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

• Type of Material: Article
• 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
• Language: English
• Date: 2017-05
• Publisher: BMJ Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/annrheumdis-2016-210324
• Title of Journal or Parent Work: Annals of the Rheumatic Diseases
• ISSN: 0003-4967
• Volume: 76
• Issue: 5
• Start Page: 906
• End Page: 913
• Grant/Funding Information: This study used the computational resources of the Biowulf system at the NIH, Bethesda, MD (http://biowulf.nih.gov).; The authors acknowledge the use of DNA from the UK Blood Services collection of Common Controls (UKBS-CC collection), which is funded by Wellcome Trust grant 076113/C/04/Z and by the USA NIH research programme grant to the National Health Service Blood and Transplant (RP-PG-0310-1002).; This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Z01-AR041198 to MJO) and the National Human Genome Research Institute (Z01-HG200370 to DLK) of the National Institutes of Health (NIH).; IT and EZ were supported by the Wellcome Trust (098051).; WT, AH, and JC are supported by the Manchester Academic Health Sciences Centre (MAHSC).; WT and JC are funded by the National Institute for Health Research Biomedical Research Unit Funding Scheme.; This research was supported in part by the Cincinnati Children's Research Foundation and its Cincinnati Genomic Control Cohort.; Additional funding was provided by NIH grants R01-AR059049 (AAG), R01AR061297 (EDM), R01-AR060893 (SP), P30-AR47363 and P01-AR48929 (ST), AG030653, AG041718 and AG005133 (MIK) and U01-DK062420 and R01-DK076025 (RHD); Arthritis Research UK Grant 20385 (WT); the German Federal Ministry of Education and Research (BMBF project 01ER0813) for the ‘ICON-JIA’ inception cohort (KM and DF); the Val A. Browning Charitable Foundation (JFB); the Marcus Foundation (SP); the Proyecto de Excelencia (CTS-2548) of the Andalousian Government (MA-R) and the Swedish Association Against Rheumatism (MA-R).; The authors acknowledge the use of DNA from the British 1958 Birth Cohort collection, which is funded by the UK Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02.; The BBOP study was supported by the Canadian Institutes of Health Research and the Arthritis Society (CIHR funding reference number 82517) and the Canadian Arthritis Network (funding reference SRI-IJD-01).; The CAPS study was funded by Arthritis Research UK Grant 20542.; SPARKS-CHARMS was funded by grants from SPARKS UK (08ICH09 and 12ICH08), the Medical Research Council (MR/M004600/1) and the UK National Institute for Health Research GOSH Biomedical Research Centre.
• Keywords: Adult onset Still's disease; Rheumatology; Juvenile idiopathic arthritis; IMPUTATION; Science & Technology; CHILDREN; GENOME-WIDE ASSOCIATION; Life Sciences & Biomedicine; VARIANTS; Gene polymorphism; ABATACEPT; LOCUS; SUSCEPTIBILITY
• Research Categories: Biology, Genetics; Health Sciences, Immunology

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.