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Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation
S. Rothwell, CI. Amos, FW. Miller, LG. Rider, IE. Lundberg, PK. Gregersen, J. Vencovsky, N. McHugh, V. Limaye, A. Selva-O'Callaghan, MG. Hanna, PM. Machado, LM. Pachman, AM. Reed, Ø. Molberg, O. Benveniste, P. Mathiesen, T. Radstake, A. Doria,...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, N.I.H., Intramural
Grantová podpora
21552
Versus Arthritis - United Kingdom
085860
Wellcome Trust - United Kingdom
21593
Versus Arthritis - United Kingdom
MR/N003322/1
Medical Research Council - United Kingdom
ZIA ES101074
Intramural NIH HHS - United States
PubMed
36580032
DOI
10.1002/art.42434
Knihovny.cz E-zdroje
- MeSH
- autoimunitní nemoci * genetika MeSH
- genetická predispozice k nemoci MeSH
- haplotypy MeSH
- lidé MeSH
- myozitida * genetika MeSH
- polymyozitida * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Intramural MeSH
OBJECTIVE: The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS: We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. RESULTS: The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSION: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.
Baylor College of Medicine Houston Texas
Department of Internal Medicine and Clinical Immunology Pitié Salpêtrière Hospital Paris France
Department of Neurology Ghent University Ghent Belgium
Department of Pediatrics Duke University Durham North Carolina
Department of Pharmacy and Pharmacology University of Bath Bath UK
Department of Rheumatology and Clinical Immunology University Medical Center Utrecht the Netherlands
Department of Rheumatology and Immunology University Hospital Bern Switzerland
Department of Rheumatology Oslo University Hospital Oslo Norway
Manchester Metropolitan University School of Healthcare Sciences Manchester UK
Rheumatology Unit Department of Medicine University of Padova Padova Italy
The Robert S Boas Center for Genomics and Human Genetics The Feinstein Institute Manhasset New York
Citace poskytuje Crossref.org
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