JRA (also known as JIA) includes the commonest chronic autoimmune arthropathies of childhood. The MHC is involved with respect to risk, either susceptibility or protection in a subtype specific manner with strong gender bias' and differences between ethnicities. Multiple MHC effects have been shown, especially in the commonest subtype, so called early onset pauciarticular JRA (Persistent Oligo in the JIA terminology) with three or more MHC regions believed to interact in generating susceptibility. An additional feature of the disease, unlike some other forms of autoimmunity, is the relative absence of common extended or ancestral haplotypes, especially those carrying HLA-DR4 and HLA-DR7 both of which are protective. The three regions include a class I region, or an area telomeric to it, and two class II regions those around HLA DR/DQ and HLA-DP. None of the regions involved are well defined nor were the specific genes involved identified. The alleles marking these regions (HLA-DR8, 11 and HLA-DPB1*0201) are atypical for autoimmunity. This is therefore an unusual MHC contribution to autoimmunity, the elucidation of which lends itself to high throughput technologies. The genetic features, although involving arthritis, are quite distinct from adult rheumatoid arthritis except for about 5% of older children. It is proposed to construct high throughput SNP maps in a family based study. Subtypes have different MHC profiles and in the rarest and most severe form of disease, systemic onset JRA, the MHC effect is rather minimal. In this form, preliminary data involving KIR gene haplotypes is available. Pursuing these KIR gene observations is proposed. The ability to leverage ongoing pheontyping and family based sample collection ensures a large and continuously growing pool of available DMAs for this project. Some of the patients will also have extensive gene expression studies allowing a comprehensive approach to the MHC and KIR genes in JRA and its subtypes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI067150-03
Application #
7236027
Study Section
Special Emphasis Panel (ZAI1-SV-I (M2))
Program Officer
Peyman, John A
Project Start
2005-09-30
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$406,200
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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
Faraco, Juliette; Lin, Ling; Kornum, Birgitte Rahbek et al. (2013) ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS Genet 9:e1003270
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
Thompson, Susan D; Barnes, Michael G; Griffin, Thomas A et al. (2010) Heterogeneity in juvenile idiopathic arthritis: impact of molecular profiling based on DNA polymorphism and gene expression patterns. Arthritis Rheum 62:2611-5
Barnes, Michael G; Grom, Alexei A; Thompson, Susan D et al. (2010) Biologic similarities based on age at onset in oligoarticular and polyarticular subtypes of juvenile idiopathic arthritis. Arthritis Rheum 62:3249-58
Barnes, Michael G; Grom, Alexei A; Griffin, Thomas A et al. (2010) Gene Expression Profiles from Peripheral Blood Mononuclear Cells Are Sensitive to Short Processing Delays. Biopreserv Biobank 8:153-162
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
Hollenbach, Jill A; Thompson, Susan D; Bugawan, Teodorica L et al. (2010) Juvenile idiopathic arthritis and HLA class I and class II interactions and age-at-onset effects. Arthritis Rheum 62:1781-91

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