학술논문
Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria
Document Type
Original Paper
Author
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; Ludviksson, Bjorn R.; Onundarson, Pall T.; Saevarsdottir, Saedis; Melsted, Pall; Norddahl, Gudmundur L.; Bjornsdottir, Unnur S.; Olafsdottir, Thorunn; Gudbjartsson, Daniel F.; Thorsteinsdottir, Unnur; Jonsdottir, Ingileif; Sulem, Patrick; Stefansson, Kari
Source
Communications Biology. 6(1)
Subject
Language
English
ISSN
2399-3642
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.
A meta-analysis of GWAS studies identified nine sequence variants associated with urticaria. These results and multi-omics analyses support the role of mast cell activation and type 2 immune response in urticaria.
A meta-analysis of GWAS studies identified nine sequence variants associated with urticaria. These results and multi-omics analyses support the role of mast cell activation and type 2 immune response in urticaria.