title: Early transcriptional programming links progression to hepatitis C virus-induced severe liver disease in transplant patients.
abstract: Liver failure resulting from chronic hepatitis C virus (HCV) infection is a major cause for liver transplantation worldwide. Recurrent infection of the graft is universal in HCV patients after transplant and results in a rapid progression to severe fibrosis and end-stage liver disease in one third of all patients. No single clinical variable, or combination thereof, has, so far, proven accurate in identifying patients at risk of hepatic decompensation in the transplant setting. A combination of longitudinal, dimensionality reduction and categorical analysis of the transcriptome from 111 liver biopsy specimens taken from 57 HCV-infected patients over time identified a molecular signature of gene expression of patients at risk of developing severe fibrosis. Significantly, alterations in gene expression occur before histologic evidence of liver disease progression, suggesting that events that occur during the acute phase of infection influence patient outcome. Additionally, a common precursor state for different severe clinical outcomes was identified.
  
  
  CONCLUSIONS
  Based on this patient cohort, incidence of severe liver disease is a process initiated early during HCV infection of the donor organ. The probable cellular network at the basis of the initial transition to severe liver disease was identified and characterized.
authors.affiliation: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Rasmussen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tchitchek
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Susnow
authors.forename: Alexei L
authors.initials: AL
authors.lastname: Krasnoselsky
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Diamond
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: Sean C
authors.initials: SC
authors.lastname: Proll
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Korth
authors.forename: Kathie-Anne
authors.initials: KA
authors.lastname: Walters
authors.forename: Sharon
authors.initials: S
authors.lastname: Lederer
authors.forename: Anne M
authors.initials: AM
authors.lastname: Larson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Carithers
authors.forename: Arndt
authors.initials: A
authors.lastname: Benecke
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
mesh_terms: D000368:Aged; D001707:Biopsy, Needle; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000235:genetics*; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D017093:Liver Failure / Q000209:etiology / Q000235:genetics / Q000601:surgery*; D016031:Liver Transplantation / Q000009:adverse effects* / Q000379:methods; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000235:genetics / Q000503:physiopathology; D011379:Prognosis; D012008:Recurrence; D018570:Risk Assessment; D012720:Severity of Illness Index; D014019:Tissue Donors; D015533:Transcriptional Activation / Q000235:genetics*