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

Author:

Saevarsdottir SaedisORCID,Bjarnadottir Kristbjörg,Markusson Thorsteinn,Berglund Jonas,Olafsdottir Thorunn A.ORCID,Halldorsson Gisli H.ORCID,Rutsdottir Gudrun,Gunnarsdottir Kristbjorg,Arnthorsson Asgeir Orn,Lund Sigrun H.ORCID,Stefansdottir Lilja,Gudmundsson Julius,Johannesson Ari J.,Sturluson Arni,Oddsson AsmundurORCID,Halldorsson BjarniORCID,Ludviksson Björn R.,Ferkingstad EgilORCID,Ivarsdottir Erna V.ORCID,Sveinbjornsson GardarORCID,Grondal Gerdur,Masson Gisli,Eldjarn Grimur HjorleifssonORCID,Thorisson Gudmundur A.,Kristjansdottir KatlaORCID,Knowlton Kirk U.,Moore Kristjan H. S.ORCID,Gudjonsson Sigurjon A.,Rognvaldsson Solvi,Knight StaceyORCID,Nadauld Lincoln D.,Holm Hilma,Magnusson Olafur T.,Sulem PatrickORCID,Gudbjartsson Daniel F.ORCID,Rafnar ThorunnORCID,Thorleifsson GudmarORCID,Melsted Pall,Norddahl Gudmundur L.,Jonsdottir IngileifORCID,Stefansson KariORCID

Abstract

AbstractAutoimmune 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.

Publisher

Springer Science and Business Media LLC

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