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

Emily R Daubney; Shannon D'Urso; Gabriel Cuellar-Partida; Dorrilyn Rajbhandari; Elizabeth Peach; Erika de Guzman; Colin McArthur; Andrew Rhodes; Jason Meyer; Simon Finfer; John Myburgh; Jeremy Cohen; Horst Joachim Schirra; Balasubramanian Venkatesh; David M Evans

doi:10.1097/CCE.0000000000001030

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

Crit Care Explor. 2024 Jan 17;6(1):e1030. doi: 10.1097/CCE.0000000000001030. eCollection 2024 Jan.

Authors

Emily R Daubney^{1

2}, Shannon D'Urso¹, Gabriel Cuellar-Partida³, Dorrilyn Rajbhandari⁴, Elizabeth Peach³, Erika de Guzman⁵, Colin McArthur⁶, Andrew Rhodes⁷, Jason Meyer^{4

8}, Simon Finfer^{4

9}, John Myburgh^{4

10}, Jeremy Cohen^{11

12

13}, Horst Joachim Schirra^{2

14

15}, Balasubramanian Venkatesh^{4

8

12

13

16}, David M Evans^{1

3

17}

Affiliations

¹ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
² Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia.
³ Frazer Institute, University of Queensland, Brisbane, QLD, Australia.
⁴ The George Institute for Global Health, Sydney, NSW, Australia.
⁵ Australian Translational Genomics Centre, Queensland University of Technology, Brisbane, QLD, Australia.
⁶ Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand.
⁷ Department of Adult Critical Care, St George's University Hospitals NHS Foundation Trust and St George's University of London, London, United Kingdom.
⁸ Intensive Care Unit, Princess Alexandra Hospital, Brisbane, QLD, Australia.
⁹ School of Public Health, Imperial College London, London, United Kingdom.
¹⁰ St George Hospital, Sydney, NSW, Australia.
¹¹ Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
¹² Intensive Care Unit, The Wesley Hospital, Brisbane, QLD, Australia.
¹³ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
¹⁴ Griffith School of Environment and Science-Chemical Sciences, Griffith University, Brisbane, QLD, Australia.
¹⁵ Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia.
¹⁶ Faculty of Health, University of New South Wales, Sydney, NSW, Australia.
¹⁷ Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.

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.

Keywords: genetics; metabolomics; molecular biology; sepsis.

Associated data

ClinicalTrials.gov/NCT01448109