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

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dc.contributor.author Ombrello, Michael J.
dc.contributor.author Arthur, Victoria L.
dc.contributor.author Remmers, Elaine F.
dc.contributor.author Hinks, Anne
dc.contributor.author Tachmazidou, Ioanna
dc.contributor.author Grom, Alexei A.
dc.contributor.author Foell, Dirk
dc.contributor.author Martini, Alberto
dc.contributor.author Gattorno, Marco
dc.contributor.author Özen, Seza
dc.contributor.author Prahalad, Sampath
dc.contributor.author Zeft, Andrew S.
dc.contributor.author Bohnsack, John F.
dc.contributor.author Ilowite, Norman T.
dc.contributor.author Mellins, Elizabeth D.
dc.contributor.author Russo, Ricardo
dc.contributor.author Len, Claudio
dc.contributor.author Hilario, Maria Odete E.
dc.contributor.author Oliveira, Sheila
dc.contributor.author Yeung, Rae S.M.
dc.contributor.author Rosenberg, Alan M.
dc.contributor.author Wedderburn, Lucy R.
dc.contributor.author Anton, Jordi
dc.contributor.author Haas, Johannes-Peter
dc.contributor.author Rosen-Wolff, Angela
dc.contributor.author Minden, Kirsten
dc.contributor.author Tenbrock, Klaus
dc.contributor.author Demirkaya, Erkan
dc.contributor.author Cobb, Joanna
dc.contributor.author Baskin, Elizabeth
dc.contributor.author Signa, Sara
dc.contributor.author Shuldiner, Emily
dc.contributor.author Duerr, Richard H.
dc.contributor.author Achkar, Jean-Paul
dc.contributor.author Kamboh, M. Ilyas
dc.contributor.author Kaufman, Kenneth M.
dc.contributor.author Kottyan, Leah C.
dc.contributor.author Pinto, Dalila
dc.contributor.author Scherer, Stephen W.
dc.contributor.author Docampo, Elisa
dc.contributor.author Estivill, Xavier, 1955-
dc.contributor.author Gül, Ahmet
dc.contributor.author Langefeld, Carl D.
dc.contributor.author Thompson, Susan
dc.contributor.author Zeggini, Eleftheria
dc.contributor.author Kastner, Daniel L.
dc.contributor.author Woo, Patricia
dc.contributor.author Thomson, Wendy
dc.date.accessioned 2018-08-21T06:18:11Z
dc.date.available 2018-08-21T06:18:11Z
dc.date.issued 2017
dc.identifier.citation Ombrello MJ, Arthur VL, Remmers EF, Hinks A, Tachmazidou I, Grom AA et al. Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications. Ann Rheum Dis. 2017 May; 76(5): 906-913. DOI: 10.1136/annrheumdis-2016-210324
dc.identifier.issn 0003-4967
dc.identifier.uri http://hdl.handle.net/10230/35341
dc.description.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.
dc.description.sponsorship 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); ArthritisResearch 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 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
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher BMJ Publishing Group
dc.relation.ispartof Annals of the Rheumatic Diseases. 2017 May;76(5):906-13
dc.rights This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial
dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
dc.subject.other Artritis
dc.subject.other Cromosomes humans
dc.subject.other Complex major d'histocompatibilitat
dc.subject.other Genètica
dc.title Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1136/annrheumdis-2016-210324
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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