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Implications of juvenile idiopathic arthritis genetic risk variants for disease pathogenesis and classification.

ABSTRACT: PURPOSE OF REVIEW:We assess the implications of recent advances in the genetics of juvenile idiopathic arthritis (JIA) for the evolving understanding of inflammatory arthritis in children. RECENT FINDINGS:JIA exhibits prominent genetic associations with the human leukocyte antigen (HLA) region, extending perhaps surprisingly even to the hyperinflammatory systemic JIA category. Some HLA associations resemble those for adult-onset inflammatory arthritides, providing evidence for pathogenic continuity across the age spectrum. Genome-wide association studies have defined an increasing number of JIA-linked non-HLA loci, many again shared with adult-onset arthritis. As most risk loci contain only noncoding variants, new experimental methods such as SNP-seq and innovative big-data strategies help identify responsible causative mutations, termed functional SNPs (fSNPs). Alternately, gene hunting in multiplex families implicates new genes in monogenic childhood arthritis, including MYD88 and the intriguing innate immune gene LACC1. SUMMARY:Genetic data indicate a continuity between JIA and adult arthritis poorly reflected in current nomenclature. Advancing methodologies will help to identify new pathogenic mechanisms that inform the understanding of biologic subdivisions within JIA. Resulting insights will facilitate the application of lessons learned across the age spectrum to the treatment of arthritis in children and adults.

SUBMITTER: Nigrovic PA

PROVIDER: S-EPMC6800096 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Implications of juvenile idiopathic arthritis genetic risk variants for disease pathogenesis and classification.

Nigrovic Peter A PA Martínez-Bonet Marta M Thompson Susan D SD

Current opinion in rheumatology 20190901 5

<h4>Purpose of review</h4>We assess the implications of recent advances in the genetics of juvenile idiopathic arthritis (JIA) for the evolving understanding of inflammatory arthritis in children.<h4>Recent findings</h4>JIA exhibits prominent genetic associations with the human leukocyte antigen (HLA) region, extending perhaps surprisingly even to the hyperinflammatory systemic JIA category. Some HLA associations resemble those for adult-onset inflammatory arthritides, providing evidence for pat ...[more]

PMID: 31169548

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Project description:OBJECTIVE:Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA-LD). METHODS:Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed. RESULTS:Eighteen patients with SJIA-LD were identified. Radiographic findings included diffuse ground-glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA-LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin-18 (IL-18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA-LD lacked genetic, serologic, or functional evidence of granulocyte-macrophage colony-stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA-LD rarely demonstrated proteinaceous material and had less lipid-laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA-LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA-LD contained elevated levels of IL-18 and the interferon-?-induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA-LD identified up-regulated type II interferon and T cell activation networks. This signature was also present in SJIA-LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA-LD. CONCLUSION:Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.

Project description:BackgroundJuvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA.MethodsWe performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry. Correlation of SNP genotype and gene expression was investigated. Then we conducted targeted resequencing of a candidate locus, among a subset of 480 cases and 480 controls. SUM test was performed to evaluate the association of the identified rare functional variants.ResultsThe CXCR4 locus on 2q22.1 was found to be significantly associated with JIA, peaking at SNP rs953387. However, this result is subjected to subpopulation stratification within the subjects of European ancestry. After adjusting for principal components, nominal significant association remained (p < 10(-4)). Because of its interesting known function in immune regulation, we carried out further analyses to assess its relationship with JIA. Expression of CXCR4 was correlated with CXCR4 rs953387 genotypes in lymphoblastoid cell lines (p = 0.014) and T-cells (p = 0.0054). In addition, rare non-synonymous and stop-gain sequence variants in CXCR4, putatively damaging for CXCR4 function, were significantly enriched in JIA cases (p = 0.015).ConclusionOur results suggest the association of CXCR4 variants with JIA, implicating that this gene may be involved in the pathogenesis of autoimmune disease. However, because this locus is subjected to population stratification within the subjects of European ancestry, additional replication is still necessary for this locus to be considered a true risk locus for JIA. This cell-surface chemokine receptor has already been targeted in other diseases and may serve as a tractable therapeutic target for a specific subset of pediatric arthritis patients with additional replication and functional validation of the locus.

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Implications of juvenile idiopathic arthritis genetic risk variants for disease pathogenesis and classification.

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Implications of juvenile idiopathic arthritis genetic risk variants for disease pathogenesis and classification.

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