| Title: | Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria |
| Journal: | Communications Biology |
| Published: | 10 Jul 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37430141/ |
| DOI: | https://doi.org/10.1038/s42003-023-05079-4 |
| URL: | https://www.nature.com/articles/s42003-023-05079-4.pdf |
Publication 10254
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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.</p>
37 Authors
- 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
Enabling scientific discoveries that improve human health