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.
- Juvenile Idiopathic Arthritis
- Autoimmune Diseases
- Rheumatoid Arthritis
- Gene Polymorphism
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Handling editor Tore K Kvien
AH and JB contributed equally.
SDT and WT contributed equally as senior authors.
Contributors WT, SDT, SR, CDL, SP, JB and AH led the study. AH, JB, SR, CDL, SP, SDT and WT wrote the paper. AH, JB, JC, HCA, MCM, MEC, MS, BH, CDL and SR performed the data and statistical analysis. MLB, JFB, PIWdB, JPH, MH, DJL, PAN, EN, MP, AMR, MR, SLS, CAW, VV, LRW, AY, RSMY contributed to the patient ascertainment, sample collection and/or genotyping. All authors reviewed the final manuscript.
Collaborators Juvenile Arthritis Consortium for Immunochip: full list of affiliations for consortia will appear in the online supplementary information.
Funding Wellcome Trust (068545/Z/01, 076113/C/04/Z); for statistical support at Wake-Forest, National Institutes of Health (NIH) grant (R01-AR-057106); National Institute for Health Research programme grant, (RP-PG-0310-1002); Doris Duke Charitable Foundation Grant (2013097); NIH (10.13039/100000002, U01 DK062418, RC2AR059092, DK062431, DK062422, DK0); for Utah samples, NIH grants (K23-AR-50177 and R01-AR-060893; UK samples, Sparks UK (08ICH09); for the UK samples and support, Arthritis Research UK (20385 and 20542); Medical Research Council (G0000934, MR/M004600/1); Canadian Institutes of Health Research (FRN-82517); the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology; NIH Federal Ministry of Education and Research, Germany (01GM0907 and 01 ZZ 0403); SR is supported by grants from the NIH (1R01AR063759); genotyping of the US JIA, German JIA and respective control collections was supported by NIAMS/NIGMS/NIAID/NIH (RC1-AR-058587, U01-AI-067150S1, N01-AR-42272, P01); Juvenile Diabetes Research Foundation International; the US sample recruitment was supported in part by NIAMS/NIGMS/NIAID/NIH and from Texas Scottish Rite Hospital for Children (N01AR62277, GM103510, AI082714, AR053483, 1296353. Patient recruitment and DNA preparation in Canada was supported by funding from the Canadian Institutes of Health Research (FRN-82517), the Canadian Arthritis Society and the Canadian Arthritis Network.
Competing interests LRW reports Honorarium for speaker at Symposium from Pfizer Inc. SP has been on advisory boards for Novartis, medac and UCB pharma. None of these had any bearing on the work reported in this publication.
Ethics approval North-West Multi-Centre Research Ethics Committee (MREC 99/8/84), the University of Manchester Committee on the Ethics of Research on Human Beings and National Research Ethics Service (NRES 02/8/104).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Additional data are included in the online supplementary data.
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