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

Kristjansson, Ragnar P.; Oskarsson, Gudjon R.; Skuladottir, Astros; Oddsson, Asmundur; Rognvaldsson, Solvi; Sveinbjornsson, Gardar; Lund, Sigrun H.; Jensson, Brynjar O.; Styrmisdottir, Edda L.; Halldorsson, Gisli H.; Ferkingstad, Egil; Eldjarn, Grimur Hjorleifsson; Beyter, Doruk; Kristmundsdottir, Snædis; Juliusson, Kristinn; Fridriksdottir, Run; Arnadottir, Gudny A.; Katrinardottir, Hildigunnur; Snorradottir, Margret H.; Tragante, Vinicius; Stefansdottir, Lilja; Ivarsdottir, Erna V.; Bjornsdottir, Gyda; Halldorsson, Bjarni V.; Thorleifsson, Gudmar; Lúðvíksson, Björn Rúnar; Önundarson, Páll Torfi; Sævarsdóttir, Sædís; Melsted, Pall; Norddahl, Gudmundur L.; Björnsdóttir, Unnur Steina; Olafsdottir, Thorunn; Gudbjartsson, Daniel F.; Thorsteinsdottir, Unnur; Jonsdottir, Ingileif; Sulem, Patrick; Stefansson, Kari

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

Titill:	Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria
Höfundur:	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 fleiri höfundar Sýna alla höfunda Ferkingstad, Egil orcid.org/0000-0001-8090-7988 Eldjarn, Grimur Hjorleifsson Beyter, Doruk orcid.org/0000-0002-3644-5760 Kristmundsdottir, Snædis Juliusson, Kristinn Fridriksdottir, Run Arnadottir, Gudny A. Katrinardottir, Hildigunnur Snorradottir, Margret H. Tragante, Vinicius Stefansdottir, Lilja Ivarsdottir, Erna V. Bjornsdottir, Gyda orcid.org/0000-0002-8100-0306 Halldorsson, Bjarni V. Thorleifsson, Gudmar orcid.org/0000-0003-4623-9087 Lúðvíksson, Björn Rúnar Önundarson, Páll Torfi Sævarsdóttir, Sædís Melsted, Pall Norddahl, Gudmundur L. Björnsdóttir, Unnur Steina Olafsdottir, Thorunn Gudbjartsson, Daniel F. Thorsteinsdottir, Unnur Jonsdottir, Ingileif orcid.org/0000-0001-8339-150X Sulem, Patrick orcid.org/0000-0001-7123-6123 Stefansson, Kari orcid.org/0000-0003-1676-864X 37 höfundar Sýna færri höfunda
Útgáfa:	2023-07-10
Tungumál:	Enska
Umfang:	1674688
Háskóli/Stofnun:	Landspitali - The National University Hospital of Iceland Reykjavik University
Svið:	Health Sciences
Deild:	Department of Engineering Faculty of Physical Sciences Faculty of Industrial Engineering, Mechanical Engineering and Computer Science Faculty of Medicine Other departments
Birtist í:	Communications Biology; 6(1)
ISSN:	2399-3642
DOI:	10.1038/s42003-023-05079-4
Efnisorð:	Ónæmisfræði; Blóðlæknisfræði; Gigtarlæknisfræði; Lungnalæknisfræði; Humans; Genome-Wide Association Study; Mast Cells; Urticaria/genetics; RNA Splicing; Proteome; General Agricultural and Biological Sciences; General Biochemistry,Genetics and Molecular Biology; Medicine (miscellaneous)
URI:	https://hdl.handle.net/20.500.11815/4495
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Tilvitnun: 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
Útdráttur: 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.
Athugasemdir: 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).