This article is part of the supplement: 2011 Pediatric Rheumatology Symposium: Abstracts

Open Access Oral presentation

Systemic juvenile idiopathic arthritis is associated with HLA-DRB1 in Europeans and Americans of European descent

Michael Ombrello19*, Elaine F Remmers19, Alexei A Grom4, Wendy Thomson1, Alberto Martini9, Marco Gattorno9, Seza Ozen12, Ahmet Gul17, John F Bohnsack30, Andrew S Zeft32, Elizabeth D Mellins24, Jane L Park23, Claudio Len28, Colleen Satorius29, Ricardo AG Russo21, Terri H Finkel5, Rae SM Yeung14, Rayfel Schneider14, Sampath Prahalad7, David N Glass4, Roger C Allen22, Nico Wulffraat31, Pierre Quartier13, Maria Odete E Hilario28, Kevin Murray20, Sheila Oliveira8, Jordi Anton15, Anne Hinks1, Eleftheria Zeggini35, Carl Langefeld34, Susan Thompson6, Jeffrey Chaitow2, Justine Ellis18, Davinder Singh2, Andre Cavalvanti28, Blanca Bica16, Flavio Sztajnbok27, Hakon Hakonarson3, Katherine A Siminovitch25, Kirsten Minden11, Peter Haas10, Tobias Schwarz33, Daniel L Kastner19 and Patricia Woo26

  • * Corresponding author: Michael Ombrello

Author Affiliations

1 Arthritis Research UK EU, University of Manchester, Manchester, UK

2 Children's Hospital at Westmead, Westmead, New South Wales, Australia

3 Children's Hospital of Philadelphia, Philadelphia, PA, USA

4 Childrens Hospital Medical Center, Cincinnati, OH, USA

5 Childrens Hospital of PA, Philadelphia, PA, USA

6 Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

7 Emory Children's Center, Atlanta, GA, USA

8 Federal University of Rio de Janiero, Rio de Janiero, Brazil

9 Gaslini Hospital, University of Genoa, Genova, Italy

10 GCRCA, Garmisch, Garmisch, Germany

11 German Rheumatism Research Center, Berlin, Germany

12 Hacettepe University Faculty of Medicine Ankara, Ankara, Turkey

13 Hopital Necker-Enfants Malades, Paris, France

14 Hospital for Sick Children, Toronto, ON, Canada

15 Hospital Sant Joan de Déu, Barcelona, Spain

16 Hospital Universitário Clementino Fraga Filho – UFRJ, Rio De Janeiro, Brazil

17 Istanbul University Faculty of Medicine, Istanbul, Turkey

18 Murdoch Children's Research Institute, Parkville, Victoria, Australia

19 NHGRI, NIH, Bethesda, MD, USA

20 Princess Margaret Hospital for Children, Perth, West Australia, Australia

21 Ricardo Russo, Buenos Aires, Argentina

22 Royal Childrens Hospital, Melbourne, Australia

23 Stanford University Medical Center, San Jose, CA, USA

24 Stanford University Medical Center, Stanford, CA, USA

25 Toronto General Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

26 University College London, London, UK

27 Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil

28 Universidade Federal de São Paulo, Sao Paulo, Brazil

29 Universidade Federal de Sao Paulo, Sao Paulo, Brazil

30 Universidade Federal de Sao Paulo, Sao Paulo, Brazil

31 University Medical Center Utrecht, Utrecht, Netherlands

32 University of Utah, Salt Lake City, UT, USA

33 University of Wuerzburg, Wuerzburg, Germany

34 Wake Forest University Health Sciences, Winston-Salem, NC, USA

35 Wellcome Trust Sanger Institute, Oxford, UK

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Pediatric Rheumatology 2012, 10(Suppl 1):A6  doi:10.1186/1546-0096-10-S1-A6


The electronic version of this article is the complete one and can be found online at: http://www.ped-rheum.com/content/10/S1/A6


Published:13 July 2012

© 2012 Ombrello et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose

Systemic juvenile idiopathic arthritis (sJIA) is a complex inflammatory disease whose etiology remains unknown. sJIA is distinguished from other forms of juvenile idiopathic arthritis (JIA) by its characteristic features including requisite quotidian fever and salmon-colored, evanescent skin rash, but also by an absence of autoantibodies. Based on its unique phenotype among JIA subtypes, it has been suggested that sJIA may be autoinflammatory rather than autoimmune in nature, and consistent with this, sJIA is distinct among JIA subtypes for its inconsistently detectable association with HLA genes. In this study, we sought to use SNP genotyping in a large patient collection to identify sJIA susceptibility loci.

