Whole blood genomic biomarkers of acute cardiac allograft rejection.
BACKGROUND
Significant progress has been made in cardiac transplantation over the past 30 years; however, the means for detection of acute cardiac allograft rejection remains in need of improvement. At present, the endomyocardial biopsy, an invasive and inconvenient procedure for patients, is required for the surveillance and diagnosis of acute cardiac allograft rejection. In the Biomarkers in Transplantation initiative, we investigated gene expression profiles in peripheral blood of cardiac transplant subjects as potential biomarkers for diagnosis of allograft rejection.


METHODS
Whole blood samples were obtained from 28 cardiac transplant subjects who consented to the study. Serial samples were collected from pre-transplant through 3 years post-transplant according to the standard protocol. Temporally correspondent biopsies were also collected, reviewed in a blinded manner, and graded according to current ISHLT guidelines. Blood samples were analyzed using Affymetrix microarrays. Genomic profiles were compared in subjects with acute rejection (AR; ISHLT Grade > or =2R) and no rejection (NR; Grade 0R). Biomarker panel genes were identified using linear discriminant analysis.


RESULTS
We found 1,295 differentially expressed probe-sets between AR and NR samples and developed a 12-gene biomarker panel that classifies our internal validation samples with 83% sensitivity and 100% specificity.


CONCLUSIONS
Based on our current results, we believe whole blood genomic biomarkers hold great potential in the diagnosis of acute cardiac allograft rejection. A prospective, Canada-wide trial will be conducted shortly to further evaluate the classifier panel in diverse patients and a range of clinical programs.
Lin
David
D
Department of Pathology and Laboratory Medicine, St. Paul's Hospital-University of British Columbia, Vancouver, British Columbia, Canada.
Hollander
Zsuzsanna
Z
Ng
Raymond T
RT
Imai
Carol
C
Ignaszewski
Andrew
A
Balshaw
Robert
R
Freue
Gabriela Cohen
GC
Wilson-McManus
Janet E
JE
Qasimi
Pooran
P
Meredith
Anna
A
Mui
Alice
A
Triche
Tim
T
McMaster
Robert
R
Keown
Paul A
PA
McManus
Bruce M
BM
D000208:Acute Disease; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000097:blood / Q000627:therapeutic use; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D006084:Graft Rejection / Q000097:blood*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D016559:Tacrolimus / Q000097:blood / Q000627:therapeutic use
D005819:Genetic Markers; D007166:Immunosuppressive Agents; D012313:RNA; D016572:Cyclosporine; D016559:Tacrolimus