title: HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis.
abstract: Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 × 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.
authors.affiliation: Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; ombrellomj@mail.nih.gov kastnerd@mail.nih.gov.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ombrello
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.affiliation: Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, United Kingdom;
authors.forename: Ioanna
authors.initials: I
authors.lastname: Tachmazidou
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors.forename: Alexei
authors.initials: A
authors.lastname: Grom
authors.affiliation: Department of Pediatric Rheumatology and Immunology, University Hospital Münster, D-48149 Münster, Germany;
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
authors.affiliation: German Center for Pediatric and Adolescent Rheumatology, 82467 Garmisch-Partenkirchen, Germany;
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Haas
authors.affiliation: Department of Pediatrics, University of Genova, 16145 Genoa, Italy; Pediatrics II Unit, G. Gaslini Institute, 16147 Genoa, Italy;
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.affiliation: Pediatrics II Unit, G. Gaslini Institute, 16147 Genoa, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.affiliation: Department of Pediatric Rheumatology, Hacettepe University, 06100 Ankara, Turkey;
authors.forename: Seza
authors.initials: S
authors.lastname: Özen
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Sampath
authors.initials: S
authors.lastname: Prahalad
authors.affiliation: Department of Pediatrics, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Zeft
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT 84113;
authors.forename: John F
authors.initials: JF
authors.lastname: Bohnsack
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305;
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Mellins
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, NY 10461;
authors.forename: Norman T
authors.initials: NT
authors.lastname: Ilowite
authors.affiliation: Service of Immunology and Rheumatology, Hospital de Pediatria Garrahan, C1245AAM Buenos Aires, Argentina;
authors.forename: Ricardo
authors.initials: R
authors.lastname: Russo
authors.affiliation: Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, 04021-001, Brazil;
authors.forename: Claudio
authors.initials: C
authors.lastname: Len
authors.affiliation: Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, 04021-001, Brazil;
authors.forename: Maria Odete E
authors.initials: MO
authors.lastname: Hilario
authors.affiliation: Universidade Federal de Rio de Janeiro, Rio de Janeiro, 21941-901, Brazil;
authors.forename: Sheila
authors.initials: S
authors.lastname: Oliveira
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, Canada M5S 1A8; Department of Immunology, University of Toronto, Toronto, Canada M5S 1A8; Institute of Medical Science, University of Toronto, Toronto, Canada M5S 1A8;
authors.forename: Rae S M
authors.initials: RS
authors.lastname: Yeung
authors.affiliation: Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada S7N 0W8;
authors.forename: Alan
authors.initials: A
authors.lastname: Rosenberg
authors.affiliation: Institute of Child Health, University College London, London, WC1N 1EH, United Kingdom; Center of Paediatric and Adolescent Rheumatology, University College London, London, WC1N 1EH, United Kingdom;
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
authors.affiliation: Pediatric Rheumatology Unit, Hospital Sant Joan de Déu, Universitat de Barcelona, 08950 Barcelona, Spain;
authors.forename: Jordi
authors.initials: J
authors.lastname: Anton
authors.affiliation: Section of Pediatric Rheumatology and Osteology, University of Würzberg, 97080 Würzberg, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwarz
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Centre, University of Manchester, Manchester, M13 9PT, United Kingdom;
authors.forename: Anne
authors.initials: A
authors.lastname: Hinks
authors.affiliation: Department of Pediatric Rheumatology, Hacettepe University, 06100 Ankara, Turkey;
authors.forename: Yelda
authors.initials: Y
authors.lastname: Bilginer
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305;
authors.forename: Jane
authors.initials: J
authors.lastname: Park
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Centre, University of Manchester, Manchester, M13 9PT, United Kingdom; National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester National Health Service Foundation Trust, Manchester Academic Health Centre, University of Manchester, Manchester, M13 9PT, United Kingdom;
authors.forename: Joanna
authors.initials: J
authors.lastname: Cobb
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Colleen L
authors.initials: CL
authors.lastname: Satorius
authors.affiliation: Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142; Division of Immunology, Allergy, and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 138-736, Republic of Korea;
authors.forename: Buhm
authors.initials: B
authors.lastname: Han
authors.affiliation: Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Baskin
authors.affiliation: Department of Pediatrics, University of Genova, 16145 Genoa, Italy;
authors.forename: Sara
authors.initials: S
authors.lastname: Signa
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Richard H
authors.initials: RH
authors.lastname: Duerr
authors.affiliation: Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195; Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: J P
authors.initials: JP
authors.lastname: Achkar
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors.forename: Leah C
authors.initials: LC
authors.lastname: Kottyan
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine At Mount Sinai, New York, NY 10029;
authors.forename: Dalila
authors.initials: D
authors.lastname: Pinto
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada;
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104; Center for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Government, PTS Granada 18016, Spain;
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics-Université de Liège, 4000-Liège, Belgium; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain;
authors.forename: Elisa
authors.initials: E
authors.lastname: Docampo
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain;
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.affiliation: Istanbul Faculty of Medicine, Istanbul University, 34390 Istanbul, Turkey;
authors.forename: Ahmet
authors.initials: A
authors.lastname: Gül
authors.affiliation: Department of Epidemiology, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands; Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands; and.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Centre, University of Manchester, Manchester, M13 9PT, United Kingdom; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142; Division of Immunology, Allergy, and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27106.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors.forename: Susan
authors.initials: S
authors.lastname: Thompson
authors.affiliation: Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, United Kingdom;
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Centre, University of Manchester, Manchester, M13 9PT, United Kingdom; National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester National Health Service Foundation Trust, Manchester Academic Health Centre, University of Manchester, Manchester, M13 9PT, United Kingdom;
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; ombrellomj@mail.nih.gov kastnerd@mail.nih.gov.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.affiliation: Center of Paediatric and Adolescent Rheumatology, University College London, London, WC1N 1EH, United Kingdom;
authors.forename: Patricia
authors.initials: P
authors.lastname: Woo
mesh_terms: D001171:Arthritis, Juvenile / Q000235:genetics*; D002648:Child; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D015201:Meta-Analysis as Topic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II
keywords: Still’s disease; autoinflammation; human leukocyte antigen; systemic juvenile idiopathic arthritis