Molecular patterns in human ulcerative colitis and correlation with response to infliximab.
BACKGROUND
As a T cell-mediated disease of the colonic epithelium, ulcerative colitis (UC) is likely to share pathogenic elements with other T cell-mediated inflammatory diseases. Recently, microarray analysis revealed large-scale molecular changes in T cell-mediated rejection of kidney and heart transplants. We hypothesized that similar disturbances might be operating in UC and could provide insights into responsiveness to therapy.


METHODS
We studied 56 colon biopsies from patients with colitis characterizing the clinical and histological features and using microarrays to define the messenger RNA phenotype. We expressed the microarray results using previously defined pathogenesis-based transcript sets. We also studied 48 published microarray files from human colon biopsies downloaded from the Gene Expression Omnibus database, classified by response to infliximab therapy, to examine whether the molecular measurements derived from our studies correlated with nonresponsiveness to treatment.


RESULTS
UC biopsies manifested coordinate transcript changes resembling rejecting transplants, with effector T cell, IFNG-induced, macrophage, and injury transcripts increasing while parenchymal transcripts decreased. The disturbance in gene expression, summarized as principal component 1 (PC1), correlated with conventional clinical and histologic assessments. When assessed in microarray results from published studies, the disturbance (PC1) predicted response to infliximab: patients with intense disturbance did not achieve clinical response, although quantitative improvement was seen even in many clinical nonresponders. Similar changes were seen in Crohn's colitis.


CONCLUSIONS
The molecular phenotype of UC manifests a large-scale coordinate disturbance reflecting changes in inflammatory cells and parenchymal elements that correlates with conventional features and predicts response to infliximab.
*Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada; †F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California; ‡Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada; §Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada; and ‖Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
Brendan
B
Halloran
Jessica
J
Chang
David Q
DQ
Shih
Dermot
D
McGovern
Konrad
K
Famulski
Chad
C
Evaschesen
Richard N
RN
Fedorak
Aducio
A
Thiesen
Stephan
S
Targan
Philip F
PF
Halloran
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism*; D002648:Child; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000139:chemically induced / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D055815:Young Adult
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D005765:Gastrointestinal Agents; D012333:RNA, Messenger; D000069285:Infliximab