title: Genomic profiles and predictors of early allograft dysfunction after human liver transplantation.
abstract: Early hepatic allograft dysfunction (EAD) manifests posttransplantation with high serum transaminases, persistent cholestasis, and coagulopathy. The biological mechanisms are poorly understood. This study investigates the molecular mechanisms involved in EAD and defines a gene expression signature revealing different biological pathways in subjects with EAD from those without EAD, a potential first step in developing a molecular classifier as a potential clinical diagnostic. Global gene expression profiles of 30 liver transplant recipients of deceased donor grafts with EAD and 26 recipients without graft dysfunction were investigated using microarrays of liver biopsies performed at the end of cold storage and after graft reperfusion prior to closure. Results reveal a shift in inflammatory and metabolic responses between the two time points and differences between EAD and non-EAD. We identified relevant pathways (PPARα and NF-κB) and targets (such as CXCL1, IL1, TRAF6, TIPARP, and TNFRSF1B) associated with the phenotype of EAD. Preliminary proof of concept gene expression classifiers that distinguish EAD from non-EAD patients, with Area Under the Curve (AUC) >0.80 were also identified. This data may have mechanistic and diagnostic implications for EAD.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: S M
authors.initials: SM
authors.lastname: Kurian
authors.affiliation: Penn Transplant Institute, Department of Surgery, University of Pennsylvania, Philadelphia, PA.|Department of Surgery and Laboratory of Experimental Transplantation and Intestinal Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: S M G
authors.initials: SM
authors.lastname: Fouraschen
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, CA.
authors.forename: P
authors.initials: P
authors.lastname: Langfelder
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, CA.
authors.forename: S
authors.initials: S
authors.lastname: Horvath
authors.affiliation: Penn Transplant Institute, Department of Surgery, University of Pennsylvania, Philadelphia, PA.
authors.forename: A
authors.initials: A
authors.lastname: Shaked
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: D R
authors.initials: DR
authors.lastname: Salomon
authors.affiliation: Penn Transplant Institute, Department of Surgery, University of Pennsylvania, Philadelphia, PA.
authors.forename: K M
authors.initials: KM
authors.lastname: Olthoff
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts; D001706:Biopsy; D005260:Female; D005820:Genetic Testing; D006084:Graft Rejection / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics; D047493:PPAR alpha / Q000235:genetics; D014019:Tissue Donors; D014158:Transcription, Genetic / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*; D066027:Transplant Recipients
chemical_list: D016328:NF-kappa B; D047493:PPAR alpha
keywords: genomics; liver disease; liver transplantation; living donor