Juvenile rheumatoid arthritis (JRA) is one of the most common chronic conditions of children affecting approximately 50,000 children in the U.S. The etiology and pathogenesis of JRA is complex, though there is clearly a genetic component. Associations between the genes of the major histocompatibility complex and susceptibility to JRA are well established, though identification of causal genetic variants, much less translation to improve clinical practice has not been forthcoming. Over the last decade, direct and indirect evidence has pointed to a role of activated T-cells, particularly of the Th1 phenotype in the pathogenesis of JRA. The goal of this project is to determine whether genetic variation in genes encoding T-cell regulatory molecules contributes to variation in JRA susceptibility, pathogenesis and treatment outcome. This will be accomplished via two specific aims. 1. Analyze genetic diversity in genes encoding ligand-receptor pairs involved in T-cell regulation. 2. Test for association and linkage between the genetic variants identified and susceptibility to JRA and or/variable expressivity of JRA. These studies will be conducted using 3 different cohorts representing the largest collection of JRA patients in the U.S.: (1)140 sibpairs with JRA (2) 500 singletons with JRA and their parents and (3) cases newly ascertained from a registry of more than 650 JRA patients living in the Intermountain West. A five year mentored program is proposed that will incorporate both didactic and research training and will be guided by two established scientists at the University of Utah. Through a NIH funded K30 award, the University of Utah General Clinical Research Center provides a unique didactic program of training in clinical research focused on the inherited basis of human disease. This program incorporates access to resources such as multi-user core facilities, large research centers at the University, and a designated unit in the University Hospital, with specific mentored intensive research experience for maturing clinical investigators. Thus, the University of Utah provides an ideal environment for maximizing the potential of this study and this applicant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AR050177-02
Application #
6938496
Study Section
Special Emphasis Panel (ZAR1-RJB-F (J1))
Program Officer
Serrate-Sztein, Susana
Project Start
2004-09-01
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$134,730
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Hinks, Anne; Marion, Miranda C; Cobb, Joanna et al. (2018) Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis. Arthritis Rheumatol 70:957-962
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
Hinks, Anne; Cobb, Joanna; Marion, Miranda C et al. (2013) Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet 45:664-9
Prahalad, Sampath; Thompson, Susan D; Conneely, Karen N et al. (2012) Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope. Arthritis Rheum 64:925-30
Anaya, Juan-Manuel; Kim-Howard, Xana; Prahalad, Sampath et al. (2012) Evaluation of genetic association between an ITGAM non-synonymous SNP (rs1143679) and multiple autoimmune diseases. Autoimmun Rev 11:276-80
Hinks, Anne; Cobb, Joanna; Sudman, Marc et al. (2012) Investigation of rheumatoid arthritis susceptibility loci in juvenile idiopathic arthritis confirms high degree of overlap. Ann Rheum Dis 71:1117-21
Thompson, Susan D; Marion, Miranda C; Sudman, Marc et al. (2012) Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13. Arthritis Rheum 64:2781-91
Angeles-Han, Sheila; Prahalad, Sampath (2010) The genetics of juvenile idiopathic arthritis: what is new in 2010? Curr Rheumatol Rep 12:87-93
Prahalad, Sampath; Zeft, Andrew S; Pimentel, Richard et al. (2010) Quantification of the familial contribution to juvenile idiopathic arthritis. Arthritis Rheum 62:2525-9
Thompson, Susan D; Sudman, Marc; Ramos, Paula S et al. (2010) The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1. Arthritis Rheum 62:3265-76

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