Contribution of Rare Genetic Variation to Disease Susceptibility in a Large Scandinavian Myositis Cohort. Issue 2 (23rd December 2021)

• Record Type: Journal Article
• Authors: Bianchi, Matteo; Kozyrev, Sergey V.; Notarnicola, Antonella; Hultin Rosenberg, Lina; Karlsson, Åsa; Pucholt, Pascal; Rothwell, Simon; Alexsson, Andrei; Sandling, Johanna K.; Andersson, Helena; Cooper, Robert G.; Padyukov, Leonid; Tjärnlund, Anna; Dastmalchi, Maryam; Meadows, Jennifer R. S.; Pyndt Diederichsen, Louise; Molberg, Øyvind; Chinoy, Hector; Lamb, Janine A.; Rönnblom, Lars; Lindblad‐Toh, Kerstin; Lundberg, Ingrid E.
• Other Names: investigator.; Lindblad‐Toh Kerstin investigator.; Pielberg Gerli Rosengren investigator.; Lobell Anna investigator.; Karlsson Åsa investigator.; Murén Eva investigator.; Ahlgren Kerstin M. investigator.; Rönnblom Lars investigator.; Eloranta Maija‐Leena investigator.; Andersson Göran investigator.; Landegren Nils investigator.; Kämpe Olle investigator.; Söderkvist Peter investigator.; investigator.; Bianchi Matteo investigator.; Kozyrev Sergey V. investigator.; Rosenberg Lina Hultin investigator.; Pucholt Pascal investigator.; Alexsson Andrei investigator.; Sandling Johanna K. investigator.; Rönnblom Lars investigator.; Eloranta Maija‐Leena investigator.; Syvänen Ann‐Christine investigator.; Leonard Dag investigator.; Almlöf Jonas Carlsson investigator.; Dahlqvist Johanna investigator.; Hagberg Niklas investigator.; Lidén Maria investigator.; Mathioudaki Argyri investigator.; Meadows Jennifer R. S. investigator.; Nordin Jessika investigator.; Nordmark Gunnel investigator.; Yavuz Sule investigator.; Lundberg Ingrid E. investigator.; Padyukov Leonid investigator.; Gunnarsson Iva investigator.; Svenungsson Elisabet investigator.; Eriksson Daniel investigator.; Molberg Øyvind investigator.; Lindblad‐Toh Kerstin investigator.; Farias Fabiana H. G. investigator.; Bengtsson Christine investigator.; Rantapää‐Dahlqvist Solbritt investigator.; Jonsson Roland investigator.; Omdal Roald investigator.; Jönsen Andreas investigator.; Bengtsson Anders A. investigator.; Sjöwall Christopher investigator.; Skogh Thomas investigator.; Wahren‐Herlenius Marie investigator.; Jalal Awat investigator.; Hanna Balsam investigator.; Hellström Helena investigator.; Husmark Tomas investigator.; Häggström Åsa investigator.; Svärd Anna investigator.;
• Is Part Of: Arthritis & rheumatology. Volume 74:Issue 2(2022)
• Page Start: 342
• Page End: 352
• Publication Date: 2021-12-23
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.41929
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : 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.