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

• Published in: Nature Communications
• Main Authors: Sævarsdóttir, Sædís, Bjarnadottir, Kristbjörg, Markusson, Thorsteinn, Berglund, Jonas, Ólafsdóttir, Þórunn Ásta, Halldórsson, Gísli Hreinn, Rutsdottir, Gudrun, Gunnarsdottir, Kristbjorg, Arnthorsson, Asgeir Orn, Lund, Sigrun H., Stefánsdóttir, Lilja, Gudmundsson, Julius, Jóhannesson, Ari J, Sturluson, Arni, Oddsson, Asmundur, Halldorsson, Bjarni, Lúðvíksson, Björn Rúnar, Ferkingstad, Egil, Ivarsdottir, Erna V., Sveinbjornsson, Gardar, Gröndal, Gerður María, Masson, Gisli, Eldjarn, Grimur Hjorleifsson, Thorisson, Gudmundur A., Kristjansdottir, Katla, Knowlton, Kirk U., Moore, Kristjan H.S., Gudjonsson, Sigurjon A., Rognvaldsson, Solvi, Knight, Stacey, Nadauld, Lincoln D., Holm, Hilma, Magnusson, Olafur T., Sulem, Patrick, Gudbjartsson, Daniel F., Rafnar, Thorunn, Thorleifsson, Gudmar, Melsted, Páll, Norddahl, Gudmundur L., Jónsdóttir, Ingileif, Stefánsson, Kári
• Other Authors: Faculty of Medicine, Other departments, Faculty of Industrial Engineering, Mechanical Engineering and Computer Science, Faculty of Physical Sciences, Landspitali - The National University Hospital of Iceland
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2024
• Subjects: Gigtarlæknisfræði; Innkirtlalæknisfræði; Ónæmisfræði; Náttúrufræðingar; General Chemistry; General Biochemistry,Genetics and Molecular Biology; General Physics and Astronomy; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/4994; https://doi.org/10.1038/s41467-024-50007-7

Publisher Copyright: © The Author(s) 2024. 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. Peer reviewed