title: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.
authors.affiliation: Emergency Medicine Service, Durham Veterans Affairs Medical Center, Durham, North Carolina 27705 USA ; Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA.
authors.forename: Ephraim L
authors.initials: EL
authors.lastname: Tsalik
authors.affiliation: National Center for Genome Resources, Santa Fe, NM 87505 USA ; Department of Immunology, Lovelace Respiratory Research Institute, Albuquerque, NM 87108 USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Langley
authors.affiliation: 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.
authors.forename: Darrell L
authors.initials: DL
authors.lastname: Dinwiddie
authors.affiliation: National Center for Genome Resources, Santa Fe, NM 87505 USA ; Center for Pediatric Genomic Medicine, Children's Mercy Hospitals and Clinic, Kansas City, MO 64108 USA.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Miller
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospitals and Clinic, Kansas City, MO 64108 USA.
authors.forename: Byunggil
authors.initials: B
authors.lastname: Yoo
authors.affiliation: National Center for Genome Resources, Santa Fe, NM 87505 USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: van Velkinburgh
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospitals and Clinic, Kansas City, MO 64108 USA.
authors.forename: Laurie D
authors.initials: LD
authors.lastname: Smith
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospitals and Clinic, Kansas City, MO 64108 USA.
authors.forename: Isabella
authors.initials: I
authors.lastname: Thiffault
authors.affiliation: Department of Emergency Medicine, Henry Ford Hospital, Detroit, Michigan 48202 USA.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Jaehne
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA.
authors.forename: Ashlee M
authors.initials: AM
authors.lastname: Valente
authors.affiliation: Department of Electrical & Computer Engineering, Duke University, Durham, NC 27710 USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Henao
authors.affiliation: Department of Electrical & Computer Engineering, Duke University, Durham, NC 27710 USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599 USA.
authors.forename: Seth W
authors.initials: SW
authors.lastname: Glickman
authors.affiliation: National Center for Genome Resources, Santa Fe, NM 87505 USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Rice
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA ; Medicine Service, Durham Veterans Affairs Medical Center, Durham, NC 27705 USA.
authors.forename: Micah T
authors.initials: MT
authors.lastname: McClain
authors.affiliation: Department of Electrical & Computer Engineering, Duke University, Durham, NC 27710 USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Carin
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA ; Medicine Service, Durham Veterans Affairs Medical Center, Durham, NC 27705 USA.
authors.forename: G Ralph
authors.initials: GR
authors.lastname: Corey
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Ginsburg
authors.affiliation: Department of Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599 USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Cairns
authors.affiliation: Department of Emergency Medicine, Henry Ford Hospital, Detroit, Michigan 48202 USA ; Department of Emergency Medicine, University of Michigan, Ann Arbor, MI 48109 USA.
authors.forename: Ronny M
authors.initials: RM
authors.lastname: Otero
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA.
authors.forename: Vance G
authors.initials: VG
authors.lastname: Fowler
authors.affiliation: Department of Emergency Medicine, Henry Ford Hospital, Detroit, Michigan 48202 USA.
authors.forename: Emanuel P
authors.initials: EP
authors.lastname: Rivers
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA ; Medicine Service, Durham Veterans Affairs Medical Center, Durham, NC 27705 USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Woods
authors.affiliation: 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.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore