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

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.