An integrated transcriptome and expressed variant analysis of sepsis survival and death
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- 作者：Ephraim L Tsalik (1) (2)
Raymond J Langley (3) (4)
Darrell L Dinwiddie (3) (5)
Neil A Miller (3) (6)
Byunggil Yoo (6)
Jennifer C van Velkinburgh (3)
Laurie D Smith (6)
Isabella Thiffault (6)
Anja K Jaehne (7)
Ashlee M Valente (2)
Ricardo Henao (8)
Xin Yuan (8)
Seth W Glickman (9)
Brandon J Rice (3)
Micah T McClain (10) (2)
Lawrence Carin (8)
G Ralph Corey (10) (2)
Geoffrey S Ginsburg (2)
Charles B Cairns (9)
Ronny M Otero (11) (7)
Vance G Fowler Jr (2)
Emanuel P Rivers (7)
Christopher W Woods (10) (2)
Stephen F Kingsmore (3) (5)
1. Emergency Medicine Service ; Durham Veterans Affairs Medical Center ; Durham ; North Carolina ; 27705 ; USA
2. Department of Medicine ; Duke University Medical Center ; Durham ; NC ; 27710 ; USA
3. National Center for Genome Resources ; Santa Fe ; NM ; 87505 ; USA
4. Department of Immunology ; Lovelace Respiratory Research Institute ; Albuquerque ; NM ; 87108 ; USA
5. Department of Pediatrics ; Center for Translational Sciences ; University of New Mexico ; Albuquerque ; NM ; 87131 ; USA
6. Center for Pediatric Genomic Medicine ; Children鈥檚 Mercy Hospitals and Clinic ; Kansas City ; MO ; 64108 ; USA
7. Department of Emergency Medicine ; Henry Ford Hospital ; Detroit ; Michigan ; 48202 ; USA
8. Department of Electrical & Computer Engineering ; Duke University ; Durham ; NC ; 27710 ; USA
9. Department of Emergency Medicine ; University of North Carolina School of Medicine ; Chapel Hill ; NC ; 27599 ; USA
10. Medicine Service ; Durham Veterans Affairs Medical Center ; Durham ; NC ; 27705 ; USA
11. Department of Emergency Medicine ; University of Michigan ; Ann Arbor ; MI ; 48109 ; USA - 刊名：Genome Medicine
- 出版年：2014
- 出版时间：November 2014
- 年：2014
- 卷：6
- 期：11
- 全文大小：949 KB
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- 出版者：BioMed Central
- ISSN：1756-994X
文摘
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.
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