Methods

We genotyped 576 children fulfilling ILAR criteria for systemic arthritis and 366 control subjects free of sJIA or autoimmune disease. The collection included 205 cases and 210 controls from Cincinnati Children’s Hospital, 185 cases from the repository at University of Manchester, 56 cases and 60 controls from University of Genova, 54 cases from Hacettepe University, 42 cases from the University of Utah, 34 cases from Stanford University, and 96 controls from Istanbul University. SNP genotyping was performed using Illumina Omni1M Quad v1.0 beadchips and iScan platform. Omni1M beadchip data from 60 unrelated CEU HapMap individuals were obtained through Illumina’s iControlDB. SNP associations were evaluated using SNP & Variation Suite 7, excluding SNPs with call rates below 95%, minor allele frequencies below 0.05, or Hardy-Weinberg Equilibrium p below 0.001, producing a dataset of 690,672 SNPs in 576 cases and 426 controls. To address population stratification, we employed principal components (PC) analysis to identify and exclude samples with differing genetic backgrounds. We excluded 60 sJIA samples on this basis, reducing the size of the collection for final analysis to 516 cases and 426 controls. After correcting for the top 10 PCs, the genomic inflation factor reflected minimal population stratification (λGC = 1.01).

Results

We identified 12 SNPs within HLA-DRB1 with PC-corrected associations that exceeded a stringent threshold for genome-wide significance (p < 5 x 10-8). These SNPs were part of a larger group of 45 SNPs with p < 5 x 10-5 in the MHC class II gene cluster. The effect size of the sJIA-associated SNPs ranged from odds ratios of 1.45 to 1.65. Notably, the effect size of this association is modest, relative to the effect of associated HLA genes in other JIA subtypes and other autoimmune diseases. Figure 1.

thumbnailFigure 1. SNP Associations surrounding HLA-DRB1 in sJIA. Displayed is a plot of the PC-corrected –log20p values of association for SNPs surrounding HLA-DRB1. Horizontal line at y=7.3 represents genome-wide significance threshold (p < 5x10-8).

Conclusion

A large collaborative effort to identify sJIA patients and a careful genetic matching strategy have allowed us to clearly detect an association signal within the class II region of the MHC of sJIA patients, albeit with more modest effect sizes than those detected in other JIA subtypes. This suggests at least some contribution of autoimmunity to the pathogenesis of this complex disorder.

Disclosure

Michael Ombrello: None; Elaine F. Remmers: None; Alexei A. Grom: None; Wendy Thomson: None; Alberto Martini: None; Marco Gattorno: None; Seza Ozen: None; Ahmet Gul: None; John F. Bohnsack: None; Andrew S. Zeft: None; Elizabeth D. Mellins: None; Jane L. Park: None; Claudio Len: None; Colleen Satorius: None; Ricardo A.G. Russo: None; Terri H. Finkel: None; Rae S.M. Yeung: None; Rayfel Schneider: None; Sampath Prahalad: None; David N. Glass: None; Roger C. Allen: None; Nico Wulffraat: None; Pierre Quartier: None; Maria Odete E. Hilario: None; Kevin Murray: None; Sheila Oliveira: None; Jordi Anton: None; Anne Hinks: None; Eleftheria Zeggini: None; Carl Langefeld: None; Susan Thompson: None; Jeffrey Chaitow: None; Justine Ellis: None; Davinder Singh: None; Andre Cavalvanti: None; Blanca Bica: None; Flavio Sztajnbok: None; Hakon Hakonarson: None; Katherine A. Siminovitch: None; Kirsten Minden: None; Peter Haas: None; Tobias Schwarz: None; Daniel L. Kastner: None; Patricia Woo: None.