An integrated transcriptome and expressed variant analysis of sepsis survival and death.
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.
Type
Journal articlePermalink
https://hdl.handle.net/10161/13120Published Version (Please cite this version)
10.1186/s13073-014-0111-5Publication Info
Tsalik, Ephraim L; Langley, Raymond J; Dinwiddie, Darrell L; Miller, Neil A; Yoo,
Byunggil; van Velkinburgh, Jennifer C; ... Kingsmore, Stephen F (2014). An integrated transcriptome and expressed variant analysis of sepsis survival and
death. Genome Med, 6(11). pp. 111. 10.1186/s13073-014-0111-5. Retrieved from https://hdl.handle.net/10161/13120.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Lawrence Carin
Professor of Electrical and Computer Engineering
Lawrence Carin earned the BS, MS, and PhD degrees in electrical engineering at the
University of Maryland, College Park, in 1985, 1986, and 1989, respectively. In 1989
he joined the Electrical Engineering Department at Polytechnic University (Brooklyn)
as an Assistant Professor, and became an Associate Professor there in 1994. In September
1995 he joined the Electrical and Computer Engineering (ECE) Department at Duke University,
where he is now a Professor. He was ECE Department Chair from 2011
Gordon Ralph Corey
Gary Hock Distinguished Professor Emeritus in Global Health, in the School of Medicine
My research is based at the Duke Clinical Research Institute, a large academic
clinical research organization designed to conduct clinical trials from small local
studies to worldwide trials. The focus of my research is bacterial infections: complicated
skin and skin structure infections; postoperative wound infections; hospital-acquired
and ventilator-associated pneumonia; bacteremia; and endocarditis. Many of these trials
are conducted in concert with the pharmaceutical industry in ord
Vance Garrison Fowler Jr.
Florence McAlister Distinguished Professor of Medicine
Determinants of Outcome in Patients with Staphylococcus aureus Bacteremia Antibacterial
ResistancePathogenesis of Bacterial Infections Tropical medicine/International Health
Geoffrey Steven Ginsburg
Adjunct Professor in the Department of Medicine
Dr. Geoffrey S. Ginsburg's research interests are in the development of novel paradigms
for developing and translating genomic information into medical practice and the integration
of personalized medicine into health care.
Ricardo Henao
Associate Professor in Biostatistics & Bioinformatics
Micah Thomas McClain
Associate Professor of Medicine
Ephraim Tsalik
Adjunct Associate Professor in the Department of Medicine
My research at Duke has focused on understanding the dynamic between host and pathogen
so as to discover and develop host-response markers that can diagnose and predict
health and disease. This new and evolving approach to diagnosing illness has the
potential to significantly impact individual as well as public health considering
the rise of antibiotic resistance.
With any potential infectious disease diagnosis, it is difficult, if not impossible,
to determine at the time of pre
Christopher Wildrick Woods
Professor of Medicine
1. Emerging Infections 2. Global Health 3. Epidemiology of infectious diseases
4. Clinical microbiology and diagnostics 5. Bioterrorism Preparedness 6. Surveillance
for communicable diseases 7. Antimicrobial resistance
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