Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: Clinical and therapeutic implications

Michael J. Ombrello, Victoria L. Arthur, Elaine F. Remmers, Anne Hinks, Ioanna Tachmazidou, Alexei A. Grom, Dirk Foell, Alberto Martini, Marco Gattorno, Seza Özen, Sampath Prahalad, Andrew S. Zeft, John F. Bohnsack, Norman T. Ilowite, Elizabeth D. Mellins, Ricardo Russo, Claudio Len, Maria Odete E. Hilario, Sheila Oliveira, Rae S.M. YeungAlan M. Rosenberg, Lucy R. Wedderburn, Jordi Anton, Johannes Peter Haas, Angela Rosen-Wolff, Kirsten Minden, Klaus Tenbrock, Erkan Demirkaya, Joanna Cobb, Elizabeth Baskin, Sara Signa, Emily Shuldiner, Richard H. Duerr, Jean Paul Achkar, M. Ilyas Kamboh, Kenneth M. Kaufman, Leah C. Kottyan, Dalila Pinto, Stephen W. Scherer, Marta E. Alarcón-Riquelme, Elisa Docampo, Xavier Estivill, Ahmet Gül, Carl D. Langefeld, Susan Thompson, Eleftheria Zeggini, Daniel L. Kastner, Patricia Woo, Wendy Thomson

Research output: Contribution to journalArticle

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Abstract

Objectives Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. Methods We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. Results The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. Conclusions The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.

Original languageEnglish (US)
Article number210324
JournalAnnals of the Rheumatic Diseases
Volume76
Issue number5
DOIs
StatePublished - May 1 2017

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Keywords

  • Adult Onset Still's Disease
  • Gene Polymorphism
  • Juvenile Idiopathic Arthritis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ombrello, M. J., Arthur, V. L., Remmers, E. F., Hinks, A., Tachmazidou, I., Grom, A. A., Foell, D., Martini, A., Gattorno, M., Özen, S., Prahalad, S., Zeft, A. S., Bohnsack, J. F., Ilowite, N. T., Mellins, E. D., Russo, R., Len, C., Hilario, M. O. E., Oliveira, S., ... Thomson, W. (2017). Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: Clinical and therapeutic implications. Annals of the Rheumatic Diseases, 76(5), [210324]. https://doi.org/10.1136/annrheumdis-2016-210324