Immunogenetics of juvenile idiopathic arthritis: A comprehensive review

doi:10.1016/j.jaut.2015.08.002

Journal of Autoimmunity

Volume 64, November 2015, Pages 113-124

https://doi.org/10.1016/j.jaut.2015.08.002 Get rights and content

Highlights

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Juvenile idiopathic arthritis is a heterogeneous group of chronic childhood arthritis.
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Most JIA categories are associated with genes encoding Human Leukocyte Antigen.
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The ImmunoChip consortium has identified a number of genes associated with JIA.
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RF-positive JIA is associated with HLA DRB1 variants encoding the shared epitope.
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Candidate gene studies point to associations in rare JIA categories.

Abstract

Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory arthropathy of childhood. Juvenile idiopathic arthritis is believed to be a complex genetic trait influenced by both genetic and environmental factors. Twin and family studies suggest a substantial role for genetic factors in the predisposition to JIA. Describing the genetics is complicated by the heterogeneity of JIA; the International League of Associations for Rheumatology (ILAR) has defined seven categories of JIA based on distinct clinical and laboratory features. Utilizing a variety of techniques including candidate gene studies, the use of genotyping arrays such as Immunochip, and genome wide association studies (GWAS), both human leukocyte antigen (HLA) and non-HLA susceptibility loci associated with JIA have been described. Several of these polymorphisms (e.g. HLA class II, PTPN22, STAT4) are shared with other common autoimmune conditions; other novel polymorphisms that have been identified may be unique to JIA.

Associations with oligoarticular and RF-negative polyarticular JIA are the best characterized. A strong association between HLA DRB1:11:03/04 and DRB1:08:01, and a protective effect of DRB1:15:01 have been described. HLA DPB1:02:01 has also been associated with oligoarticular and RF-negative polyarticular JIA. Besides PTPN22, STAT4 and PTPN2 variants, IL2, IL2RA, IL2RB, as well as IL6 and IL6R loci also harbor variants associated with oligoarticular and RF-negative polyarticular JIA. RF-positive polyarticular JIA is associated with many of the shared epitope encoding HLA DRB1 alleles, as well as PTPN22, STAT4 and TNFAIP3 variants. ERA is associated with HLA B27. Most other associations between JIA categories and HLA or non-HLA variants need confirmation. The formation of International Consortia to ascertain and analyze large cohorts of JIA categories, validation of reported findings in independent cohorts, and functional studies will enhance our understanding of the genetic underpinnings of JIA.

Introduction

Juvenile Idiopathic Arthritis (JIA), also previously termed Juvenile Rheumatoid Arthritis (JRA) or Juvenile Chronic Arthritis (JCA), is the most common chronic arthropathy of childhood and affects hundreds of thousands of children in the United States and around the world [1]. It is a serious disorder of childhood with potentially devastating consequences for the individual and society. JIA has the potential to disrupt growth, and adversely affect the joints resulting in permanent joint damage and long-term functional limitation and disability. Most children with JIA continue to have active disease years after onset, and in the majority of cases, the disease persists into adulthood, dispelling the notion that children can “outgrow” JIA [2], [3]. Furthermore, JIA is associated with a substantial economic burden [4].

Section snippets

Overview of JIA genetics

JIA is believed to be a complex genetic trait influenced by both genetic and environmental factors [5]. There is substantial evidence for genetic contribution to JIA. Twin and affected sibling pair studies have supported a role for genetic susceptibility to JIA. Twin studies have shown that the monozygotic twin concordance rates for JIA range between 25 and 40%, a risk that is substantially greater than the population prevalence of 1 in 1000 [6], [7], [8]. In the largest twin study from the JIA

JIA categories

Genetic studies for JIA are complicated by the heterogeneity of the condition. There are seven categories of JIA as defined by International League of Associations for Rheumatology (ILAR) classification criteria [16]. By definition, all patients with JIA have a chronic arthropathy with symptoms beginning at <16 years of age, however each category of JIA varies in its clinical symptoms and associated laboratory studies [16]. Systemic-onset JIA is characterized by fever and rash in addition to

Genetics of oligoarticular JIA/polyarticular RF-negative JIA

Oligoarticular JIA is the most common category of JIA, affecting up to 40% of all patients with JIA. Patients with oligoarticular JIA have 4 or fewer joints affected during the first six months of the disease. After 6 months following onset, if the arthritis is confined to 4 or fewer joints, the disease is referred to as “persistent” oligoarticular JIA, whereas when more than 4 joints are involved, it is referred to as “extended” oligoarticular JIA [16]. Oligoarticular JIA has its peak

