Article Text
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.
- Juvenile Idiopathic Arthritis
- Adult Onset Still's Disease
- Gene Polymorphism
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Footnotes
Handling editor Tore K Kvien
Twitter Follow NIAMS/NIH/DHHS @NIH_NIAMS; Ricardo Russo @el_reumatologo; University of Manchester, Centre for Musculoskeletal Disease @UoMMskResearch
Collaborators Full membership of collaborating consortia are listed in the supplementary text: British Society of Pediatric and Adolescent Rheumatology Study Group, Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis Study Group, Childhood Arthritis Prospective Study Group, Randomized Placebo Phase Study of Rilonacept in sJIA Investigators, Sparks-Childhood Arthritis Response to Medication Study Group and Biologically Based Outcome Predictors in JIA Group.
Contributors All authors participated in study design; AAG, DF, AM, MG, SÖ, SP, ASZ, JFB, NTI, EDM, RR, CL, MOEH, SO, RSMY, AMR, LRW, JA, J-PH, AR-W, KM, KT, ED, BSPAR, ICON-JIA, CAPS, RAPPORT, CHARMS, BBOP, RHD, JPA, MIK, KMK, LCK, DP, SWS, MEA-R, ED, XE and AG provided samples for the study; MJO, VLA, EFR, AH, IT, EZ, PW and WT performed the research and analysis and interpreted the data; all authors drafted and/or substantively edited the manuscript and have thoroughly reviewed and approved of the content.
Funding 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). 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). IT and EZ were supported by the Wellcome Trust (098051). WT and JC are funded by the National Institute for Health Research Biomedical Research Unit Funding Scheme. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. The CAPS study was funded by Arthritis Research UK Grant 20542. WT, AH, and JC are supported by the Manchester Academic Health Sciences Centre (MAHSC). 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. 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). This research was supported in part by the Cincinnati Children's Research Foundation and its Cincinnati Genomic Control Cohort. 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). 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. This study used the computational resources of the Biowulf system at the NIH, Bethesda, MD (http://biowulf.nih.gov).
Competing interests AAG: consulting fees and honoraria from Novimmune, Novartis, Roche. AM: consulting fees and honoraria from Abbvie, Boehringer, Celgene, CrescendoBio, Janssen, Meddimune, Novaris, NovoNordisk, Pfizer, Sanofi Aventis, Vertex and Servier, contributions have been received by G. Gaslini Hospital and the PRINTO network by BMS, GlaxoSmithKline, Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Abbot, Francesco Angelini S.P.A., Sobi, and Merck Serono. MG: consulting and speaker fees from SOBI and Novartis, unrestricted grants to Eurofever from SOBI and Novartis. SP: consulting fees from Novartis. EDM: consulting fees from Novartis. LRW: speaker fees from Pfizer.
Ethics approval University of Manchester.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The quality control processed directly genotyped SNP genotype data from sJIA cases genotyped for this study will be deposited into the National Institutes of Health’s Database of Genotypes and Phenotypes, where allowable by the Ethics and consent documents. The future use of these data will be dictated by the terms of Ethics and consent documents and the institutional certifications provided by the collaborating centres.