ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2410

Genetic Architecture of Systemic Juvenile Idiopathic Arthritis Distinguishes It from Oligoarticular and Polyarticular Forms of Juvenile Idiopathic Arthritis

Michael J. Ombrello1, Victoria Arthur1, Elaine F. Remmers2, Anne Hinks3, Alexei Grom4, Dirk Föll5, Alberto Martini6, Marco Gattorno7, Seza Ozen8, Sampath Prahalad9, Andrew Zeft10, John F. Bohnsack11, Norman Ilowite12, Ricardo Russo13, Elizabeth D. Mellins14, Claudio A. Len15, Maria Odete E. Hilário16, Sheila Oliveira17, Rae S.M. Yeung18, Alan Rosenberg19, Lucy R. Wedderburn20, Jordi Anton21, Johannes Peter Haas22, Angela Rösen-Wolff23, Klaus Tenbrock24, Susan D Thompson25, Daniel L. Kastner26, Patricia Woo27, Wendy Thomson28 and International Childhood Arthritis Genetics (INCHARGE) Consortium, 1Translational Genetics and Genomics Unit, NIAMS, NIH, Bethesda, MD, 2National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 3ARC Epidemiology Unit, University of Manchester, Manchester, United Kingdom, 4Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 5University of Muenster, Muenster, Germany, 6Istituto Giannina Gaslini, Genoa, Italy, 7UO Pediatria 2, Istituto Giannina Gaslini, Genova, Italy, 8Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey, 9Pediatric Rheumatology, Emory University School of Medicine, Atlanta, GA, 10Pediatrics Rheumatology, Cleveland Clinic, Cleveland, OH, 11Division of Allergy, Immunology and Pediatric Rheumatology, University of Utah, Salt Lake City, UT, 12Rheumatology, Children's Hospital Montefiore, Bronx, NY, 13Hospital de Pediatria Garrahan, Buenos Aires, Argentina, 14Dept of Pediatrics CCSR, Stanford University Med Ctr, Stanford, CA, 15Pediatrics, Universidade Federal de São Paulo, São Paulo,, Brazil, 16Pediatric Rheumatology Collaborative Study Group (PRCSG), Cincinnati, OH, 17Pediatric Rheumatology, Universidade F Rio De Janeiro, Rio De Janeiro, Brazil, 18Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada, 19Pediatrics, Pediatrics, Saskatoon, SK, Canada, 20Institute of Child Health, UCL, London, United Kingdom, 21Unitat de Reumatologia Pediàtrica, Hospital Sant Joan de Déu, Barcelona, Spain, 22German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany, 23Children's Hospital Dresden, Dresden, Germany, 24University Aachen, Aachen, Germany, 25Division of Rheumatology, Cincinnati Children's Hospital, Cincinnati, OH, 26Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 27Great Ormond Street Hospital, University College London Medical School, London, United Kingdom, 28Arthritis Research UK Centre for Genetics and Genomics,The University of Manchester, Manchester, United Kingdom

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: , ,

Session Information

Date: Tuesday, November 15, 2016

Title: Pediatric Rheumatology – Pathogenesis and Genetics - Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:  JIA is a heterogeneous group of conditions that are unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA that is characterized by episodic systemic inflammation and chronic arthritis. Approximately half of children with sJIA go on to develop destructive, life-long arthritis that has phenotypic similarities with the oligoarticular / RF negative polyarticular (polygo) or RF positive polyarticular (RF+poly) forms of JIA. Therapies effective in treating other forms of JIA are much less effective in sJIA, particularly among patients with persistent arthritis. Investigating the genetic architecture of sJIA and comparing it with other forms of JIA may improve our understanding of these differences. However because of its rare nature, genomic studies of sJIA have been limited, providing few insights into its pathophysiology. Therefore we sought to identify genetic factors that influence sJIA pathogenesis and to compare the genetic architecture of sJIA with the other common forms of JIA.

