Juvenile idiopathic arthrifis (JIA) is the most common rheumatic disease of childhood and constitutes a heterogeneous group of pediatric arthropathies that range from mild and self-limited to severe and disabling. The etiology of JIA is complex and includes genetic factors. Our recent genome-wide association study (GWAS) in JIA identified single nucleotide polymorphisms (SNPs) as risk factors for development of disease. These included SNPs in genes that are associated with other autoimmune diseases, as well as SNPs in genes uniquely associated with JIA. Two genes strongly implicated as risk factors have plausible functions in disease that are supported by our gene expression data. Specifically, JMJD1C is a histone demethylase that may be involved in transcripfional programming and determining cell fate, and PTPN2 is a key regulator of immune cell signaling including regulation of JAK-STAT pathways. In the first cycle of the Program Project, analysis of peripheral blood mononuclear cell (PBMC) samples in patients prior to the start of methotrexate (MTX), demonstrated that transcripts for both PTPN2 and JMJD1C were expressed in greater amounts in patients who subsequentiy did not respond to MTX compared to those who did respond Furthermore, increased expression of both genes was associated with a PBMC T Cell Signature that was associated with persistently active disease and will be studied in Project 1. In fact, JMJD1C was one of the 50 genes that defined this T Cell Signature. Based on these findings, we hypothesize that genetic variability in PTPN2 and/or JMJD1C is important to both JIA susceptibility and clinical variability in treatment response Following from this, an overiap is predicted between the biological pathways influenced by effective drugs and pathways that influence disease risk. The gene expression datasets available in this Program Project place us in a particularly powerful position to evaluate relationships between genetic variants and gene expression signatures. We will focus on PTPN2 and JMJD1C as two key players, potentially risk factors for disease (or sub-phenotype) and predictors of outcomes. We propose to first catalogue genefic variation in both the JMJD1C and PTPN2 regions using re-sequencing and fine mapping approaches. Next, we will utilize the gene expression datasets being developed within the Program Project to complete an integrative analysis of genotype and gene expression data. Finally, we will evaluate risk-altering variants relative to differential splicing, histone methylation (JMJD1C), and STAT1 phosphorylation {PTPN2). Our long-term objective is to understand the molecular basis for JIA in a way that reduces heterogeneity and informs the development of DNA tests that guide treatment choices in JIA.

Public Health Relevance

We have identified two genes that we believe are key players as risk factors for juvenile arthritis and predictors of response to treatment or disease outcome. In this project, we will evaluate DNA sequence variation within these genes and relate it to patterns of gene expression in blood cells. We look for differences between patients and controls and difference between patients who respond to treatment and those who do not respond. Understanding how the variation in these two genes relates to disease and response to treatment may sen/e to identify DNA markers to guide treatment.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZAR1-HL)
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Cincinnati Children's Hospital Medical Center
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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
Clement, Cristina C; Moncrieffe, Halima; Lele, Aditi et al. (2016) Autoimmune response to transthyretin in juvenile idiopathic arthritis. JCI Insight 1:
Lu, Rufei; Munroe, Melissa E; Guthridge, Joel M et al. (2016) Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies. J Autoimmun 74:182-193
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 68:1290-300
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
Cutler, David J; Zwick, Michael E; Okou, David T et al. (2015) Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping. PLoS One 10:e0128074
Schulert, Grant S; Grom, Alexei A (2015) Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies. Annu Rev Med 66:145-59
Schulert, Grant S; Grom, Alexei A (2014) Macrophage activation syndrome and cytokine-directed therapies. Best Pract Res Clin Rheumatol 28:277-92
Moncrieffe, Halima; Prahalad, Sampath; Thompson, Susan D (2014) Genetics of juvenile idiopathic arthritis: new tools bring new approaches. Curr Opin Rheumatol 26:579-84

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