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Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups
S. Rothwell, H. Chinoy, JA. Lamb, FW. Miller, LG. Rider, LR. Wedderburn, NJ. McHugh, AL. Mammen, ZE. Betteridge, SL. Tansley, J. Bowes, J. Vencovský, CT. Deakin, K. Dankó, L. Vidya, A. Selva-O'Callaghan, LM. Pachman, AM. Reed, Ø. Molberg, O....
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
MR/K000608/1
Medical Research Council - United Kingdom
20380
Arthritis Research UK - United Kingdom
MR/N003322/1
Medical Research Council - United Kingdom
18474
Arthritis Research UK - United Kingdom
MR/S005021/1
Medical Research Council - United Kingdom
G0601943
Medical Research Council - United Kingdom
NLK
ProQuest Central
od 1939-01-01 do Před 6 měsíci
Health & Medicine (ProQuest)
od 1939-01-01 do Před 6 měsíci
Family Health Database (ProQuest)
od 1939-01-01 do Před 6 měsíci
- MeSH
- alely MeSH
- autoprotilátky genetika imunologie MeSH
- běloši genetika MeSH
- dospělí MeSH
- genotyp MeSH
- haplotypy MeSH
- HLA-DRB1 řetězec genetika imunologie MeSH
- hlavní histokompatibilní komplex genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- myozitida genetika imunologie MeSH
- polymorfismus genetický MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
Arthritis Research UK Centre for Genetics and Genomics The University of Manchester Manchester UK
Centre for Epidemiology The University of Manchester Manchester UK
Centre for Genetics and Genomics Arthritis Research UK University of Manchester Manchester UK
Department of Neurology Ghent University Ghent Belgium
Department of Paediatrics and Adolescent Medicine Rigshospitalet Copenhagen Denmark
Department of Rheumatology and Clinical Immunology Utrecht Medical Center Utrecht The Netherlands
Department of Rheumatology University of Oslo Oslo Norway
Division of Rheumatology Department of Medicine Karolinska University Hospital Stockholm Sweden
Division of Rheumatology University of Padova Padova Italy
Institute of Rheumatology and Department of Rheumatology Charles University Prague Czech Republic
Internal Medicine University of Debrecen Debrecen Hungary
Pediatrics Duke University Durham North Carolina USA
Pharmacy and Pharmacology University of Bath Bath UK
Rheumatology Unit Royal Adelaide Hospital University of Adelaide Adelaide South Australia Australia
Citace poskytuje Crossref.org
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- $a Rothwell, Simon $u Centre for Genetics and Genomics, Arthritis Research UK, University of Manchester, Manchester, UK s.rothwell@manchester.ac.uk.
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- $a 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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