HLA-DRB1*11and 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.

HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications

“…Specifically, oligoarticular JIA (≤ 4 joints), RF-positive polyarticular JIA (≥ 5 joints), and systemic JIA are linked to different HLA alleles. Susceptibility alleles for oligoarticular JIA are HLA-DRB1*08, HLA-DRB1*11 and HLA-DPB1*02:01 202,203 , for RF+ polyarticular JIA are DRB1 SE alleles 204 , and for systemic JIA, HLA-DRB1*11:01 and HLA-DRB1*11:04 172 . The association of some HLA class II alleles with particular phenotypes in JIA provides support for the existence of particular clinical subtypes of JIA 31 .…”

Juvenile arthritis caused by a novel FAMIN (LACC1) mutation in two children with systemic and extended oligoarticular course

“…Previously, genome wide association studies (GWAS) of unrelated patients with sJIA did not reveal significant -log 10 p values for the FAMIN locus [9]. Therefore, variants within this gene do not seem to play a role in patients suffering from the common forms of sJIA.…”

“…Furthermore, an association of polymorphisms within the IL1 and IL1R cluster genes [6, 7], the macrophages migration inhibitor factor (MIF) and the IL10 cytokine cluster [8] has previously been described. Furthermore, a current genome wide association study (GWAS) identified the MHC locus as a bona fide susceptibility locus for the phenotype of sJIA [9]. …”

Juvenile Arthritis durch neue Mutation in FAMIN (LACC1) bei zwei Patientinnen mit systemischem und oligoartikulärem Verlauf

“…B. IL-1β, IL-18, IL-6 und der S100-Moleküle) auslöst, und hierdurch eine proinflammatorische Antwort unterhalten wird (2)(3)(4)(5). Es wurden außerdem in den vergangenen Jahren eine Reihe genetischer Assoziationen identifiziert: Zum einen konnten bei sJIA-Polymorphismen innerhalb des IL-1-und IL1R-Clustergens (6, 7) des Makrophagen-Migrationsinhibitorfaktors (MIF) und des IL-10-Zytokin-Clusters (8) nachgewiesen, und zum anderen der MHC-Locus mithilfe einer genomweiten Assoziationsstudie (GWAS) als Suszeptibilitätsort für die sJIA beschrieben werden (9).…”