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Type 1 Diabetes and the HLA Region: Genetic Association Besides Classical HLA Class II Genes

Type 1 diabetes is an autoimmune disease with rising incidence in high-income countries. Genetic and environmental predisposing factors contribute to the etiology of the disease, although their interaction is not sufficiently understood to allow for preventive action. Strongest known associations wi...

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Autores principales: Sticht, Jana, Álvaro-Benito, Miguel, Konigorski, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248358/
https://www.ncbi.nlm.nih.gov/pubmed/34220961
http://dx.doi.org/10.3389/fgene.2021.683946
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author Sticht, Jana
Álvaro-Benito, Miguel
Konigorski, Stefan
author_facet Sticht, Jana
Álvaro-Benito, Miguel
Konigorski, Stefan
author_sort Sticht, Jana
collection PubMed
description Type 1 diabetes is an autoimmune disease with rising incidence in high-income countries. Genetic and environmental predisposing factors contribute to the etiology of the disease, although their interaction is not sufficiently understood to allow for preventive action. Strongest known associations with genetic variation map to classical HLA class II genes. Because of its genetic complexity, the HLA region has been under-represented in genome-wide association studies, having potentially hindered the identification of relevant associations underlying the etiology of the disease. Here, we performed a comprehensive HLA-wide genetic association analysis of type 1 diabetes including multi-allelic and rare variants. We used high-density whole-exome sequencing data of the HLA region in the large UK Biobank dataset to apply gene-based association tests with a carefully defined type 1 diabetes phenotype (97 cases and 48,700 controls). Exon-based and single-variant association tests were used to complement the analysis. We replicated the known association of type 1 diabetes with the classical HLA-DQ gene. Tailoring the analysis toward rare variants, we additionally identified the lysine methyl transferase EHMT2 as associated. Deeper insight into genetic variation associated with disease as presented and discussed in detail here can help unraveling mechanistic details of the etiology of type 1 diabetes. More specifically, we hypothesize that genetic variation in EHMT2 could impact autoimmunity in type 1 diabetes development.
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spelling pubmed-82483582021-07-02 Type 1 Diabetes and the HLA Region: Genetic Association Besides Classical HLA Class II Genes Sticht, Jana Álvaro-Benito, Miguel Konigorski, Stefan Front Genet Genetics Type 1 diabetes is an autoimmune disease with rising incidence in high-income countries. Genetic and environmental predisposing factors contribute to the etiology of the disease, although their interaction is not sufficiently understood to allow for preventive action. Strongest known associations with genetic variation map to classical HLA class II genes. Because of its genetic complexity, the HLA region has been under-represented in genome-wide association studies, having potentially hindered the identification of relevant associations underlying the etiology of the disease. Here, we performed a comprehensive HLA-wide genetic association analysis of type 1 diabetes including multi-allelic and rare variants. We used high-density whole-exome sequencing data of the HLA region in the large UK Biobank dataset to apply gene-based association tests with a carefully defined type 1 diabetes phenotype (97 cases and 48,700 controls). Exon-based and single-variant association tests were used to complement the analysis. We replicated the known association of type 1 diabetes with the classical HLA-DQ gene. Tailoring the analysis toward rare variants, we additionally identified the lysine methyl transferase EHMT2 as associated. Deeper insight into genetic variation associated with disease as presented and discussed in detail here can help unraveling mechanistic details of the etiology of type 1 diabetes. More specifically, we hypothesize that genetic variation in EHMT2 could impact autoimmunity in type 1 diabetes development. Frontiers Media S.A. 2021-06-17 /pmc/articles/PMC8248358/ /pubmed/34220961 http://dx.doi.org/10.3389/fgene.2021.683946 Text en Copyright © 2021 Sticht, Álvaro-Benito and Konigorski. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Sticht, Jana
Álvaro-Benito, Miguel
Konigorski, Stefan
Type 1 Diabetes and the HLA Region: Genetic Association Besides Classical HLA Class II Genes
title Type 1 Diabetes and the HLA Region: Genetic Association Besides Classical HLA Class II Genes
title_full Type 1 Diabetes and the HLA Region: Genetic Association Besides Classical HLA Class II Genes
title_fullStr Type 1 Diabetes and the HLA Region: Genetic Association Besides Classical HLA Class II Genes
title_full_unstemmed Type 1 Diabetes and the HLA Region: Genetic Association Besides Classical HLA Class II Genes
title_short Type 1 Diabetes and the HLA Region: Genetic Association Besides Classical HLA Class II Genes
title_sort type 1 diabetes and the hla region: genetic association besides classical hla class ii genes
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248358/
https://www.ncbi.nlm.nih.gov/pubmed/34220961
http://dx.doi.org/10.3389/fgene.2021.683946
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