Communications Biology (Jul 2023)
Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria
- Ragnar P. Kristjansson,
- Gudjon R. Oskarsson,
- Astros Skuladottir,
- Asmundur Oddsson,
- Solvi Rognvaldsson,
- Gardar Sveinbjornsson,
- Sigrun H. Lund,
- Brynjar O. Jensson,
- Edda L. Styrmisdottir,
- Gisli H. Halldorsson,
- Egil Ferkingstad,
- Grimur Hjorleifsson Eldjarn,
- Doruk Beyter,
- Snædis Kristmundsdottir,
- Kristinn Juliusson,
- Run Fridriksdottir,
- Gudny A. Arnadottir,
- Hildigunnur Katrinardottir,
- Margret H. Snorradottir,
- Vinicius Tragante,
- Lilja Stefansdottir,
- Erna V. Ivarsdottir,
- Gyda Bjornsdottir,
- Bjarni V. Halldorsson,
- Gudmar Thorleifsson,
- Bjorn R. Ludviksson,
- Pall T. Onundarson,
- Saedis Saevarsdottir,
- Pall Melsted,
- Gudmundur L. Norddahl,
- Unnur S. Bjornsdottir,
- Thorunn Olafsdottir,
- Daniel F. Gudbjartsson,
- Unnur Thorsteinsdottir,
- Ingileif Jonsdottir,
- Patrick Sulem,
- Kari Stefansson
Affiliations
- Ragnar P. Kristjansson
- deCODE genetics/Amgen Inc.
- Gudjon R. Oskarsson
- deCODE genetics/Amgen Inc.
- Astros Skuladottir
- deCODE genetics/Amgen Inc.
- Asmundur Oddsson
- deCODE genetics/Amgen Inc.
- Solvi Rognvaldsson
- deCODE genetics/Amgen Inc.
- Gardar Sveinbjornsson
- deCODE genetics/Amgen Inc.
- Sigrun H. Lund
- deCODE genetics/Amgen Inc.
- Brynjar O. Jensson
- deCODE genetics/Amgen Inc.
- Edda L. Styrmisdottir
- deCODE genetics/Amgen Inc.
- Gisli H. Halldorsson
- deCODE genetics/Amgen Inc.
- Egil Ferkingstad
- deCODE genetics/Amgen Inc.
- Grimur Hjorleifsson Eldjarn
- deCODE genetics/Amgen Inc.
- Doruk Beyter
- deCODE genetics/Amgen Inc.
- Snædis Kristmundsdottir
- deCODE genetics/Amgen Inc.
- Kristinn Juliusson
- deCODE genetics/Amgen Inc.
- Run Fridriksdottir
- deCODE genetics/Amgen Inc.
- Gudny A. Arnadottir
- deCODE genetics/Amgen Inc.
- Hildigunnur Katrinardottir
- deCODE genetics/Amgen Inc.
- Margret H. Snorradottir
- deCODE genetics/Amgen Inc.
- Vinicius Tragante
- deCODE genetics/Amgen Inc.
- Lilja Stefansdottir
- deCODE genetics/Amgen Inc.
- Erna V. Ivarsdottir
- deCODE genetics/Amgen Inc.
- Gyda Bjornsdottir
- deCODE genetics/Amgen Inc.
- Bjarni V. Halldorsson
- deCODE genetics/Amgen Inc.
- Gudmar Thorleifsson
- deCODE genetics/Amgen Inc.
- Bjorn R. Ludviksson
- Faculty of Medicine, School of Health Sciences, University of Iceland
- Pall T. Onundarson
- Faculty of Medicine, School of Health Sciences, University of Iceland
- Saedis Saevarsdottir
- deCODE genetics/Amgen Inc.
- Pall Melsted
- deCODE genetics/Amgen Inc.
- Gudmundur L. Norddahl
- deCODE genetics/Amgen Inc.
- Unnur S. Bjornsdottir
- Department of Medicine, Landspitali, the National University Hospital of Iceland
- Thorunn Olafsdottir
- deCODE genetics/Amgen Inc.
- Daniel F. Gudbjartsson
- deCODE genetics/Amgen Inc.
- Unnur Thorsteinsdottir
- deCODE genetics/Amgen Inc.
- Ingileif Jonsdottir
- deCODE genetics/Amgen Inc.
- Patrick Sulem
- deCODE genetics/Amgen Inc.
- Kari Stefansson
- deCODE genetics/Amgen Inc.
- DOI
- https://doi.org/10.1038/s42003-023-05079-4
- Journal volume & issue
-
Vol. 6,
no. 1
pp. 1 – 9
Abstract
Abstract 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.
