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

• Authors: Michael J. Ombrello, National Institutes of Health; Victoria L. Arthur, National Institutes of Health; Elaine F. Remmers, National Institutes of Health; Anne Hinks, Manchester Academic Health Science Centre; Ioanna Tachmazidou, The Wellcome Trust Sanger Institute; Alexei A. Grom, University of Cincinnati; Dirk Foell, University Hospital Münster; Alberto Martini, University of Genova; Marco Gattorno, Giannina Gaslini Institute; Seza Ozen, Hacettepe University; Sampath Prahalad, Emory University
• Journal Title: Annals of the Rheumatic Diseases
• Volume: Volume 76, Number 5
• Publisher: BMJ Publishing Group | 2017-05, Pages 906-913
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1136/annrheumdis-2016-210324
• Subjects: Biology, Genetics; Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Rheumatology; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY; IMPUTATION; ABATACEPT; VARIANTS; CHILDREN; LOCUS; Juvenile idiopathic arthritis; Adult onset Still's disease; Gene polymorphism

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.