Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis

Clinical and therapeutic implications

British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis (ICON-JIA) Study Group, Childhood Arthritis Prospective Study (CAPS) Group, Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators, Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group, Biologically Based Outcome Predictors in JIA (BBOP) Group

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
JournalAnnals of the Rheumatic Diseases
DOIs
Publication statusAccepted/In press - 7 Dec 2016

Fingerprint

Juvenile Arthritis
Genes
Chromosomes
Polymorphism
Nucleotides
Arthritis
Therapeutics
Genetics
Chromosomes, Human, Pair 1
Genome-Wide Association Study
Major Histocompatibility Complex
Single Nucleotide Polymorphism
Genome
Inflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis (ICON-JIA) Study Group, Childhood Arthritis Prospective Study (CAPS) Group, Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators, Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group, & Biologically Based Outcome Predictors in JIA (BBOP) Group (Accepted/In press). Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: Clinical and therapeutic implications. Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2016-210324

Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis : Clinical and therapeutic implications. / British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group; Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis (ICON-JIA) Study Group; Childhood Arthritis Prospective Study (CAPS) Group; Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators; Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group; Biologically Based Outcome Predictors in JIA (BBOP) Group.

In: Annals of the Rheumatic Diseases, 07.12.2016.

Research output: Contribution to journalArticle

British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis (ICON-JIA) Study Group, Childhood Arthritis Prospective Study (CAPS) Group, Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators, Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group & Biologically Based Outcome Predictors in JIA (BBOP) Group 2016, 'Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: Clinical and therapeutic implications', Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2016-210324
British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis (ICON-JIA) Study Group, Childhood Arthritis Prospective Study (CAPS) Group, Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators, Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group, Biologically Based Outcome Predictors in JIA (BBOP) Group. Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: Clinical and therapeutic implications. Annals of the Rheumatic Diseases. 2016 Dec 7. https://doi.org/10.1136/annrheumdis-2016-210324
British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group ; Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis (ICON-JIA) Study Group ; Childhood Arthritis Prospective Study (CAPS) Group ; Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators ; Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group ; Biologically Based Outcome Predictors in JIA (BBOP) Group. / Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis : Clinical and therapeutic implications. In: Annals of the Rheumatic Diseases. 2016.
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title = "Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: Clinical and therapeutic implications",
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.",
author = "{British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group} and {Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis (ICON-JIA) Study Group} and {Childhood Arthritis Prospective Study (CAPS) Group} and {Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators} and {Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group} and {Biologically Based Outcome Predictors in JIA (BBOP) Group} and Ombrello, {Michael J.} and Arthur, {Victoria L.} and Remmers, {Elaine F.} and Anne Hinks and Ioanna Tachmazidou and Grom, {Alexei A.} and Dirk Foell and Alberto Martini and Marco Gattorno and Seza {\"o}zen and Sampath Prahalad and Zeft, {Andrew S.} and Bohnsack, {John F.} and Ilowite, {Norman T.} and Mellins, {Elizabeth D.} and Ricardo Russo and Claudio Len and Hilario, {Maria Odete E.} and Sheila Oliveira and Yeung, {Rae S.M.} and Rosenberg, {Alan M.} and Wedderburn, {Lucy R.} and Jordi Anton and Haas, {Johannes Peter} and Angela Rosen-Wolff and Kirsten Minden and Klaus Tenbrock and Erkan Demirkaya and Joanna Cobb and Elizabeth Baskin and Sara Signa and Emily Shuldiner and Duerr, {Richard H.} and Achkar, {Jean Paul} and Kamboh, {M. Ilyas} and Kaufman, {Kenneth M.} and Kottyan, {Leah C.} and Dalila Pinto and Scherer, {Stephen W.} and Alarc{\'o}n-Riquelme, {Marta E.} and Elisa Docampo and Estivill, {Xavier P.} and Ahmet G{\"u}l and Langefeld, {Carl D.} and Susan Thompson and Eleftheria Zeggini and Kastner, {Daniel L.} and Patricia Woo and Wendy Thomson",
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month = "12",
day = "7",
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language = "English",
journal = "Annals of the Rheumatic Diseases",
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TY - JOUR

T1 - Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis

T2 - Clinical and therapeutic implications

AU - British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group

AU - Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis (ICON-JIA) Study Group

AU - Childhood Arthritis Prospective Study (CAPS) Group

AU - Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators

AU - Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group

AU - Biologically Based Outcome Predictors in JIA (BBOP) Group

AU - Ombrello, Michael J.

AU - Arthur, Victoria L.

AU - Remmers, Elaine F.

AU - Hinks, Anne

AU - Tachmazidou, Ioanna

AU - Grom, Alexei A.

AU - Foell, Dirk

AU - Martini, Alberto

AU - Gattorno, Marco

AU - özen, Seza

AU - Prahalad, Sampath

AU - Zeft, Andrew S.

AU - Bohnsack, John F.

AU - Ilowite, Norman T.

AU - Mellins, Elizabeth D.

AU - Russo, Ricardo

AU - Len, Claudio

AU - Hilario, Maria Odete E.

AU - Oliveira, Sheila

AU - Yeung, Rae S.M.

AU - Rosenberg, Alan M.

AU - Wedderburn, Lucy R.

AU - Anton, Jordi

AU - Haas, Johannes Peter

AU - Rosen-Wolff, Angela

AU - Minden, Kirsten

AU - Tenbrock, Klaus

AU - Demirkaya, Erkan

AU - Cobb, Joanna

AU - Baskin, Elizabeth

AU - Signa, Sara

AU - Shuldiner, Emily

AU - Duerr, Richard H.

AU - Achkar, Jean Paul

AU - Kamboh, M. Ilyas

AU - Kaufman, Kenneth M.

AU - Kottyan, Leah C.

AU - Pinto, Dalila

AU - Scherer, Stephen W.

AU - Alarcón-Riquelme, Marta E.

AU - Docampo, Elisa

AU - Estivill, Xavier P.

AU - Gül, Ahmet

AU - Langefeld, Carl D.

AU - Thompson, Susan

AU - Zeggini, Eleftheria

AU - Kastner, Daniel L.

AU - Woo, Patricia

AU - Thomson, Wendy

PY - 2016/12/7

Y1 - 2016/12/7

N2 - 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.

AB - 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.

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U2 - 10.1136/annrheumdis-2016-210324

DO - 10.1136/annrheumdis-2016-210324

M3 - Article

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

ER -