Suchergebnisse

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. ; Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases ; National Human Genome Research Institute of the National Institutes of Health (NIH) ; NIH ; Arthritis Research UK ; German Federal Ministry of Education and Research (BMBF) ; Val A. Browning Charitable Foundation ; Marcus Foundation ; Proyecto de Excelencia of the Andalousian Government (MA-R) ; Swedish Association Against Rheumatism (MA-R) ; Wellcome Trust ; National Institute for Health Research Biomedical Research Unit Funding Scheme ; Manchester Academic Health Sciences Centre (MAHSC) ; SPARKS UK ; Medical Research Council ; UK National Institute for Health Research GOSH Biomedical Research Centre ; Canadian Institutes of Health Research ; Arthritis Society (CIHR) ; Canadian Arthritis Network ; Cincinnati Children's Research Foundation and its Cincinnati Genomic Control Cohort ; USA NIH research programme ; UK Medical Research Council ; Natl Inst Arthrit & Musculoskeletal & Skin Dis, Natl Inst Hlth, US Dept Hlth & Human Serv, Translat Genet & Genom Unit, Bethesda, MD USA ; NHGRI, Natl Inst Hlth, Inflammatory Dis Sect, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA ; Manchester Acad Hlth Sci Ctr, Arthrit Res UK Ctr Genet & Genom, Ctr Musculoskeletal Res, Manchester, Lancs, England ; Wellcome Trust Sanger Inst, Human Genet, Hinxton, England ; Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA ; Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA ; Univ Hosp Munster, Dept Pediat Rheumatol & Immunol, Munster, Germany ; Univ Genoa, Dept Pediat, Genoa, Italy ; Giannina Gaslini Inst, Pediat Unit 2, Genoa, Italy ; Hacettepe Univ, Dept Pediat Rheumatol, Ankara, Turkey ; Emory Univ, Sch Med, Dept Pediat & Human Genet, Atlanta, GA 30322 USA ; Childrens Healthcare Atlanta, Atlanta, GA USA ; Cleveland Clin, Dept Pediat, Cleveland, OH 44106 USA ; Univ Utah, Dept Pediat, Salt Lake City, UT USA ; Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA ; Childrens Hosp Montefiore, Bronx, NY USA ; Stanford Univ, Dept Pediat, Stanford, CA 94305 USA ; Hosp Pediat Garrahan, Serv Immunol & Rheumatol, Buenos Aires, DF, Argentina ; Univ Fed Sao Paulo, Dept Pediat, Sao Paulo, Brazil ; Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil ; Univ Toronto, Dept Pediat, Toronto, ON, Canada ; Univ Toronto, Dept Pediat, Toronto, ON, Canada ; Univ Toronto, Inst Med Sci, Toronto, ON, Canada ; Univ Saskatchewan, Dept Pediat, Saskatoon, SK, Canada ; UCL, Inst Child Hlth, London, England ; UCL, Ctr Paediat & Adolescent Rheumatol, London, England ; Univ Barcelona, Hosp Sant Joan Deu, Pediat Rheumatol Unit, Barcelona, Spain ; German Ctr Pediat & Adolescent Rheumatol, Garmisch Partenkirchen, Germany ; Univ Hosp Cal Gustav Carus, Dresden, Germany ; Charite, Dept Rheumatol & Clin Immunol, Berlin, Germany ; German Rheumatism Res Ctr, Epidemiol Unit, Berlin, Germany ; Rhein Westfal TH Aachen, Dept Pediat, Aachen, Germany ; Univ Manchester, Manchester Acad Hlth Sci Ctr, Cent Manchester Univ Hosp NHS Fdn Trust, Natl Inst Hlth Res Manchester Musculoskeletal Bio, Manchester, Lancs, England ; Univ Pittsburgh, Dept Med, Pittsburgh, PA USA ; Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA ; Cleveland Clin, Dept Gastroenterol & Hepatol, Cleveland, OH 44106 USA ; Cleveland Clin, Dept Pathobiol, Cleveland, OH 44106 USA ; Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA ; Hosp Sick Children, Ctr Appl Gen, Toronto, ON, Canada ; Pfizer Univ Granada Andalusian Govt, Ctr Genom & Oncol Res, Granada, Spain ; Karolinska Inst, Inst Environm Med, Unit Chron Inflammatory Dis, Solna, Sweden ; Interdisciplinary Cluster Appl Genoprote Univ Lie, Liege, Belgium ; Barcelona Inst Sci & Technol, Ctr Gene Regulat, Barcelona, Spain ; Univ Pompeu Fabra UPF, Barcelona, Spain ; Sidra Med & Res Ctr, Doha, Qatar ; Istanbul Univ, Istanbul Fac Med, Istanbul, Turkey ; Wake Forest Univ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA ; Univ Fed Sao Paulo, Dept Pediat, Sao Paulo, Brazil ; Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases: Z01-AR041198 ; National Human Genome Research Institute of the National Institutes of Health (NIH): Z01-HG200370 ; NIH: R01-AR059049 ; NIH: R01AR061297 ; NIH: R01-AR060893 ; NIH: P30-AR47363 ; NIH: P01-AR48929 ; NIH: AG030653 ; NIH: AG041718 ; NIH: AG005133 ; NIH: U01-DK062420 ; NIH: R01-DK076025 ; Arthritis Research UK: 20385 ; Arthritis Research UK: 20542 ; German Federal Ministry of Education and Research (BMBF): 01ER0813 ; Proyecto de Excelencia of the Andalousian Government (MA-R): CTS-2548 ; Wellcome Trust: 098051 ; Wellcome Trust: 076113/C/04/Z ; Wellcome Trust: 068545/Z/02 ; SPARKS UK: 08ICH09 ; SPARKS UK: 12ICH08 ; Medical Research Council: MR/M004600/1 ; Arthritis Society (CIHR): 82517 ; Canadian Arthritis Network: SRI-IJD-01 ; USA NIH research programme: RP-PG-0310-1002 ; UK Medical Research Council: G0000934 ; Web of Science

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. ; 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