Dataset Information

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

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.

SUBMITTER: Daubney ER

PROVIDER: S-EPMC10796137 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Daubney Emily R ER D'Urso Shannon S Cuellar-Partida Gabriel G Rajbhandari Dorrilyn D Peach Elizabeth E de Guzman Erika E McArthur Colin C Rhodes Andrew A Meyer Jason J Finfer Simon S Myburgh John J Cohen Jeremy J Schirra Horst Joachim HJ Venkatesh Balasubramanian B Evans David M DM

Critical care explorations 20240117 1

<h4>Objectives</h4>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.<h4>Design</h4>Retrospective multicenter cohort studies of septic shock patients.<h4>Setting</h4>All participants who were admitted to 27 participating hospital sites in three countries (Australia, New Zealand, and the United Kingdom) were eligible for inclusion.<h4>Patients< ...[more]

PMID: 38239409

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Project description:BACKGROUND:As early and appropriate care of severe septic patients is associated with better outcome, understanding of the very first events in the disease process is needed. Pan-genomic analyses offer an interesting opportunity to study global genomic response within the very first hours after sepsis. The objective of this study was to investigate the systemic genomic response in severe intensive care unit (ICU) patients and determine whether patterns of gene expression could be associated with clinical severity evaluated by the severity score. METHODS:Twenty-eight ICU patients were enrolled at the onset of septic shock. Blood samples were collected within 30 min and 24 and 48 h after shock and genomic response was evaluated using microarrays. The genome-wide expression pattern of blood leukocytes was sequentially compared to healthy volunteers and after stratification based on Simplified Acute Physiology Score II (SAPSII) score to identify potential mechanisms of dysregulation. RESULTS:Septic shock induces a global reprogramming of the whole leukocyte transcriptome affecting multiple functions and pathways (>71% of the whole genome was modified). Most altered pathways were not significantly different between SAPSII-high and SAPSII-low groups of patients. However, the magnitude and the duration of these alterations were different between these two groups. Importantly, we observed that the more severe patients did not exhibit the strongest modulation. This indicates that some regulation mechanisms leading to recovery seem to take place at the early stage. CONCLUSIONS:In conclusion, both pro- and anti-inflammatory processes, measured at the transcriptomic level, are induced within the very first hours after septic shock. Interestingly, the more severe patients did not exhibit the strongest modulation. This highlights that not only the responses mechanisms by themselves but mainly their early and appropriate regulation are crucial for patient recovery. This reinforces the idea that an immediate and tailored aggressive care of patients, aimed at restoring an appropriately regulated immune response, may have a beneficial impact on the outcome.

Project description:Background To determine the clinical significance of variations in serum sestrin2 protein levels in the development of septic cardiomyopathy in septic shock patients. Methods The serum sestrin2 concentrations of each sample were determined using ELISA in a total of 67 control persons and 188 patients with septic shock. Furthermore, using transthoracic echocardiography, septic shock patients were split into two groups based on whether or not cardiomyopathy had developed, and the differences in each index between the two groups were analyzed. We looked at the relationship between serum sestrin2 levels, norepinephrine dosage, and NTproBNP levels. The influencing variables for the prediction of septic cardiomyopathy linked with the development of septic cardiomyopathy and clinical prognosis in septic cardiomyopathy were determined using multivariate binary logistic regression. Results Assessment of left ventricular systolic function by measurement of LVEF revealed that 61/188 (32.4%) of the 188 patients with septic shock included in the research satisfied the diagnostic criteria for septic cardiomyopathy. (1) Sestrin2 protein levels showed a significant difference between septic shock and healthy controls (p < 0.01). (2) Compared to the group without septic cardiomyopathy, the group with combined septic cardiomyopathy had lower serum sestrin2 protein levels (p < 0.05), lower systolic blood pressure (p < 0.05), and higher plasma NTproBNP levels (p < 0.01) and used greater norepinephrine dosages (p < 0.01). The levels of serum sestrin2 protein revealed a little negative relationship with NTproBNP and norepinephrine dose. However, a binary logistic regression analysis revealed that none of these factors was an independent predictor of septic shock. (3) Age, lactate level, SOFA score, positive bacteremia, and sestrin2 protein were shown to be substantial discrepancies in clinical outcomes in patients with septic cardiomyopathy, becoming variables that impact clinical outcomes. Positive bacteremia (p = 0.031, OR = 5.084), SOFA score (p = 0.021, OR = 1.304), and sestrin2 protein (p = 0.039, OR = 0.897) were revealed to have independent influences in predicting clinical mortality outcome in septic cardiomyopathy using multivariate binary logistic regression. Conclusion High serum sestrin2 levels clearly distinguish septic shock patients from healthy controls, whereas low serum sestrin2 levels are related with cardiac dysfunction to some extent but are not an independent influence factor for septic cardiomyopathy. Low serum sestrin2 levels were shown to be useful in predicting clinical outcome in patients with septic cardiomyopathy.

Dataset Information

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

Objectives

Design

Setting

Patients

Interventions

Measurements and main results

Conclusions

Publications

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

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