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

J. Bowes, J. Cobb, H. C. Ainsworth, M. C. Marion, M. E. Comeau, M. Sudman, B. Han, M. L. Becker, J. F. Bohnsack, P. I W de Bakker, J. P. Haas, M. Hazen, D. J. Love, P. A. Nigrovic, E. Nordal, M. Punnaro, A. M. Rosenberg, M. Rygg, S. L. Smith, C. A. WiseV. Videm, L. R. Wedderburn, A. Yarwood, R. S M Yeung, S. Prahalad, C. D. Langefeld, S. Raychaudhuri, S. D. Thompson, W. Thomson

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAnnals of the Rheumatic Diseases
DOIs
StateAccepted/In press - Dec 20 2016

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Genetic Heterogeneity
Juvenile Arthritis
HLA Antigens
Arthritis
Rheumatoid Factor
Amino Acids
Pediatrics
Polymorphism
Rheumatoid Arthritis
Nucleotides
Single Nucleotide Polymorphism
Alleles
Genotype

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. / Bowes, J.; Cobb, J.; Ainsworth, H. C.; Marion, M. C.; Comeau, M. E.; Sudman, M.; Han, B.; Becker, M. L.; Bohnsack, J. F.; de Bakker, P. I W; Haas, J. P.; Hazen, M.; Love, D. J.; Nigrovic, P. A.; Nordal, E.; Punnaro, M.; Rosenberg, A. M.; Rygg, M.; Smith, S. L.; Wise, C. A.; Videm, V.; Wedderburn, L. R.; Yarwood, A.; Yeung, R. S M; Prahalad, S.; Langefeld, C. D.; Raychaudhuri, S.; Thompson, S. D.; Thomson, W.

In: Annals of the Rheumatic Diseases, 20.12.2016.

Research output: Contribution to journalArticle

Bowes, J, Cobb, J, Ainsworth, HC, Marion, MC, Comeau, ME, Sudman, M, Han, B, Becker, ML, Bohnsack, JF, de Bakker, PIW, Haas, JP, Hazen, M, Love, DJ, Nigrovic, PA, Nordal, E, Punnaro, M, Rosenberg, AM, Rygg, M, Smith, SL, Wise, CA, Videm, V, Wedderburn, LR, Yarwood, A, Yeung, RSM, Prahalad, S, Langefeld, CD, Raychaudhuri, S, Thompson, SD & Thomson, W 2016, 'Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases', Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2016-210025
Bowes, J. ; Cobb, J. ; Ainsworth, H. C. ; Marion, M. C. ; Comeau, M. E. ; Sudman, M. ; Han, B. ; Becker, M. L. ; Bohnsack, J. F. ; de Bakker, P. I W ; Haas, J. P. ; Hazen, M. ; Love, D. J. ; Nigrovic, P. A. ; Nordal, E. ; Punnaro, M. ; Rosenberg, A. M. ; Rygg, M. ; Smith, S. L. ; Wise, C. A. ; Videm, V. ; Wedderburn, L. R. ; Yarwood, A. ; Yeung, R. S M ; Prahalad, S. ; Langefeld, C. D. ; Raychaudhuri, S. ; Thompson, S. D. ; Thomson, W. / Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. In: Annals of the Rheumatic Diseases. 2016.
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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.",
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T1 - Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases

AU - Bowes, J.

AU - Cobb, J.

AU - Ainsworth, H. C.

AU - Marion, M. C.

AU - Comeau, M. E.

AU - Sudman, M.

AU - Han, B.

AU - Becker, M. L.

AU - Bohnsack, J. F.

AU - de Bakker, P. I W

AU - Haas, J. P.

AU - Hazen, M.

AU - Love, D. J.

AU - Nigrovic, P. A.

AU - Nordal, E.

AU - Punnaro, M.

AU - Rosenberg, A. M.

AU - Rygg, M.

AU - Smith, S. L.

AU - Wise, C. A.

AU - Videm, V.

AU - Wedderburn, L. R.

AU - Yarwood, A.

AU - Yeung, R. S M

AU - Prahalad, S.

AU - Langefeld, C. D.

AU - Raychaudhuri, S.

AU - Thompson, S. D.

AU - Thomson, W.

PY - 2016/12/20

Y1 - 2016/12/20

N2 - 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.

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