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  • Bianchi, MatteoUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Reumatologi (author)

Contribution of rare genetic variation to disease susceptibility in a large Scandinavian myositis cohort

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2021-12-23
  • John Wiley & Sons,2022
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-458674
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-458674URI
  • https://doi.org/10.1002/art.41929DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:148416308URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

Subject headings and genre

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  • Kozyrev, Sergey V.Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)sekoz957 (author)
  • Notarnicola, AntonellaKarolinska Institutet (author)
  • Hultin-Rosenberg, LinaUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)linhu641 (author)
  • Karlsson, ÅsaUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)asaka483 (author)
  • Pucholt, Pascal,Dr,1985-Uppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)paspu920 (author)
  • Rothwell, SimonCentre for Musculoskeletal Research Faculty of Biology, Medicine and Health The University of Manchester Manchester UK (author)
  • Alexsson, AndreiUppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi(Swepub:uu)andax639 (author)
  • Sandling, Johanna K.Uppsala universitet,Science for Life Laboratory, SciLifeLab,Reumatologi,Molekylär epidemiologi(Swepub:uu)josan062 (author)
  • Andersson, HelenaDepartment of Rheumatology Oslo University Hospital 0372 Oslo, Norway (author)
  • Cooper, Robert G.MRC/ARUK Centre for Integrated Research into Musculoskeletal Ageing University of Liverpool Liverpool UK; Department of Rheumatology Aintree University Hospital, Liverpool UK (author)
  • Padyukov, LeonidKarolinska Institutet (author)
  • Tjärnlund, AnnaDivision of Rheumatology, Department of Medicine, Solna Karolinska Institutet, and Karolinska University Hospital, Stockholm Sweden (author)
  • Dastmalchi, MaryamDivision of Rheumatology, Department of Medicine, Solna Karolinska Institutet, and Karolinska University Hospital, Stockholm Sweden (author)
  • Meadows, JenniferUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)jenme818 (author)
  • Pyndt Diederichsen, LouiseDepartment of Rheumatology Odense University Hospital Odense Denmark; Center for Rheumatology and Spine Diseases Copenhagen University Hospital, Rigshospitalet, Copenhagen Denmark (author)
  • Molberg, ØyvindDepartment of Rheumatology Oslo University Hospital Oslo Norway; Institute of Clinical Medicine University of Oslo, Oslo Norway (author)
  • Chinoy, HectorNational 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 (author)
  • Lamb, JanineEpidemiology 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 (author)
  • Rönnblom, LarsUppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)larsronn (author)
  • Lindblad-Toh, KerstinUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Broad Institute of MIT and Harvard Cambridge MA USA(Swepub:uu)kerli865 (author)
  • Lundberg, Ingrid E.Karolinska Institutet (author)
  • Molberg, O (author)
  • Uppsala universitetInstitutionen för medicinsk biokemi och mikrobiologi (creator_code:org_t)

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  • In:Arthritis & Rheumatology: John Wiley & Sons74:2, s. 342-3522326-51912326-5205

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