A Genome-Wide Association Study of Serum Metabolite Profiles in Septic Shock Patients

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Daubney, Emily R
D'Urso, Shannon
Cuellar-Partida, Gabriel
Rajbhandari, Dorrilyn
Peach, Elizabeth
de Guzman, Erika
McArthur, Colin
Rhodes, Andrew
Meyer, Jason
Finfer, Simon
Myburgh, John
Cohen, Jeremy
Schirra, Horst Joachim
Venkatesh, Balasubramanian
Evans, David M
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2024
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http://creativecommons.org/licenses/by-nc-nd/4.0/
Abstract

OBJECTIVES: We sought to assess whether genetic associations with metabolite concentrations in septic shock patients could be used to identify pathways of potential importance for understanding sepsis pathophysiology.

DESIGN: Retrospective multicenter cohort studies of septic shock patients.

SETTING: All participants who were admitted to 27 participating hospital sites in three countries (Australia, New Zealand, and the United Kingdom) were eligible for inclusion.

PATIENTS: Adult, critically ill, mechanically ventilated patients with septic shock (n = 230) who were a subset of the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock trial (ClinicalTrials.gov number: NCT01448109).

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: A genome-wide association study was conducted for a range of serum metabolite levels for participants. Genome-wide significant associations (p ≤ 5 × 10–8) were found for the two major ketone bodies (3-hydroxybutyrate [rs2456680] and acetoacetate [rs2213037] and creatinine (rs6851961). One of these single-nucleotide polymorphisms (SNPs) (rs2213037) was located in the alcohol dehydrogenase cluster of genes, which code for enzymes related to the metabolism of acetoacetate and, therefore, presents a plausible association for this metabolite. None of the three SNPs showed strong associations with risk of sepsis, 28- or 90-day mortality, or Acute Physiology and Chronic Health Evaluation score (a measure of sepsis severity).

CONCLUSIONS: We suggest that the genetic associations with metabolites may reflect a starvation response rather than processes involved in sepsis pathophysiology. However, our results require further investigation and replication in both healthy and diseased cohorts including those of different ancestry.

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Critical Care Explorations
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6
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1
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© 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBYNC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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Clinical sciences
genetics
metabolomics
molecular biology
sepsis
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Daubney, ER; D'Urso, S; Cuellar-Partida, G; Rajbhandari, D; Peach, E; de Guzman, E; McArthur, C; Rhodes, A; Meyer, J; Finfer, S; Myburgh, J; Cohen, J; Schirra, HJ; Venkatesh, B; Evans, DM, A Genome-Wide Association Study of Serum Metabolite Profiles in Septic Shock Patients, Critical Care Explorations, 2024, 6 (1), pp. e1030
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