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

Saevarsdottir, Saedis; Bjarnadottir, Kristbjörg; Markusson, Thorsteinn; Berglund, Jonas; Olafsdottir, Thorunn A.; Halldorsson, Gisli H.; Rutsdottir, Gudrun; Gunnarsdottir, Kristbjorg; Arnthorsson, Asgeir Orn; Lund, Sigrun H.; Stefansdottir, Lilja; Gudmundsson, Julius; Johannesson, Ari J.; Sturluson, Arni; Oddsson, Asmundur; Halldorsson, Bjarni; Ludviksson, Björn R.; Ferkingstad, Egil; Ivarsdottir, Erna V.; Sveinbjornsson, Gardar; Grondal, Gerdur; 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, Pall; Norddahl, Gudmundur L.; Jonsdottir, Ingileif; Stefansson, Kari

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

Saedis Saevarsdottir (), Kristbjörg Bjarnadottir, Thorsteinn Markusson, Jonas Berglund, Thorunn A. Olafsdottir, Gisli H. Halldorsson, Gudrun Rutsdottir, Kristbjorg Gunnarsdottir, Asgeir Orn Arnthorsson, Sigrun H. Lund, Lilja Stefansdottir, Julius Gudmundsson, Ari J. Johannesson, Arni Sturluson, Asmundur Oddsson, Bjarni Halldorsson, Björn R. Ludviksson, Egil Ferkingstad, Erna V. Ivarsdottir, Gardar Sveinbjornsson, Gerdur Grondal, Gisli Masson, Grimur Hjorleifsson Eldjarn, Gudmundur A. Thorisson, Katla Kristjansdottir, Kirk U. Knowlton, Kristjan H. S. Moore, Sigurjon A. Gudjonsson, Solvi Rognvaldsson, Stacey Knight, Lincoln D. Nadauld, Hilma Holm, Olafur T. Magnusson, Patrick Sulem, Daniel F. Gudbjartsson, Thorunn Rafnar, Gudmar Thorleifsson, Pall Melsted, Gudmundur L. Norddahl, Ingileif Jonsdottir and Kari Stefansson ()
Additional contact information
Saedis Saevarsdottir: Inc.
Kristbjörg Bjarnadottir: Inc.
Thorsteinn Markusson: Inc.
Jonas Berglund: Inc.
Thorunn A. Olafsdottir: Inc.
Gisli H. Halldorsson: Inc.
Gudrun Rutsdottir: Inc.
Kristbjorg Gunnarsdottir: Inc.
Asgeir Orn Arnthorsson: Inc.
Sigrun H. Lund: Inc.
Lilja Stefansdottir: Inc.
Julius Gudmundsson: Inc.
Ari J. Johannesson: the National University Hospital of Iceland
Arni Sturluson: Inc.
Asmundur Oddsson: Inc.
Bjarni Halldorsson: Inc.
Björn R. Ludviksson: University of Iceland
Egil Ferkingstad: Inc.
Erna V. Ivarsdottir: Inc.
Gardar Sveinbjornsson: Inc.
Gerdur Grondal: University of Iceland
Gisli Masson: Inc.
Grimur Hjorleifsson Eldjarn: Inc.
Gudmundur A. Thorisson: Inc.
Katla Kristjansdottir: Inc.
Kirk U. Knowlton: Intermountain Heart Institute
Kristjan H. S. Moore: Inc.
Sigurjon A. Gudjonsson: Inc.
Solvi Rognvaldsson: Inc.
Stacey Knight: Intermountain Heart Institute
Lincoln D. Nadauld: Intermountain Healthcare
Hilma Holm: Inc.
Olafur T. Magnusson: Inc.
Patrick Sulem: Inc.
Daniel F. Gudbjartsson: Inc.
Thorunn Rafnar: Inc.
Gudmar Thorleifsson: Inc.
Pall Melsted: Inc.
Gudmundur L. Norddahl: Inc.
Ingileif Jonsdottir: Inc.
Kari Stefansson: Inc.

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50007-7

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