Genetics of polyarticular RF-positive JIA

Polyarticular RF- positive JIA, which can considered the childhood onset of seropositive adult rheumatoid arthritis, represents about 10% of all cases of JIA. Patients are typically diagnosed in late childhood/adolescence. As with adult RA, patients have a chronic symmetric, erosive polyarticular arthritis. To have polyarticular RF- positive disease, the ILAR classification requires the involvement of 5 or more joints [16]. Also, by definition, patients with polyarticular RF + positive JIA must

Genetics of systemic onset JIA

In North America and Europe, systemic onset JIA accounts for about 10% of all cases of JIA. It affects males and females equally, which is a distinguishing feature from other forms of JIA (except ERA) which have a female predominance. Systemic onset JIA occurs throughout the pediatric age spectrum from toddlerhood to adolescence. This is in contrast to oligoarticular JIA and RF-negative polyarticular JIA which tend to have its onset in early childhood (<10 years of age). Perhaps the most

Genetics of enthesitis-related arthritis (ERA)

As defined by the ILAR classification, ERA (previously termed juvenile ankylosing spondylitis or seronegative arthritis and enthesitis (SEA) syndrome) is diagnosed in a child with arthritis AND enthesitis or in a child with arthritis OR enthesitis as well as two of the following: sacroiliac joint tenderness and/or inflammatory back pain, HLAB27 positive, family history of one first or second degree relative with HLAB27 associated disease, acute anterior uveitis or onset of arthritis in a boy

Psoriatic JIA

The ILAR criteria define psoriatic JIA as the presence of both arthritis and psoriasis, or the presence of arthritis, with at least two of the following criteria: family history of psoriasis in a first degree relative, dactylitis, and nail pitting or onycholysis [16]. It has been proposed that psoriatic JIA might actually comprise two distinct subgroups, an older onset phenotype with male predominance, enthesitis and axial involvement, and an early-onset subphenotype resembling early onset

Conclusions

Juvenile idiopathic arthritis is a complex heterogeneous entity with multiple disease phenotypes included under that broad umbrella of “JIA”. While earlier studies often grouped all children with JIA in genetic studies, more recent studies have focused on the differences in categories and have reported data based on JIA categories, allowing us to understand the differences in genetic association between various categories. For oligoarticular and RF-negative polyarticular JIA, there are numerous

Acknowledgements

Dr. Prahalad is supported by grants from The National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR060893), The Marcus Foundation Inc. and The Arthritis Foundation. Dr. Hersh is supported by a grant from the The National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23-AR066064). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Arthritis and Musculoskeletal and Skin

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Juvenile idiopathic arthritis (JIA) is an autoimmune, inflammatory joint disease with complex genetic etiology. Previous GWAS have found many genetic loci associated with JIA. However, the biological mechanism behind JIA remains unknown mainly because most risk loci are located in non-coding genetic regions. Interestingly, increasing evidence has found that regulatory elements in the non-coding regions can regulate the expression of distant target genes through spatial (physical) interactions. Here, we used information on the 3D genome organization (Hi-C data) to identify target genes that physically interact with SNPs within JIA risk loci. Subsequent analysis of these SNP-gene pairs using data from tissue and immune cell type-specific expression quantitative trait loci (eQTL) databases allowed the identification of risk loci that regulate the expression of their target genes. In total, we identified 59 JIA-risk loci that regulate the expression of 210 target genes across diverse tissues and immune cell types. Functional annotation of spatial eQTLs within JIA risk loci identified significant overlap with gene regulatory elements (i.e., enhancers and transcription factor binding sites). We found target genes involved in immune-related pathways such as antigen processing and presentation (e.g., ERAP2, HLA class I and II), the release of pro-inflammatory cytokines (e.g., LTBR, TYK2), proliferation and differentiation of specific immune cell types (e.g., AURKA in Th17 cells), and genes involved in physiological mechanisms related to pathological joint inflammation (e.g., LRG1 in arteries). Notably, many of the tissues where JIA-risk loci act as spatial eQTLs are not classically considered central to JIA pathology. Overall, our findings highlight the potential tissue and immune cell type-specific regulatory changes contributing to JIA pathogenesis. Future integration of our data with clinical studies can contribute to the development of improved JIA therapy.
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Juvenile Idiopathic Arthritis (JIA) is a multi-factorial disease influenced both by environmental and genetic factors. Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive genetic disorder affecting multiple joints, mimicking JIA. Aim of the work: to reveal the frequency of HLA-DR types among the studied patients and to correlate the different allele variations clinically. Patients and methods: Thirty JIA patients, in addition to 15 molecularly diagnosed PPD patients were subjected to full history taking and clinical examination. HLA-DRB1 typing was performed to 24/30 JIA and 12/15 PPD cases and thirty healthy age and sex matched children who were included as a control group. Results: The JIA patients were 22 females and 8 males with mean age of 15.8 ± 1.96 years and disease duration 5.3 ± 4.4 years. PPD patients were 8 males and 7 females with mean age of 8.7 ± 3.06 years and disease duration 3.95 ± 2.68 years. A significant frequency of HLA-DRB 04 (p = 0.049) among JIA patients was present in comparison to the controls (OR = 2.81, CI:1.02–7.75), other risky alleles were HLA-DRB 10, 13 and 15. However, HLA-DRB 01, 03, 07, 11 and 14 were found to be protective. HLA-DRB 01, 04, 10 and 13 were found to be risky alleles in PPD. However, HLA 03, 07, 11 and 15 were found to be protective alleles among PPD patients. Conclusion: HLA-DRB 04 was found in a higher frequency in JIA patients with a significant difference in comparison to the controls, denoting that it may play a role in the genetic pathogenesis of JIA.

