Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria
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...
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Nature Portfolio
2023-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05079-4 |
| _version_ | 1797778682759086080 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ragnar P. Kristjansson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T23:20:58Z |
| format | Article |
| id | doaj.art-1e7c03c21b63437397dd6ce3465df5ca |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-12T23:20:58Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-1e7c03c21b63437397dd6ce3465df5ca2023-07-16T11:25:03ZengNature PortfolioCommunications Biology2399-36422023-07-01611910.1038/s42003-023-05079-4Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticariaRagnar P. Kristjansson0Gudjon R. Oskarsson1Astros Skuladottir2Asmundur Oddsson3Solvi Rognvaldsson4Gardar Sveinbjornsson5Sigrun H. Lund6Brynjar O. Jensson7Edda L. Styrmisdottir8Gisli H. Halldorsson9Egil Ferkingstad10Grimur Hjorleifsson Eldjarn11Doruk Beyter12Snædis Kristmundsdottir13Kristinn Juliusson14Run Fridriksdottir15Gudny A. Arnadottir16Hildigunnur Katrinardottir17Margret H. Snorradottir18Vinicius Tragante19Lilja Stefansdottir20Erna V. Ivarsdottir21Gyda Bjornsdottir22Bjarni V. Halldorsson23Gudmar Thorleifsson24Bjorn R. Ludviksson25Pall T. Onundarson26Saedis Saevarsdottir27Pall Melsted28Gudmundur L. Norddahl29Unnur S. Bjornsdottir30Thorunn Olafsdottir31Daniel F. Gudbjartsson32Unnur Thorsteinsdottir33Ingileif Jonsdottir34Patrick Sulem35Kari Stefansson36deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.Faculty of Medicine, School of Health Sciences, University of IcelandFaculty of Medicine, School of Health Sciences, University of IcelanddeCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.Department of Medicine, Landspitali, the National University Hospital of IcelanddeCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.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.https://doi.org/10.1038/s42003-023-05079-4 |
| spellingShingle | 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 Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria Communications Biology |
| title | Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria |
| title_full | Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria |
| title_fullStr | Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria |
| title_full_unstemmed | Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria |
| title_short | Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria |
| title_sort | sequence variant affects gcsaml splicing mast cell specific proteins and risk of urticaria |
| url | https://doi.org/10.1038/s42003-023-05079-4 |
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