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Contribution of rar...
Contribution of rare genetic variation to disease susceptibility in a large Scandinavian myositis cohort
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- Bianchi, Matteo (författare)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Reumatologi
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- Kozyrev, Sergey V. (författare)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Notarnicola, Antonella (författare)
- Karolinska Institutet
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- Hultin-Rosenberg, Lina (författare)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Karlsson, Åsa (författare)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Pucholt, Pascal, Dr, 1985- (författare)
- Uppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab
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- Rothwell, Simon (författare)
- Centre for Musculoskeletal Research Faculty of Biology, Medicine and Health The University of Manchester Manchester UK
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- Alexsson, Andrei (författare)
- Uppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi
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- Sandling, Johanna K. (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Reumatologi,Molekylär epidemiologi
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- Andersson, Helena (författare)
- Department of Rheumatology Oslo University Hospital 0372 Oslo, Norway
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- Cooper, Robert G. (författare)
- MRC/ARUK Centre for Integrated Research into Musculoskeletal Ageing University of Liverpool Liverpool UK; Department of Rheumatology Aintree University Hospital, Liverpool UK
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- Padyukov, Leonid (författare)
- Karolinska Institutet
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- Tjärnlund, Anna (författare)
- Division of Rheumatology, Department of Medicine, Solna Karolinska Institutet, and Karolinska University Hospital, Stockholm Sweden
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- Dastmalchi, Maryam (författare)
- Division of Rheumatology, Department of Medicine, Solna Karolinska Institutet, and Karolinska University Hospital, Stockholm Sweden
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- Meadows, Jennifer (författare)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Pyndt Diederichsen, Louise (författare)
- Department of Rheumatology Odense University Hospital Odense Denmark; Center for Rheumatology and Spine Diseases Copenhagen University Hospital, Rigshospitalet, Copenhagen Denmark
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- Molberg, Øyvind (författare)
- Department of Rheumatology Oslo University Hospital Oslo Norway; Institute of Clinical Medicine University of Oslo, Oslo Norway
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- Chinoy, Hector (författare)
- National Institute for Health Research Manchester Biomedical Research Centre Manchester University NHS Foundation Trust Manchester Academic Health Science Centre University of Manchester Manchester UK; Department of Rheumatology Salford Royal NHS Foundation Trust Manchester Academic Health Science Centre Salford UK
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- Lamb, Janine (författare)
- Epidemiology and Public Health Group Division of Population Health Health Services Research & Primary Care Faculty of Biology, Medicine and Health Manchester Academic Health Science Centre University of Manchester, Manchester UK
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- Rönnblom, Lars (författare)
- Uppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab
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- Lindblad-Toh, Kerstin (författare)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Broad Institute of MIT and Harvard Cambridge MA USA
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- Lundberg, Ingrid E. (författare)
- Karolinska Institutet
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Molberg, O (författare)
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(creator_code:org_t)
- 2021-12-23
- 2022
- Engelska.
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Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 74:2, s. 342-352
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Objective Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs.Methods Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case–control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant– and gene-level enrichment analyses, was implemented to explore genotype–phenotype relations.Results Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle–specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants.Conclusion Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
Nyckelord
- Immunology
- Rheumatology
- Immunology and Allergy
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Bianchi, Matteo
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Kozyrev, Sergey ...
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Notarnicola, Ant ...
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Hultin-Rosenberg ...
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Karlsson, Åsa
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Pucholt, Pascal, ...
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Rothwell, Simon
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Alexsson, Andrei
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Sandling, Johann ...
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Andersson, Helen ...
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Cooper, Robert G ...
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Padyukov, Leonid
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Tjärnlund, Anna
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Dastmalchi, Mary ...
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Meadows, Jennife ...
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Pyndt Diederichs ...
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Molberg, Øyvind
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Chinoy, Hector
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Lamb, Janine
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Rönnblom, Lars
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Lindblad-Toh, Ke ...
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Lundberg, Ingrid ...
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Molberg, O
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