Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups
Rothwell, Simon; Chinoy, Hector; Lamb, Janine A.; Miller, Frederick W.; Rider, Lisa G.; Wedderburn, Lucy R.; McHugh, Neil J.; Mammen, Andrew L.; Betteridge, Zoe E.; Tansley, Sarah L.; Bowes, John; Vencovský, Ji I.; Deakin, Claire T.; Dankó, Katalin; Vidya, Limaye; Selva-O'Callaghan, Albert; Pachman, Lauren M.; Reed, Ann M.; Molberg, Yvind; Benveniste, Olivier; Mathiesen, Pernille R.; Radstake, Timothy R.D.J.; Doria, Andrea; De Bleecker, Jan; Lee, Annette T.; Hanna, Michael G.; Machado, Pedro M.; Ollier, William E.; Gregersen, Peter K.; Padyukov, Leonid; O'Hanlon, Terrance P.; Cooper, Robert G.; Lundberg, Ingrid E.
(2019) Annals of the Rheumatic Diseases, volume 78, issue 7, pp. 996 - 1002
(Article)
Abstract
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
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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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Keywords: autoantibody, genetics, HLA, idiopathic inflammatory myopathy, myositis, Rheumatology, Immunology and Allergy, Immunology, General Biochemistry,Genetics and Molecular Biology
ISSN: 0003-4967
Publisher: BMJ Publishing Group
Note: Funding Information: Competing interests JV reports grants from Ministry of Health in the czech republic, grants from european community’s FP6, autocure lsHB cT-2006-01866, grants from european science Foundation, during the conduct of the study. iel reports grants from swedish research council, grants from european science Foundation, grants from association Francaise contre les Myopathies (aFM), grants from stockholm county council, grants from The european Union sixth Framework Programme, during the conduct of the study. Funding Information: Funding This study was supported in part by: association Francaise contre les Myopathies (aFM), The european Union sixth Framework Programme (project autocure; lsH-018661), european science Foundation (esF) in the framework of the research networking Programme european Myositis network (eUMYoneT), The swedish research council and grants provided by the stockholm county council (alF project), the swedish rheumatism association, King Gustaf V 80 year Foundation, the intramural research programs of the national institute of environmental Health sciences (nieHs) and the national institute of arthritis and Musculoskeletal and skin Diseases (niaMs), the national institutes of Health (niH), european community’s FP6, autocure lsHB cT-2006-018661, The UK Myositis support Group, arthritis research UK (18474 and 20380), Medical research council (Mr/n003322/1), The cure JM Foundation, the Wellcome Trust, the Henry smith charity UK, action Medical UK. The czech cohort was supported by Project for conceptual Development of research organization 00023728 from Ministry of Health in the czech republic. antibody testing in the UK JDrG cohort was supported by a BMa Dorris Hillier Grant 2012 and the Bath institute of rheumatic Diseases. Thank you to the research Fund of region Zeeland, Denmark. Pedro M. Machado is supported by the national institute for Health research (niHr) University college london Hospitals (Ucl) Biomedical research centre (Brc). lrW is supported by the national institute for Health research (niHr) Great ormond street Hospital (GosH) Biomedical research centre (Brc). This report includes independent research supported by the niHr Biomedical research centre Funding scheme. Publisher Copyright: © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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