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Septic Shock: A Genomewide Association Study and Polygenic Risk Score Analysis

Published online by Cambridge University Press:  05 August 2020

Shannon D’Urso
Affiliation:
The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia
Dorrilyn Rajbhandari
Affiliation:
The George Institute for Global Health, Sydney, Australia
Elizabeth Peach
Affiliation:
The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia
Erika de Guzman
Affiliation:
Australian Translational Genomics Centre, Queensland University of Technology, Brisbane, Australia
Qiang Li
Affiliation:
The George Institute for Global Health, Sydney, Australia
Sarah E. Medland
Affiliation:
QIMR Berghofer Medical Research Institute, Brisbane, Australia
Scott D. Gordon
Affiliation:
QIMR Berghofer Medical Research Institute, Brisbane, Australia
Nicholas G. Martin
Affiliation:
QIMR Berghofer Medical Research Institute, Brisbane, Australia
Symen Ligthart
Affiliation:
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Intensive Care, Erasmus University Medical Center, Rotterdam, The Netherlands
Matthew A. Brown
Affiliation:
Guy’s & St Thomas’ NHS Foundation Trust and King’s College London NIHR Biomedical Research Centre, London, England
Joseph Powell
Affiliation:
Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute, Sydney, Australia UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, Australia
Colin McArthur
Affiliation:
Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand
Andrew Rhodes
Affiliation:
Department of Adult Critical Care, St George’s University Hospitals NHS Foundation Trust and St George’s University of London, London, UK
Jason Meyer
Affiliation:
The George Institute for Global Health, Sydney, Australia Intensive Care Unit, Princess Alexandra Hospital, Brisbane, Australia
Simon Finfer
Affiliation:
The George Institute for Global Health, Sydney, Australia
John Myburgh
Affiliation:
The George Institute for Global Health, Sydney, Australia
Antje Blumenthal
Affiliation:
The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia
Jeremy Cohen
Affiliation:
Royal Brisbane and Women’s Hospital, Brisbane, Australia Intensive Care Unit, The Wesley Hospital, Brisbane, QLD, Australia Faculty of Medicine, University of Queensland, Brisbane, Australia
Balasubramanian Venkatesh
Affiliation:
The George Institute for Global Health, Sydney, Australia Intensive Care Unit, Princess Alexandra Hospital, Brisbane, Australia Intensive Care Unit, The Wesley Hospital, Brisbane, QLD, Australia Faculty of Medicine, University of Queensland, Brisbane, Australia Faculty of Health, University of New South Wales, Sydney, Australia
Gabriel Cuellar-Partida
Affiliation:
The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia
David M. Evans
Affiliation:
The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
Corresponding
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Abstract

Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.

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© The Author(s), 2020. Published by Cambridge University Press

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