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

2024; Nature Portfolio; Volume: 15; Issue: 1 Linguagem: Inglês

10.1038/s41467-024-50007-7

2041-1723

Saedís Saevarsdóttir, Kristbjörg Bjarnadóttir, Thorsteinn Markusson, Jonas Berglund, Thorunn A. Olafsdottir, Gísli H. Halldórsson, Gudrun Rutsdottir, Kristbjörg Gunnarsdóttir, Asgeir Ö. Arnthórsson, Sigrún H. Lund, Lilja Stefánsdóttir, Jūlı́us Guðmundsson, Ari Jóhannesson, Árni Sturluson, Ásmundur Oddsson, Bjarni V. Halldórsson, Bjórn R. Lúdvíksson, Egil Ferkingstad, Erna V. Ivarsdottir, Garðar Sveinbjörnsson, Gerður Gröndal, Gísli Másson, Grímur Hjörleifsson Eldjárn, Guðmundur Á. Þórisson, Katla Kristjánsdóttir, Kirk U. Knowlton, Kristjan H. S. Moore, Sigurjón A. Guðjónsson, Sölvi Rögnvaldsson, Stacey Knight, Lincoln Nadauld, Hilma Hólm, Ólafur Þ. Magnússon, Patrick Sulem, Daníel F. Guðbjartsson, Þórunn Rafnar, Guðmar Þorleifsson, Páll Melsted, Gudmundur L. Norddahl, Ingileif Jónsdóttir, Kári Stéfansson,

T-cell and B-cell Immunology

Abstract 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.