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

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

Title: Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria
Author: Kristjansson, Ragnar P.
Oskarsson, Gudjon R.
Skuladottir, Astros
Oddsson, Asmundur   orcid.org/0000-0002-4606-5163
Rognvaldsson, Solvi
Sveinbjornsson, Gardar   orcid.org/0000-0003-2429-9468
Lund, Sigrun H.
Jensson, Brynjar O.
Styrmisdottir, Edda L.
Halldorsson, Gisli H.
... 27 more authors Show all authors
Date: 2023-07-10
Language: English
Scope: 1674688
University/Institute: Landspitali - The National University Hospital of Iceland
Reykjavik University
School: Health Sciences
Department: Department of Engineering
Faculty of Physical Sciences
Faculty of Industrial Engineering, Mechanical Engineering and Computer Science
Faculty of Medicine
Other departments
Series: Communications Biology; 6(1)
ISSN: 2399-3642
DOI: 10.1038/s42003-023-05079-4
Subject: Ónæmisfræði; Blóðlæknisfræði; Gigtarlæknisfræði; Lungnalæknisfræði; Humans; Genome-Wide Association Study; Mast Cells; Urticaria/genetics; RNA Splicing; Proteome; Agricultural and Biological Sciences (all); Biochemistry, Genetics and Molecular Biology (all); Medicine (miscellaneous)
URI: https://hdl.handle.net/20.500.11815/4495

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Kristjansson , R P , Oskarsson , G R , Skuladottir , A , Oddsson , A , Rognvaldsson , S , Sveinbjornsson , G , Lund , S H , Jensson , B O , Styrmisdottir , E L , Halldorsson , G H , Ferkingstad , E , Eldjarn , G H , Beyter , D , Kristmundsdottir , S , Juliusson , K , Fridriksdottir , R , Arnadottir , G A , Katrinardottir , H , Snorradottir , M H , Tragante , V , Stefansdottir , L , Ivarsdottir , E V , Bjornsdottir , G , Halldorsson , B V , Thorleifsson , G , Lúðvíksson , B R , Önundarson , P T , Sævarsdóttir , S , Melsted , P , Norddahl , G L , Björnsdóttir , U S , Olafsdottir , T , Gudbjartsson , D F , Thorsteinsdottir , U , Jonsdottir , I , Sulem , P & Stefansson , K 2023 , ' Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria ' , Communications Biology , vol. 6 , no. 1 , 703 . https://doi.org/10.1038/s42003-023-05079-4


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.


Funding Information: The authors thank the individuals who participated in this study and whose contributions made this work possible. We also thank our valued colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. This research has been conducted using the UK Biobank Resource under application numbers 24711 and 24898. Publisher Copyright: © 2023, The Author(s).

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