Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups
Rothwell, Simon (University of Manchester)
Chinoy, Hector (Salford Royal NHS Foundation Trust)
Lamb, Janine A. (The University of Manchester)
Miller, Frederick W. (National Institute of Environmental Health Sciences)
Rider, Lisa G. (National Institute of Environmental Health Sciences)
Wedderburn, Lucy R. (University College London)
McHugh, Neil J. (University of Bath)
Mammen, Andrew L. (Johns Hopkins University School of Medicine)
Betteridge, Zoe E. (University of Bath)
Tansley, Sarah L. (Royal United Hospitals Bath NHS Foundation Trust)
Bowes, John (The University of Manchester)
Vencovský, Jiří (Charles University)
Deakin, Claire T. (University College London)
Dankó, Katalin (University of Debrecen)
Vidya, Limaye (Royal Adelaide Hospital)
Selva-O'Callaghan, Albert (Hospital Universitari Vall d'Hebron)
Pachman, Lauren M. (Northwestern University, Feinberg School of Medicine)
Reed, Ann M. (Duke University)
Molberg, Øyvind (University of Oslo)
Benveniste, Olivier (Pitié-Salpêtrière University Hospital)
Mathiesen, Pernille R. (University of Copenhagen)
Radstake, Timothy R. D. J. (Utrecht Medical Center)
Doria, Andrea (Division of Rheumatology, University of Padova)
De Bleecker, Jan (Ghent University)
Lee, Annette T. (The Feinstein Institute for Medical Research)
Hanna, M. G (University College London Institute of Neurology)
Machado, Pedro M. (London North West University Healthcare NHS Trust)
Ollier, William E. (Manchester Metropolitan University)
Gregersen, Peter K. (The Feinstein Institute for Medical Research)
Padyukov, Leonid (Karolinska University Hospital and Karolinska Institutet (Suècia))
O'Hanlon, Terrance P. (National Institute of Environmental Health Sciences)
Cooper, Robert G. (University of Liverpool)
Lundberg, Ingrid E. (Karolinska University Hospital and Karolinska Institutet (Suècia))
Universitat Autònoma de Barcelona

Date:	2019
Abstract:	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. 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. 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. 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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Genetics ; Idiopathic inflammatory myopathy ; Myositis ; HLA ; Autoantibody
Published in:	Annals of the rheumatic diseases, Vol. 78 (may 2019) , p. 996-1002, ISSN 1468-2060

DOI: 10.1136/annrheumdis-2019-215046
PMID: 31138531

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