Dataset Information

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

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.

SUBMITTER: Saevarsdottir S

PROVIDER: S-EPMC11233504 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Saevarsdottir Saedis S Bjarnadottir Kristbjörg K Markusson Thorsteinn T Berglund Jonas J Olafsdottir Thorunn A TA Halldorsson Gisli H GH Rutsdottir Gudrun G Gunnarsdottir Kristbjorg K Arnthorsson Asgeir Orn AO Lund Sigrun H SH Stefansdottir Lilja L Gudmundsson Julius J Johannesson Ari J AJ Sturluson Arni A Oddsson Asmundur A Halldorsson Bjarni B Ludviksson Björn R BR Ferkingstad Egil E Ivarsdottir Erna V EV Sveinbjornsson Gardar G Grondal Gerdur G Masson Gisli G Eldjarn Grimur Hjorleifsson GH Thorisson Gudmundur A GA Kristjansdottir Katla K Knowlton Kirk U KU Moore Kristjan H S KHS Gudjonsson Sigurjon A SA Rognvaldsson Solvi S Knight Stacey S Nadauld Lincoln D LD Holm Hilma H Magnusson Olafur T OT Sulem Patrick P Gudbjartsson Daniel F DF Rafnar Thorunn T Thorleifsson Gudmar G Melsted Pall P Norddahl Gudmundur L GL Jonsdottir Ingileif I Stefansson Kari K

Nature communications 20240709 1

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 ...[more]

PMID: 38982041

Similar Datasets

Project description:BackgroundEmerging evidence suggests that α-synuclein (α-syn) aggregation and intercellular transmission contributes to pathogenesis of Parkinson's disease (PD) and the toxic fibrillary α-syn binds lymphocyte-activation gene 3 (LAG3) receptor that mediates α-syn transmission. The deletion of LAG3 in animal models was shown to limit α-syn spreading and alleviate the pathological changes of dopaminergic neurons and animal behavioral deficits induced by α-syn aggregation. However, little is known about the genetic association of LAG3 variation with human PD development.ObjectiveHere we investigated LAG3 single nucleotide polymorphisms (SNPs) and examined the levels of soluble LAG3 (sLAG3) of CSF and serum from Chinese PD patients.MethodsWe enrolled 646 PD patients and 536 healthy controls to conduct a case-control study. All the participants were genotyped using Sequenom iPLEX Assay and the partial cerebrospinal fluid (CSF) and serum samples were assessed by Meso Scale Discovery electrochemiluminescence (MSD-ECL) immunoassay to measure sLAG3 concentration.ResultsAs a result, distributions of rs1922452-AA (1.975, 95% confidence interval (CI) 1.311-2.888, p = 0.001) and rs951818-CC (OR = 2.03, 95% CI 1.369-3.010, p = 0.001) genotype frequencies were found higher in the female PD patients than controls, respectively, and a strong linkage disequilibrium (LD) was calculated on the variants. The level of sLAG3 in CSF of PD patients was found to significantly differ from that of controls (51.56 ± 15.05 pg/ml vs 88.49 ± 62.96 pg/ml, p < 0.0001). Meanwhile, the concentration of α-synuclein in CSF of patients was significantly lower than that of controls (939.9 ± 2900 pg/ml vs 2476 ± 4403 pg/ml, p < 0.0001) and the level of sLAG3 was detected to be positive correlation with that of α-synuclein in the control group (r = 0.597, p = 0.0042), but not in PD group (r = 0.111, p = 0.408).ConclusionIn summary, our data suggested that LAG3 SNPs increase the PD risk of Chinese female population and the sLAG3 may be a potential biomarker predicted for PD development.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets