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Article Dans Une Revue Annals of the Rheumatic Diseases Année : 2019

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups

Simon Rothwell
Hector Chinoy
Lisa Rider
  • Fonction : Auteur
Lucy Wedderburn
  • Fonction : Auteur
Neil Mchugh
Zoe Betteridge
  • Fonction : Auteur
Sarah Tansley
  • Fonction : Auteur
John Bowes
Claire Deakin
  • Fonction : Auteur
Katalin Dankó
  • Fonction : Auteur
Limaye Vidya
  • Fonction : Auteur
Albert Selva-O'Callaghan
  • Fonction : Auteur
Lauren Pachman
  • Fonction : Auteur
Ann Reed
  • Fonction : Auteur
Pernille Mathiesen
  • Fonction : Auteur
Timothy Radstake
  • Fonction : Auteur
Andrea Doria
Jan de Bleecker
  • Fonction : Auteur
Annette Lee
  • Fonction : Auteur
Michael Hanna
  • Fonction : Auteur
Pedro Machado
  • Fonction : Auteur
William Ollier
  • Fonction : Auteur
Peter Gregersen
  • Fonction : Auteur
Leonid Padyukov
  • Fonction : Auteur
Terrance O'Hanlon
  • Fonction : Auteur
Robert Cooper
  • Fonction : Auteur
Ingrid Lundberg
  • Fonction : Auteur

Résumé

Objectives Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. Methods We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. Results We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10 –5 . Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10 –53 and HLA-DRB1*03:01, p=3.25×10 –9 ), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10 –26 ) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10 –11 ). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10 –13 ) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10 –6 ). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10 –64 ) and position 9 of HLA-B (p=7.03×10 –11 ). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. Conclusions These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
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Dates et versions

hal-03831144 , version 1 (15-11-2022)

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Simon Rothwell, Hector Chinoy, Janine Lamb, Frederick Miller, Lisa Rider, et al.. Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups. Annals of the Rheumatic Diseases, 2019, 78 (7), pp.996-1002. ⟨10.1136/annrheumdis-2019-215046⟩. ⟨hal-03831144⟩
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