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Proc Natl Acad Sci U S A. 2015 Dec 29;112(52):15970-5. doi: 10.1073/pnas.1520779112. Epub 2015 Nov 23.

HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis.

Collaborators (210)

Achkar JP, Alarcón-Riquelme ME, Allen R, Anton J, Baskin E, Berg S, Bica B, Bilginer Y, Bohnsack JF, Cavalcanti A, Chaitow J, Cobb J, Cuttica R, de Bakker PI, Docampo E, Duerr R, Ellis J, Estivill X, Finkel TH, Foell D, Gattorno M, Grom A, Gül A, Haas JP, Hakonarson H, Han B, Hilario MO, Hinks A, Ilowite NT, Kamboh MI, Kastner DL, Kaufman K, Kottyan LC, Langefeld C, Len C, Martini A, Mellins ED, Minden K, Murray K, Oliveira S, Ombrello MJ, Ozen S, Park J, Pinto D, Prahalad S, Quartier P, Raychaudhuri S, Remmers EF, Rosenberg A, Russo R, Satorius C, Scherer SW, Schneider R, Schwarz T, Singh-Gerwal D, Tachmazidou I, Thompson S, Thomson W, Wedderburn LR, Woo P, Wulffraat N, Yeung RS, Zeft AS, Zeggini E, Abinum M, Bell A, Craft AW, Crawley E, David J, Foster H, Gardener-Medwin J, Griffin J, Hall A, Hall M, Herrick AL, Hollingworth P, Holt L, Jones S, Pountain G, Ryder C, Southwood T, Stewart I, Venning H, Wedderburn LR, Woo P, Wyatt S, Baildam E, Bishop N, Brown L, Buckley J, Chieng A, Carrasco R, Cobb J, Cook L, Davidson J, Duggan A, Eltringham M, Foster H, Friel E, Friswell M, Gardner-Medwin J, Gilbert P, Gould V, Hadfield K, Hyrich K, Jones J, Lal S, Lay M, Lloyd G, Lloyd O, Lydon C, Makengo N, McGovern A, Meijer A, Mills-Wierda N, Moorcroft T, Price V, Qiao L, Riding K, Sim J, Southwood T, Thomson W, Todd M, Tremble S, Venter K, Wade D, Ward P, Watson S, Webster G, Wedderburn LR, Zelenovic J, Birmingham JD, Elder M, Gottlieb BS, Ilowite NT, Imundo LF, Kimura Y, Lokhnygina Y, Miller ML, Milojevic D, O'Neil K, Punaro MG, Prather K, Ruth NM, Sandborg CI, Schanberg LE, Sherry DD, Singer NG, Spalding SJ, Tarvin SE, Verbsky JW, Wallace CA, Zemel LS, Burkle K, Cobb J, Etheridge A, Gilbert P, Hinks A, Hirani S, Kassoumeri L, Lal S, Melville L, Moncrieffe H, Mulligan K, Newman S, Patrick F, Southwood T, Thomson W, Ursu S, Wedderburn LR, Whitworth P, Woo P, Baxter-Jones A, Benseler S, Boire G, Cabral DA, Cameron B, Campillo S, Chedeville G, Chetaille AL, Dancey P, Duffy C, Duffy KW, Ellsworth J, Feldman B, Gibbon M, Guillet C, Guzman J, Houghton K, Huber A, Jurencak R, Lang B, Laxer R, Maenz L, Matheson L, Oen K, Petty R, Ramsey S, Rezaei E, Rosenberg A, Roth J, Schneider R, Scuccimarri R, Silverman E, Spiegel L, Stringer E, Tse S, Tucker LB, Turvey S, Yeung RS.

Author information

1
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.
2
Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
3
Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, United Kingdom;
4
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
5
Department of Pediatric Rheumatology and Immunology, University Hospital Münster, D-48149 Münster, Germany;
6
German Center for Pediatric and Adolescent Rheumatology, 82467 Garmisch-Partenkirchen, Germany;
7
Department of Pediatrics, University of Genova, 16145 Genoa, Italy; Pediatrics II Unit, G. Gaslini Institute, 16147 Genoa, Italy;
8
Pediatrics II Unit, G. Gaslini Institute, 16147 Genoa, Italy;
9
Department of Pediatric Rheumatology, Hacettepe University, 06100 Ankara, Turkey;
10
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322;
11
Department of Pediatrics, Cleveland Clinic, Cleveland, OH 44195;
12
Department of Pediatrics, University of Utah, Salt Lake City, UT 84113;
13
Department of Pediatrics, Stanford University, Stanford, CA 94305;
14
Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, NY 10461;
15
Service of Immunology and Rheumatology, Hospital de Pediatria Garrahan, C1245AAM Buenos Aires, Argentina;
16
Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, 04021-001, Brazil;
17
Universidade Federal de Rio de Janeiro, Rio de Janeiro, 21941-901, Brazil;
18
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;
19
Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada S7N 0W8;
20
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;
21
Pediatric Rheumatology Unit, Hospital Sant Joan de Déu, Universitat de Barcelona, 08950 Barcelona, Spain;
22
Section of Pediatric Rheumatology and Osteology, University of Würzberg, 97080 Würzberg, Germany;
23
Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Centre, University of Manchester, Manchester, M13 9PT, United Kingdom;
24
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;
25
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;
26
Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
27
Department of Pediatrics, University of Genova, 16145 Genoa, Italy;
28
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261;
29
Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195; Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195;
30
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;
31
Department of Genetics and Genomic Sciences, Icahn School of Medicine At Mount Sinai, New York, NY 10029;
32
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada;
33
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;
34
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;
35
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain;
36
Istanbul Faculty of Medicine, Istanbul University, 34390 Istanbul, Turkey;
37
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.
38
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;
39
Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27106.
40
Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; ombrellomj@mail.nih.gov kastnerd@mail.nih.gov.
41
Center of Paediatric and Adolescent Rheumatology, University College London, London, WC1N 1EH, United Kingdom;

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.

KEYWORDS:

Still’s disease; autoinflammation; human leukocyte antigen; systemic juvenile idiopathic arthritis

PMID:
26598658
PMCID:
PMC4702958
DOI:
10.1073/pnas.1520779112
[Indexed for MEDLINE]
Free PMC Article

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