This Program Project renewal seeks to build upon the success of the first cycle, where many exciting discoveries were made regarding gene expression in peripheral blood of children with Juvenile Idiopathic Arthritis (JIA). This proposal takes advantage of significant investments made in the first cycle that produced valuable resources for further studies, including a large gene expression dataset, a substantial collection of biological samples (DNA, RNA, whole blood for RNA, peripheral blood mononuclear cells (PBMC) for RNA, plasma, and serum), and a well-developed infrastructure for sample collection and analysis. Among the most important findings of the first cycle was identification of gene expression """"""""signatures"""""""" that indicated heterogeneity among and within several JIA subtypes. These signatures may not only contribute to redefining JIA categories by offering molecular phenotypes, but also may provide insight into fundamental pathobiological processes in JIA, with potential implications for differential responses to treatments, and novel links to understanding genetic susceptibility to JIA. For example, a """"""""T Cell Signature"""""""" expressed in many older polyarticular JIA patients appears to predict inadequate responses to methotrexate, and it is also associated with increased expression of putative JIA susceptibility loci. The four projects proposed in this renewal synergistically approach important questions regarding gene expression in JIA that have been raised by findings in the first cycle;leveraging data, samples and infrastructure developed in the first cycle. In Project 1, Dr. Griffin will investigate cellular pathobiology associated with three gene expression signatures identified in polyarticular and oligoarticular JIA. In Project 2, Dr. Lovell will investigate the relationship of these signatures with clinical responses to methotrexate and anti-TNF biologies, as well as determine if PBMC gene expression profiling can help guide withdrawal of anti-TNF agents from patients in remission on medication. In Project 3, Dr. Thompson will investigate genetic susceptibility loci that have remarkable connections to gene expression differences in JIA. In Project 4, Dr. Grom will use gene expression profiling to study pathobiology of monomyelocytoid cells in systemic-onset JIA. All four projects will be supported by Administrative (Dr. Glass), Tissue (Dr. Thompson), and Informatics (Dr. Wagner) Cores that will facilitate efficient and effective use of resources. Gene expression profiling offers a molecular approach for advancing knowledge of pathobiology, clinical outcomes and genetic associations in JIA, with discoveries made in this Program Project having the potential to dramatically improve diagnosis and management of JIA.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAR1-HL (M2))
Program Officer
Wang, Yan Z
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Langefeld, Carl D; Ainsworth, Hannah C; Cunninghame Graham, Deborah S et al. (2017) Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun 8:16021
McIntosh, Laura A; Marion, Miranda C; Sudman, Marc et al. (2017) Genome-Wide Association Meta-Analysis Reveals Novel Juvenile Idiopathic Arthritis Susceptibility Loci. Arthritis Rheumatol 69:2222-2232
Hinks, A; Bowes, J; Cobb, J et al. (2017) Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. Ann Rheum Dis 76:765-772
Ombrello, Michael J; Arthur, Victoria L; Remmers, Elaine F et al. (2017) Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications. Ann Rheum Dis 76:906-913
Schulert, Grant S; Fall, Ndate; Harley, John B et al. (2016) Monocyte MicroRNA Expression in Active Systemic Juvenile Idiopathic Arthritis Implicates MicroRNA-125a-5p in Polarized Monocyte Phenotypes. Arthritis Rheumatol 68:2300-13
Prahalad, Sampath; McCracken, Courtney E; Ponder, Lori A et al. (2016) Familial autoimmunity in the Childhood Arthritis and Rheumatology Research Alliance registry. Pediatr Rheumatol Online J 14:14
Grom, Alexei A; Horne, AnnaCarin; De Benedetti, Fabrizio (2016) Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol 12:259-68
Clement, Cristina C; Moncrieffe, Halima; Lele, Aditi et al. (2016) Autoimmune response to transthyretin in juvenile idiopathic arthritis. JCI Insight 1:
Liu, Ke; Kurien, Biji T; Zimmerman, Sarah L et al. (2016) X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. Arthritis Rheumatol 68:1290-1300
Schulert, Grant S; Bove, Kevin; McMasters, Richard et al. (2015) 11-Month-Old Infant With Periodic Fevers, Recurrent Liver Dysfunction, and Perforin Gene Polymorphism. Arthritis Care Res (Hoboken) 67:1173-9

Showing the most recent 10 out of 50 publications