Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
A Whole Blood Gene Expression Profile of Untreated Children with Polyarticular JIA Enrolled in the TREAT Trial.
Frank3, Mark Barton, Jiang2, Kaiyu, Chen2, Yanmin, Bebak3, Melissa, Wallace4, Carol A., Thompson1, Susan, Jarvis2, James N.
The Trial of Early Aggressive Therapy (TREAT) in Juvenile Idiopathic Arthritis is a once-in-a-generation, multi-institutional trial comparing methotrexate with etanercept + methotrexate + prednisone as initial treatments of polyarticular JIA. To maximize the scientific utility of this trial, biological samples have been collected for translational research to answer questions of high relevance to the field of pediatric rheumatology; these samples include whole blood preserved in stabilizers to perform gene expression profiling. We report here the first translational study to emerge from the TREAT trial, which will be completed in late October, 2010.
We received 45 samples from children with untreated polyarticular JIA at the time of their enrollment within the TREAT trial. All children were rheumatoid factor negative. Of these 45 samples, RNA was degraded in 11 and was insufficient for microarray analysis on another 5. Thus, microarray analysis was performed on 29 children entering the TREAT trial and 19 healthy control children. RNA purification, assessment of RNA purity and integrity, labeling, and hybridization were all undertaken using conventional methods. The Illumina microarray platform was used and conventional biocomputational approaches were taken to identifying differentially expressed genes.
130 genes distinguished TREAT baseline from control samples with a 5% false discovery rate and a minimum 1.5-fold difference between groups. These genes were largely subsumed into 5 large overlapping networks, demonstrating that pathological systems, like physiologic systems, demonstrate a property referred to by systems biologists as modularity. Gene networks also showed the hub-and-node structure (scale free systems) that we have previously described in the pathologic networks associated with childhood-onset rheumatic diseases. As is typical with gene array experiments, signaling molecules (JNK, Akt) and transcription factors (MYC, HNF4A, NFkB) represented prominent hubs in these networks. Small groups of genes regulated by type 1 and type 2 interferons and TGFB were also seen. A network of IL-243-regulated genes, not previously recognized on our earlier array studies, was down-regulated in untreated JIA patients. Hierarchical cluster analysis of the array data suggested that the JIA subjects could be divided into 2 dichotomous groups. As the TREAT study is still blinded, it is not possible at the present time to determine whether there is a specific phenotype associated with those clusters.
Whole blood gene expression profiling of untreated subjects from the TREAT trial demonstrates multiple gene networks that distinguish children with polyarticular JIA from healthy control children. The complexity of these gene networks demonstrates the challenge still facing us in understanding JIA at the cell and molecular level. At the same time, translational samples collected from the TREAT trial will allow us to understand how these networks change in response to therapy and provide unprecedented insight into the biology of therapeutic response.
To cite this abstract, please use the following information:
Frank, Mark Barton, Jiang, Kaiyu, Chen, Yanmin, Bebak, Melissa, Wallace, Carol A., Thompson, Susan, et al; A Whole Blood Gene Expression Profile of Untreated Children with Polyarticular JIA Enrolled in the TREAT Trial. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :243