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.


Discovery and Replication of JIA Predisposition Genes by Genome-Wide Association and Validation of Candidates in Fibroblast-Like Synoviocytes.

Finkel9,  Terri H., Zhang1,  Haitao, Lie10,  Benedicte A., Behrens3,  Edward M., Becker2,  Mara L., Wise6,  Carol, Punaro7,  Marilynn

Center for Applied Genomics, The Children's Hospital of Philadelphia
Institute of Immunology, Oslo University Hospital, Rikshospitalet, Norway
Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia
Children's Mercy Hospital, Kansas City, MO
Childrens Hospital of Phil, Philadelphia, PA
Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Norway
Division of Genetics, The Children's Hospital of Philadelphia, University of Pennsylvania
Division of Medical Genetics, Texas Scottish Rite Hospital for Children
Division of Rheumatology, Texas Scottish Rite Hospital for Children
Division of Rheumatology, The Children's Hospital of Philadelphia Research Institute
Division of Rheumatology, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA

Purpose:

Juvenile Idiopathic Arthritis (JIA) is the #1 cause of acquired disability in children. We recently identified TRAF1-C5 as a genetic locus associated with JIA, and have undertaken a comprehensive translational approach to elucidate its genetic contribution to this disease. Here, we identify single nucleotide polymorphisms (SNPs) associated with JIA by a genome-wide association (GWA) screen of a large well-phenotyped patient cohort. We validate expression of GW significant candidates in B cells and in synovial lining cells (human fibroblast-like synoviocytes, HFLS), the tissue targeted by inflammatory arthritis. HFLS provide a readily available and renewable source of patient-derived tissues to examine JIA risk alleles/genotypes and screen drugs that might alter the risk phenotype.

Method:

We use a GWA approach to identify risk alleles that associate with JIA in a discovery cohort of 1500 cases (diagnosed by revised ILAR criteria) recruited from greater Philadelphia and internationally (Stage 1). In Stage 2, we genotype an additional 1000 existing samples from well-phenotyped JIA cases recruited by other collaborating sites. This database is leveraged against matched samples from >10,000 genotyped controls. In parallel studies, we study allele-specific gene expression in:

1) genotyped lymphoblastoid cell lines (LCLs) from HapMap-CEU population samples and 2) primary HFLS established from synovial fluid samples obtained from a subset of the >200 JIA patients undergoing arthrocentesis each year at Children's Hospital, obtained after informed consent.

Results:

We have completed full genome genotyping of 1166 JIA cases and 8793 matched healthy controls using the Illumina HumanHap610Q BeadChip to track 600,000 polymorphisms, and have demonstrated significant associations of JIA to MHC loci, and to the non-MHC loci, PTPN22, IL2RA, and ANTXR2, as previously reported in inflammatory arthritidies. We have also discovered GW significant associations within a locus encoding a novel chemokine receptor (CKR; discovery p-value = 4.32 × 10-11; odds ratio = 0.66), for which replication is pending. We have demonstrated allele-specific effects on gene expression for significantly associated loci by assaying total RNA in genotyped LCLs from HapMap-CEU population samples, comparing individuals homozygous for risk vs. non-risk genotypes, and in primary HFLS established from JIA synovial fluid samples, analyzing allele-specific changes for our most significantly associated SNPs.

Conclusion:

PTPN22, IL2RA, ANTXR2, and a novel CKR are associated with all forms of JIA, thereby potentially functioning as "master switches" predisposing to arthritis. The functional role of these genes is assessed for the first time in the disease-target tissue, HFLS, from children with JIA. HFLS are quiescent synovial lining cells that become highly proliferative and invasive in arthritis, and provide us with a renewable, druggable source of patient-derived cell types/tissues expressing our gene(s) of interest.

To cite this abstract, please use the following information:
Finkel, Terri H., Zhang, Haitao, Lie, Benedicte A., Behrens, Edward M., Becker, Mara L., Wise, Carol, et al; Discovery and Replication of JIA Predisposition Genes by Genome-Wide Association and Validation of Candidates in Fibroblast-Like Synoviocytes. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2219
DOI: 10.1002/art.29983

Abstract Supplement

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2010 ACR/ARHP