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Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups
S. Rothwell, RG. Cooper, IE. Lundberg, FW. Miller, PK. Gregersen, J. Bowes, J. Vencovsky, K. Danko, V. Limaye, A. Selva-O'Callaghan, MG. Hanna, PM. Machado, LM. Pachman, AM. Reed, LG. Rider, J. Cobb, H. Platt, Ø. Molberg, O. Benveniste, P....
Language English Country England, Great Britain
Document type Journal Article, Multicenter Study
NLK
ProQuest Central
from 1939-01-01 to 6 months ago
Health & Medicine (ProQuest)
from 1939-01-01 to 6 months ago
Family Health Database (ProQuest)
from 1939-01-01 to 6 months ago
- MeSH
- Alleles MeSH
- Autoimmunity genetics MeSH
- Genome-Wide Association Study MeSH
- Dermatomyositis genetics MeSH
- Genetic Predisposition to Disease MeSH
- Genotype MeSH
- HLA Antigens genetics MeSH
- Polymorphism, Single Nucleotide MeSH
- Humans MeSH
- Quantitative Trait Loci MeSH
- Myositis genetics immunology MeSH
- Polymyositis genetics MeSH
- Risk Factors MeSH
- Case-Control Studies MeSH
- Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
OBJECTIVES: The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. RESULTS: The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10(-8)). Nine regions were associated at a significance level of p<2.25×10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM. CONCLUSIONS: This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.
Centre for Genetics and Genomics Arthritis Research UK University of Manchester Manchester UK
Centre for Integrated Genomic Medical Research University of Manchester Manchester UK
Department of Internal Medicine Vall d'Hebron Hospital Barcelona Spain
Department of Medicine University of Padova Padova Italy
Department of Neurology Neuromuscular Reference Centre Ghent University Hospital Ghent Belgium
Department of Pediatrics Duke University Durham North Carolina USA
Department of Rheumatology Oslo University Hospital Oslo Norway
Geisel School of Medicine Dartmouth College Hanover New Hampshire USA
Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt Neuherberg Germany
MRC Centre for Neuromuscular Diseases UCL Institute of Neurology London UK
Paediatric Department Naestved Hospital Næstved Denmark
Pitié Salpêtrière Hospital UPMC APHP Paris France
Royal Adelaide Hospital and University of Adelaide Adelaide South Australia Australia
References provided by Crossref.org
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- $a Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups / $c S. Rothwell, RG. Cooper, IE. Lundberg, FW. Miller, PK. Gregersen, J. Bowes, J. Vencovsky, K. Danko, V. Limaye, A. Selva-O'Callaghan, MG. Hanna, PM. Machado, LM. Pachman, AM. Reed, LG. Rider, J. Cobb, H. Platt, Ø. Molberg, O. Benveniste, P. Mathiesen, T. Radstake, A. Doria, J. De Bleecker, B. De Paepe, B. Maurer, WE. Ollier, L. Padyukov, TP. O'Hanlon, A. Lee, CI. Amos, C. Gieger, T. Meitinger, J. Winkelmann, LR. Wedderburn, H. Chinoy, JA. Lamb, . ,
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- $a OBJECTIVES: The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. RESULTS: The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10(-8)). Nine regions were associated at a significance level of p<2.25×10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM. CONCLUSIONS: This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.
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