title: Gene expression profiling distinguishes a molecular signature for grade 1B mild acute cellular rejection in cardiac allograft recipients.
abstract: BACKGROUND
  Gene expression profiling distinguishes the absence or presence of moderate to severe grades of acute cellular rejection in cardiac allograft recipients using a 20-gene classifier. We explored the hypothesis that the rejection classifier also differentiates various forms of mild rejection and we performed sub-analyses based on time post-transplant and confirmatory pathology interpretations.
  
  
  METHODS
  A post hoc analysis of 265 CARGO study patients and 714 clinical encounters focused on the correlation of rejection classifier-derived gene expression (GE) scores for blood samples accompanying endomyocardial biopsies. Biopsy grades assigned by a study center pathologist (center) were re-interpreted by three pathologists (panel) in a blinded manner.
  
  
  RESULTS
  Mean GE scores not only differentiated Grades >or=3A from Grade 0 (p < 0.00001, center or panel), but also from Grades 1A or 2 (p < 0.05, center or panel), based on mild rejection sub-groups defined by the ISHLT 1990 grading system. In contrast, mean GE scores for Grades 1B and >or=3A were indistinguishable, using either center or panel interpretation. Sub-group analyses of encounters from 2 to 6 months or >6 months post-transplant showed similar results for the classifier's ability to discriminate moderate to severe rejection from Grades 1A and 2 mild rejection, but indistinguishable mean GE scores for Grades >or=3A and the Grade 1B sub-group. Of the classifier's 11 informative genes, expression of MIR and WDR40 showed statistically significant increases for both Grade 1B and Grade >or=3A rejection, while expression of PDCD1 or SEMA7A showed similar directional patterns without achieving statistical significance.
  
  
  CONCLUSIONS
  These data demonstrate that GE scores discriminate moderate to severe rejection from Grades 1A and 2 mild rejection. However, a sub-group of mild rejection cases, defined as Grade 1B according to the 1990 grading system, share a molecular signature more consistent with moderate to severe rejection. The clinical relevance of these data remains to be defined.
authors: Department of Pediatrics (Cardiology), Stanford University, Stanford, California 94304, USA. danb@stanford.edu
authors: Daniel
authors: D
authors: Bernstein
authors: Gavin E
authors: GE
authors: Williams
authors: Howard
authors: H
authors: Eisen
authors: Seema
authors: S
authors: Mital
authors: Jay G
authors: JG
authors: Wohlgemuth
authors: Tod M
authors: TM
authors: Klingler
authors: Kenneth C
authors: KC
authors: Fang
authors: Mario C
authors: MC
authors: Deng
authors: Jon
authors: J
authors: Kobashigawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D015703:Antigens, CD / Q000097:blood / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000097:blood / Q000235:genetics; D001706:Biopsy; D005260:Female; D058851:GPI-Linked Proteins; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000145:classification* / Q000175:diagnosis / Q000235:genetics*; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor; D039961:Semaphorins / Q000097:blood / Q000235:genetics; D012720:Severity of Illness Index; D044767:Ubiquitin-Protein Ligases / Q000097:blood / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D058851:GPI-Linked Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C118753:SEMA7A protein, human; D039961:Semaphorins; C403126:MYLIP protein, human; D044767:Ubiquitin-Protein Ligases