Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria.

Autor: Kristjansson RP; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Oskarsson GR; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Skuladottir A; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Oddsson A; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Rognvaldsson S; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Sveinbjornsson G; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Lund SH; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Jensson BO; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Styrmisdottir EL; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Halldorsson GH; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Ferkingstad E; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Eldjarn GH; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Beyter D; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Kristmundsdottir S; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Science and Engineering, Reykjavik University, Reykjavik, Iceland., Juliusson K; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Fridriksdottir R; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Arnadottir GA; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Katrinardottir H; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Snorradottir MH; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Tragante V; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Stefansdottir L; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Ivarsdottir EV; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Bjornsdottir G; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Halldorsson BV; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Science and Engineering, Reykjavik University, Reykjavik, Iceland., Thorleifsson G; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Ludviksson BR; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.; Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland., Onundarson PT; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.; Department of Laboratory Hematology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland., Saevarsdottir S; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.; Rheumatology Unit, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.; Department of Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland., Melsted P; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Norddahl GL; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Bjornsdottir US; Department of Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.; The Medical Center Mjodd, Reykjavik, Iceland., Olafsdottir T; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Gudbjartsson DF; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Thorsteinsdottir U; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Jonsdottir I; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Sulem P; deCODE genetics/Amgen Inc., Reykjavik, Iceland. patrick.sulem@decode.is., Stefansson K; deCODE genetics/Amgen Inc., Reykjavik, Iceland. kstefans@decode.is.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. kstefans@decode.is.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 Jul 10; Vol. 6 (1), pp. 703. Date of Electronic Publication: 2023 Jul 10.
DOI: 10.1038/s42003-023-05079-4
Abstrakt: Urticaria is a skin disorder characterized by outbreaks of raised pruritic wheals. In order to identify sequence variants associated with urticaria, we performed a meta-analysis of genome-wide association studies for urticaria with a total of 40,694 cases and 1,230,001 controls from Iceland, the UK, Finland, and Japan. We also performed transcriptome- and proteome-wide analyses in Iceland and the UK. We found nine sequence variants at nine loci associating with urticaria. The variants are at genes participating in type 2 immune responses and/or mast cell biology (CBLB, FCER1A, GCSAML, STAT6, TPSD1, ZFPM1), the innate immunity (C4), and NF-κB signaling. The most significant association was observed for the splice-donor variant rs56043070[A] (hg38: chr1:247556467) in GCSAML (MAF = 6.6%, OR = 1.24 (95%CI: 1.20-1.28), P-value = 3.6 × 10 -44 ). We assessed the effects of the variants on transcripts, and levels of proteins relevant to urticaria pathophysiology. Our results emphasize the role of type 2 immune response and mast cell activation in the pathogenesis of urticaria. Our findings may point to an IgE-independent urticaria pathway that could help address unmet clinical need.
(© 2023. The Author(s).)
Databáze: MEDLINE
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