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

Proc Natl Acad Sci U S A 2015 Dec 23;112(52):15970-5. Epub 2015 Nov 23.

Center of Paediatric and Adolescent Rheumatology, University College London, London, WC1N 1EH, United Kingdom;

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.

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http://dx.doi.org/10.1073/pnas.1520779112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702958PMC
December 2015
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(Supplied by CrossRef)
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J Rheumatol 2004
Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis
Behrens et al.
J Rheumatol 2007
Systemic juvenile idiopathic arthritis
Schneider et al.
2011
Increased frequency of DR4 in systemic onset juvenile chronic arthritis
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Clin Exp Rheumatol 1992

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