Histone deactylase gene expression profiles are associated with outcomes in blunt trauma patients

Martin Sillesen, Ted Bambakidis, Simone E Dekker, Rasmus Fabricius, Peter Svenningsen, Peter James Bruhn, Lars Bo Svendsen, Jens Hillingsø, Hasan B Alam

14 Citationer (Scopus)

Abstract

INTRODUCTION: Treatment with histone deacetylase (HDAC) inhibitors, such as valproic acid (VPA), increase survival in animal models of trauma and sepsis. VPA is a pan-inhibitor that blocks most of the known HDAC isoforms. Targeting individual HDAC isoforms may increase survival and reduce complications, but little is known of the natural history of HDAC gene expression following trauma. We hypothesized that distinct HDAC isoform gene expression patterns would be associated with differences in outcomes following trauma.

METHODS: 28 day longitudinal HDAC leukocyte gene expression profiles in 172 blunt trauma patients were extracted from the Inflammation And Host Response to Injury (Glue Grant) dataset. Outcome was classified as complicated (death or no recovery by day 28, n=51) or uncomplicated (n=121). Mixed modeling was used to compare the HDAC expression trajectories between the groups, corrected for Injury Severity Score, base deficit, and volume of blood products transfused over the initial 12 hours following admission. Weighted gene correlation network analysis (WGCNA) identified modules of genes with significant co-expression, and HDAC genes were mapped to these modules. Biological function of these modules was investigated using the Gene Ontology database.

RESULTS: Elevated longitudinal HDAC expression trajectories for HDAC 1,3,6 and 11 were associated with complicated outcomes. In contrast, suppressed expression of Sirtuin (SIRT) 3 was associated with adverse outcome (p<0.01). WGCNA analysis identified significant co-expression of HDAC and SIRT genes with genes involved in ribosomal function and downregulation of protein translation in response to stress (HDAC1), T-cell signaling and T-cell selection (HDAC3), as well as coagulation and hemostasis (SIRT3). No co-expression of HDAC11 was identified.

CONCLUSION: Expression trajectories of HDAC 1,3,6,11 and SIRT3 correlate with outcomes following trauma, and may potentially serve as biomarkers. They may also be promising targets for pharmacological intervention. The effects of HDAC and SIRT gene expression in trauma may be mediated through pathways involved in ribosomal and T-cell function as well as coagulation and hemostasis.

LEVEL OF EVIDENCE: III STUDY TYPE: Prognostic.

OriginalsprogEngelsk
TidsskriftThe journal of trauma and acute care surgery
Vol/bind80
Udgave nummer1
Sider (fra-til)26-33
ISSN0022-5282
DOI
StatusUdgivet - 2016

Fingeraftryk

Dyk ned i forskningsemnerne om 'Histone deactylase gene expression profiles are associated with outcomes in blunt trauma patients'. Sammen danner de et unikt fingeraftryk.

Citationsformater