Methods:  We performed a genome-wide association study of 982 children with sJIA from 9 countries. Following stringent quality control procedures, over 6 million single nucleotide polymorphisms (SNPs) were tested for association with sJIA by logistic regression in 9 geographically-defined strata and association results were meta-analyzed. Weighted genetic risk scores (wGRS) based on established genetic risk factors for polygo or RF+poly JIA were calculated and wGRS were compared between sJIA cases and healthy controls using the Wilcoxon Rank Sum test. The correlation of wGRS with sJIA was tested by both logistic regression and by analysis of receiver operating characteristic (ROC) curves with calculation of the area under the curve. Quantile-quantile (QQ) plots were used to determine whether sJIA-associated SNPs were enriched within the set of polygo-associated SNPs from the Immunochip study by Hinks and colleagues.

Results:  The HLA locus and a second locus on chromosome 1 both showed association with sJIA that exceeded the threshold for genome-wide significance (p<5E-8), and 23 additional loci had evidence suggestive of association with sJIA (p<5E-6). There was virtually no overlap between the sJIA susceptibility loci and the known risk loci for other forms of JIA. ROC curve analysis and logistic regression of wGRS found no correlation between sJIA and either polygo or RF+poly JIA. QQ plots showed no evidence for enrichment of sJIA associations among polygo-associated SNPs. Collectively, we found no evidence of shared genetic architecture between sJIA and either polygo or RF+poly JIA.

Conclusion: sJIA has a distinct genetic architecture without evidence of shared genetic risk factors with other common JIA subtypes. This indicates that sJIA is unique in its pathophysiology, relative to the other JIA subtypes. As such, sJIA must be investigated separately from the other JIA subtypes to identify mechanisms and therapeutic targets specific to sJIA. Moreover, the management of children with sJIA should be directed by studies of sJIA, and not by trials or observations of other subtypes of JIA.

Disclosure: M. J. Ombrello, None; V. Arthur, None; E. F. Remmers, None; A. Hinks, None; A. Grom, Novartis Pharmaceutical Corporation, 5,novimmune, 5; D. Föll, None; A. Martini, Abbott, Abbvie, Amgen, Baxalta Biosimilars, Biogenidec, Bristol Meyers Squibb, Astellas, Boehringer, Italfarmaco, Janssen, MedImmune, Novartis, NovoNordisk, Pfizer, Sanofi, Roche, Servier, Takeda, UCB Biosciences, GmbH, 8,Abbott, Bristol Meyers Squibb, Francesco Angelini S.P.A., Glaxo Smith Kline, Janssen Biotech Inc., Novartis, Pfizer, Roche, Sanofi, Aventis, Schwarz Biosciences GmbH, 2; M. Gattorno, Novartis, SOBI, 2,Novartis, SOBI, 5,Novartis, SOBI, 8; S. Ozen, None; S. Prahalad, Novartis, 5,Medac pharma, 5; A. Zeft, Merck Pharmaceuticals, 1,OPKO, 1,ARNI, 1; J. F. Bohnsack, None; N. Ilowite, SOBI, 5,Novartis Pharmaceutical Corporation, 5; R. Russo, None; E. D. Mellins, None; C. A. Len, None; M. O. E. Hilário, None; S. Oliveira, None; R. S. M. Yeung, Novartis, 2; A. Rosenberg, None; L. R. Wedderburn, None; J. Anton, None; J. P. Haas, None; A. Rösen-Wolff, None; K. Tenbrock, None; S. D. Thompson, None; D. L. Kastner, None; P. Woo, None; W. Thomson, None.

To cite this abstract in AMA style:

Ombrello MJ, Arthur V, Remmers EF, Hinks A, Grom A, Föll D, Martini A, Gattorno M, Ozen S, Prahalad S, Zeft A, Bohnsack JF, Ilowite N, Russo R, Mellins ED, Len CA, Hilário MOE, Oliveira S, Yeung RSM, Rosenberg A, Wedderburn LR, Anton J, Haas JP, Rösen-Wolff A, Tenbrock K, Thompson SD, Kastner DL, Woo P, Thomson W. Genetic Architecture of Systemic Juvenile Idiopathic Arthritis Distinguishes It from Oligoarticular and Polyarticular Forms of Juvenile Idiopathic Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/genetic-architecture-of-systemic-juvenile-idiopathic-arthritis-distinguishes-it-from-oligoarticular-and-polyarticular-forms-of-juvenile-idiopathic-arthritis/. Accessed .

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