Single nucleotide variant rs982764G was also associated with a lower relative expression of the transcript for soluble as opposed to transmembrane Fas and higher cell surface expression of Fas on CD4+ T cells. CONCLUSIONS: We found that single nucleotide variant rs982764G was associated with lower plasma soluble Fas concentrations in a discovery and validation population, and single nucleotide variant rs982764G was also associated with lower organ dysfunction on day 3. These findings support further study of the Fas pathway as a potential mediator of organ dysfunction in critically ill patients.
Authors: Dennis C Ko; Kajal P Shukla; Christine Fong; Michael Wasnick; Mitchell J Brittnacher; Mark M Wurfel; Tarah D Holden; Grant E O'Keefe; Brian Van Yserloo; Joshua M Akey; Samuel I Miller Journal: Am J Hum Genet Date: 2009-08-06 Impact factor: 11.025
Authors: Sayantan Das; Lukas Forer; Sebastian Schönherr; Carlo Sidore; Adam E Locke; Alan Kwong; Scott I Vrieze; Emily Y Chew; Shawn Levy; Matt McGue; David Schlessinger; Dwight Stambolian; Po-Ru Loh; William G Iacono; Anand Swaroop; Laura J Scott; Francesco Cucca; Florian Kronenberg; Michael Boehnke; Gonçalo R Abecasis; Christian Fuchsberger Journal: Nat Genet Date: 2016-08-29 Impact factor: 38.330
Authors: Christian Hundhausen; Alena Roth; Elizabeth Whalen; Janice Chen; Anya Schneider; S Alice Long; Shan Wei; Rebecca Rawlings; MacKenzie Kinsman; Stephen P Evanko; Thomas N Wight; Carla J Greenbaum; Karen Cerosaletti; Jane H Buckner Journal: Sci Transl Med Date: 2016-09-14 Impact factor: 17.956