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

Author:

Kristjansson Ragnar P.,Oskarsson Gudjon R.ORCID,Skuladottir AstrosORCID,Oddsson AsmundurORCID,Rognvaldsson SolviORCID,Sveinbjornsson GardarORCID,Lund Sigrun H.ORCID,Jensson Brynjar O.ORCID,Styrmisdottir Edda L.,Halldorsson Gisli H.ORCID,Ferkingstad EgilORCID,Eldjarn Grimur Hjorleifsson,Beyter DorukORCID,Kristmundsdottir SnædisORCID,Juliusson Kristinn,Fridriksdottir Run,Arnadottir Gudny A.ORCID,Katrinardottir Hildigunnur,Snorradottir Margret H.,Tragante ViniciusORCID,Stefansdottir Lilja,Ivarsdottir Erna V.ORCID,Bjornsdottir GydaORCID,Halldorsson Bjarni V.ORCID,Thorleifsson GudmarORCID,Ludviksson Bjorn R.,Onundarson Pall T.,Saevarsdottir SaedisORCID,Melsted Pall,Norddahl Gudmundur L.,Bjornsdottir Unnur S.,Olafsdottir ThorunnORCID,Gudbjartsson Daniel F.ORCID,Thorsteinsdottir Unnur,Jonsdottir IngileifORCID,Sulem PatrickORCID,Stefansson KariORCID

Abstract

AbstractUrticaria 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.

Publisher

Springer Science and Business Media LLC

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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