Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Imputation
Rothwell, Simon (University of Manchester)
Amos, Christopher I. (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Miller, Frederick W. (National Institute of Environmental Health Sciences, NIH)
Rider, Lisa G. (National Institute of Environmental Health Sciences, NIH)
Lundberg, Ingrid E. (Karolinska University Hospital)
Gregersen, Peter K. (Feinstein Institute for Medical Research)
Vencovsky, Jiri (Charles University)
McHugh, Neil (University of Bath)
Limaye, Vidya (Adelaide University)
Selva O'Callaghan, Albert (Vall d'Hebron Institut de Recerca (VHIR))
Hanna, M. G. (University College London)
Machado, Pedro M. (University College London)
Pachman, Lauren M. (Northwestern University Feinberg School of Medicine)
Reed, Ann M. (Duke University)
Molberg, Øyvind (Oslo University Hospital (Oslo, Noruega))
Benveniste, Olivier (Hospital de la Pitié-Salpêtrière (París, França))
Mathiesen, Pernille (University of Copenhagen)
Radstake, Timothy (University Medical Center)
Doria, Andrea (University of Padova)
De Bleecker, Jan (Ghent University)
De Paepe, Boel (Ghent University)
Maurer, Britta (University Hospital)
Ollier, William E. (Manchester Metropolitan University)
Padyukov, Leonid (Karolinska University Hospital)
O'Hanlon, Terrance P. (National Institute of Environmental Health Sciences, NIH)
Lee, Annette (The Feinstein Institute)
Wedderburn, Lucy R. (University College London)
Chinoy, Hector (Salford Royal NHS Foundation Trust (Salford, Regne Unit))
Lamb, Janine A. (University of Manchester)
Universitat Autònoma de Barcelona

Data:	2023
Resum:	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. 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. 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. We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.
Drets:	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, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Arthritis & rheumatology (Malden), Vol. 75 (march 2023) , p. 1021-1027, ISSN 2326-5205

DOI: 10.1002/art.42434
PMID: 36580032

7 p, 608.5 KB

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