Start codon variant in LAG3 is associated with decreased LAG-3 expression and increased risk of autoimmune thyroid disease.

Autor: Saevarsdottir S; deCODE genetics/Amgen, Inc., Reykjavik, Iceland. saedis.saevarsdottir@decode.is.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. saedis.saevarsdottir@decode.is.; Department of Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland. saedis.saevarsdottir@decode.is., Bjarnadottir K; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Markusson T; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Berglund J; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Olafsdottir TA; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Halldorsson GH; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Rutsdottir G; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Gunnarsdottir K; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Arnthorsson AO; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Lund SH; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Stefansdottir L; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Gudmundsson J; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Johannesson AJ; Department of Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland., Sturluson A; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Oddsson A; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Halldorsson B; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Ludviksson BR; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.; Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland., Ferkingstad E; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Ivarsdottir EV; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Sveinbjornsson G; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Grondal G; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.; Department of Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland., Masson G; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Eldjarn GH; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Thorisson GA; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Kristjansdottir K; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Knowlton KU; Intermountain Medical Center, Intermountain Heart Institute, Salt Lake City, UT, USA.; School of Medicine, University of Utah, Salt Lake City, UT, USA., Moore KHS; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Gudjonsson SA; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Rognvaldsson S; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Knight S; Intermountain Medical Center, Intermountain Heart Institute, Salt Lake City, UT, USA., Nadauld LD; Precision Genomics, Intermountain Healthcare, Saint George, UT, USA., Holm H; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Magnusson OT; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Sulem P; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Gudbjartsson DF; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Rafnar T; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Thorleifsson G; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Melsted P; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Norddahl GL; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Jonsdottir I; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.; Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland., Stefansson K; deCODE genetics/Amgen, Inc., Reykjavik, Iceland. kstefans@decode.is.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. kstefans@decode.is.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 09; Vol. 15 (1), pp. 5748. Date of Electronic Publication: 2024 Jul 09.
DOI: 10.1038/s41467-024-50007-7
Abstrakt: Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported. Multiomics analysis yields 235 candidate genes outside the MHC-region and the findings highlight the importance of genes involved in T-cell regulation. A rare 5'-UTR variant (rs781745126-T, MAF = 0.13% in Iceland) in LAG3 has the largest effect (OR = 3.42, P = 2.2 × 10 -16 ) and generates a novel start codon for an open reading frame upstream of the canonical protein translation initiation site. rs781745126-T reduces mRNA and surface expression of the inhibitory immune checkpoint LAG-3 co-receptor on activated lymphocyte subsets and halves LAG-3 levels in plasma among heterozygotes. All three homozygous carriers of rs781745126-T have AITD, of whom one also has two other T-cell mediated diseases, that is vitiligo and type 1 diabetes. rs781745126-T associates nominally with vitiligo (OR = 5.1, P = 6.5 × 10 -3 ) but not with type 1 diabetes. Thus, the effect of rs781745126-T is akin to drugs that inhibit LAG-3, which unleash immune responses and can have thyroid dysfunction and vitiligo as adverse events. This illustrates how a multiomics approach can reveal potential drug targets and safety concerns.
(© 2024. The Author(s).)
Databáze: MEDLINE
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