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

dc.contributor.author

Tsalik, Ephraim L

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Langley, Raymond J

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Dinwiddie, Darrell L

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Miller, Neil A

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Yoo, Byunggil

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van Velkinburgh, Jennifer C

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Smith, Laurie D

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Thiffault, Isabella

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Jaehne, Anja K

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Valente, Ashlee M

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Henao, Ricardo

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Yuan, Xin

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Glickman, Seth W

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Rice, Brandon J

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McClain, Micah T

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Carin, Lawrence

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Corey, G Ralph

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Ginsburg, Geoffrey S

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Cairns, Charles B

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Otero, Ronny M

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Fowler, Vance G

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Rivers, Emanuel P

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Woods, Christopher W

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Kingsmore, Stephen F

dc.coverage.spatial

England

dc.date.accessioned

2016-12-02T16:02:10Z

dc.date.issued

2014

dc.description.abstract

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.

dc.identifier

http://www.ncbi.nlm.nih.gov/pubmed/25538794

dc.identifier

111

dc.identifier.uri

https://hdl.handle.net/10161/13120

dc.language

eng

dc.publisher

Springer Science and Business Media LLC

dc.relation.ispartof

Genome Med

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10.1186/s13073-014-0111-5

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Tsalik, Ephraim L|0000-0002-6417-2042

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Henao, Ricardo|0000-0003-4980-845X

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Ginsburg, Geoffrey S|0000-0003-4739-9808

duke.contributor.orcid

Fowler, Vance G|0000-0002-8048-0897

duke.contributor.orcid

Woods, Christopher W|0000-0001-7240-2453

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/25538794

pubs.begin-page

111

pubs.issue

11

pubs.organisational-group

Basic Science Departments

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Biomedical Engineering

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Clinical Science Departments

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Duke

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Duke Cancer Institute

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Duke Clinical Research Institute

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Electrical and Computer Engineering

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Global Health Institute

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Institutes and Centers

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Institutes and Provost's Academic Units

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Medicine

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Medicine, Cardiology

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Medicine, Infectious Diseases

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Molecular Genetics and Microbiology

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Pathology

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Pratt School of Engineering

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School of Medicine

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School of Nursing

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School of Nursing - Secondary Group

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University Institutes and Centers

pubs.publication-status

Published online

pubs.volume

6

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