Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases

Abstract

Objectives: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides.

Methods: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed.

Results: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA.

Conclusions: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.

Keywords: Autoimmune Diseases; Gene Polymorphism; Juvenile Idiopathic Arthritis; Rheumatoid Arthritis.

Figure 1

Heatmap showing genetic correlation for human leucocyte antigen (HLA) between the juvenile idiopathic arthritis (JIA) categories. Each square shows the level of correlation between each JIA category. With a scale of red colour representing higher correlation through orange to yellow for low correlation. The numbers within the squares represent the correlation values ranging from 0 to 1 for high correlation. Note that this plot is symmetrical. POligo, persistent oligoarthritis; EOligo, extended oligoarthritis; RF, rheumatoid factor; RFnegpoly, RF-negative polyarthritis; RFpospoly, RF-positive polyarthritis; sJIA, systemic JIA; ERA, enthesitis-related arthritis; jPsA, juvenile psoriatic arthritis.

Figure 2

Different effect sizes (ORs and 95% CIs) for amino acid residues at human leucocyte antigen (HLA)-DRB1 position 13 between the combined dataset of oligoarthritis and rheumatoid factor (RF)-negative polyarthritis compared with those for RF-positive polyarthritis.

Figure 3

Analysis in the combined dataset of persistent and extended oligoarthritis and rheumatoid factor (RF)-negative polyarthritis, evidence for multiple independent effects across the major histocompatibility region (MHC). (A) Association results for all human leucocyte antigen (HLA) markers, HLA-DRB1 amino acid position 13 showed the strongest association (p<10⁻³⁷⁷). (B) Conditioning on all HLA-DRB1 two-digit and four-digit alleles, HLA-DPB1*02:01 was associated (p<10⁻⁵⁷). (C) Conditioning on all HLA-DRB1 two-digit and four-digit alleles and HLA-DPB1*02:01, HLA-A amino acid position 95 was associated (p<10⁻³⁷). (D) Conditioning on all HLA-DRB1 two-digit and four-digit alleles, HLA-DPB1*02:01 and HLA-A amino acid position 95, HLA-B amino acid position 152 was associated (p<10⁻¹⁰).