An integrated transcriptome and expressed variant analysis of sepsis survival and death.

Genome Med 2014 26;6(11):111. Epub 2014 Nov 26.

National Center for Genome Resources, Santa Fe, NM 87505 USA ; Department of Pediatrics, Center for Translational Sciences, University of New Mexico, Albuquerque, NM 87131 USA.

Background: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.

Methods: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes.

Results: The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology.

Conclusions: The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies.

Trial Registration: ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-014-0111-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274761PMC
December 2014
58 Reads

Publication Analysis

Top Keywords

sepsis survivors
20
sepsis
19
sepsis non-survivors
12
sepsis survival
8
association sepsis
8
missense variants
8
survivors sepsis
8
variants associated
8
sirs sepsis
8
sepsis outcome
8
genes differed
8
expression
6
genes
5
variants
5
survivors
5
subjects sirs
4
sepsis reflecting
4
immune
4
reflecting immune
4
differed subjects
4

Similar Publications