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Review articleImmunogenetics of juvenile idiopathic arthritis: A comprehensive review

Highlights

Abstract

Introduction

Section snippets

Overview of JIA genetics

JIA categories

Genetics of oligoarticular JIA/polyarticular RF-negative JIA

Genetics of polyarticular RF-positive JIA

Genetics of systemic onset JIA

Genetics of enthesitis-related arthritis (ERA)

Psoriatic JIA

Conclusions

Acknowledgements

Semi. Arthritis Rheum.

Clin. Immunol. Immunopathol.

Infect. Genet. Evol.: journal of molecular epidemiology and evolutionary genetics in infectious diseases

Hum. Immunol.

Inflamm. Res.: official journal of the European Histamine Research Society [et al]

Hum. Immunol.

Semin. Cell Dev. Biol.

Hum. Immunol.

Remission in juvenile chronic arthritis: a cohort study of 683 consecutive cases with a mean 10 year followup

J. Rheumatol.

Long-term outcome in patients with juvenile idiopathic arthritis

Arthritis Rheum.

Burden and cost of illness in patients with juvenile idiopathic arthritis

Ann. Rheum. Dis.

Juvenile rheumatoid arthritis as a complex genetic trait

Arthritis Rheum.

Familial aggregation and twin studies in Still's disease. Juvenile chronic polyarthritis

Rheumatology

Juvenile rheumatoid arthritis in monozygotic twins: a case report and review of the literature

Arthritis Rheum.

Magnitude of the genetic component in juvenile idiopathic arthritis

Ann. Rheum. Dis.

Twins concordant for juvenile rheumatoid arthritis

Arthritis Rheum.

Juvenile rheumatoid arthritis in affected sibpairs

Arthritis Rheum.

Juvenile rheumatoid arthritis affected sibpairs: extent of clinical phenotype concordance

Arthritis Rheum.

Familial aggregation of juvenile idiopathic arthritis

Arthritis Rheum.

Quantification of the familial contribution to juvenile idiopathic arthritis

Arthritis Rheum.

Increased prevalence of familial autoimmunity in simplex and multiplex families with juvenile rheumatoid arthritis

Arthritis Rheum.

Familial autoimmunity: maternal parent-of-origin effect in juvenile idiopathic arthritis

Clin. Rheumatol.

International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001

J. Rheumatol.

Genetic susceptibility to early onset pauciarticular juvenile chronic arthritis: a study of HLA and complement markers in 158 British patients

Ann. Rheum. Dis.

HLA-DP/DR interaction in early onset pauciarticular juvenile chronic arthritis

Immunogenetics

DR, C4, and Bf allotypes in juvenile rheumatoid arthritis

Arthritis Rheum.

Juvenile idiopathic arthritis and HLA class I and class II interactions and age-at-onset effects

Arthritis Rheum.

Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles

Arthritis Rheum.

Overlap of disease susceptibility loci for rheumatoid arthritis and juvenile idiopathic arthritis

Ann. Rheum. Dis.

The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1

Arthritis Rheum.

Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis

Nat. Genet.

Promise and pitfalls of the Immunochip

Arthritis Res. Ther.

Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

Nat. Genet.

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Nature

High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

Nat. Genet.

Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci

Nat. Genet.

Independent confirmation of juvenile idiopathic arthritis genetic risk loci previously identified by immunochip array analysis

Pediatr. Rheumatol. Online J.

Review article
Immunogenetics of juvenile idiopathic arthritis: A comprehensive review