Critical care explorations · 2024
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
Аннотация
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.
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.