Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks
Type 1 diabetes (T1D) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk regions across the human genome, marked by si...
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| Format: | Article |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2018.00535/full |
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| author | Denis M. Nyaga Mark H. Vickers Craig Jefferies Craig Jefferies Jo K. Perry Justin M. O’Sullivan |
| author_facet | Denis M. Nyaga Mark H. Vickers Craig Jefferies Craig Jefferies Jo K. Perry Justin M. O’Sullivan |
| author_sort | Denis M. Nyaga |
| collection | DOAJ |
| description | Type 1 diabetes (T1D) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk regions across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue- and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 246 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, PTEN, TYK2, CTSH, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signaling, and programmed cell death protein-1 (PD-1). Our results implicate T1D-associated variants in tissue and cell-type specific regulatory networks that contribute to pancreatic beta cell inflammation and destruction, adaptive immune signaling, and immune-cell proliferation and activation. A number of other regulatory changes we identified are not typically considered to be central to the pathology of T1D. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic, and therapeutic interventions in T1D. |
| first_indexed | 2024-12-12T06:36:15Z |
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| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-12T06:36:15Z |
| publishDate | 2018-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-3c8db66aef434b438a955d7caf76a7ee2022-12-22T00:34:28ZengFrontiers Media S.A.Frontiers in Genetics1664-80212018-11-01910.3389/fgene.2018.00535419069Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory NetworksDenis M. Nyaga0Mark H. Vickers1Craig Jefferies2Craig Jefferies3Jo K. Perry4Justin M. O’Sullivan5The Liggins Institute, The University of Auckland, Auckland, New ZealandThe Liggins Institute, The University of Auckland, Auckland, New ZealandThe Liggins Institute, The University of Auckland, Auckland, New ZealandStarship Children’s Health, Auckland, New ZealandThe Liggins Institute, The University of Auckland, Auckland, New ZealandThe Liggins Institute, The University of Auckland, Auckland, New ZealandType 1 diabetes (T1D) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk regions across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue- and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 246 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, PTEN, TYK2, CTSH, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signaling, and programmed cell death protein-1 (PD-1). Our results implicate T1D-associated variants in tissue and cell-type specific regulatory networks that contribute to pancreatic beta cell inflammation and destruction, adaptive immune signaling, and immune-cell proliferation and activation. A number of other regulatory changes we identified are not typically considered to be central to the pathology of T1D. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic, and therapeutic interventions in T1D.https://www.frontiersin.org/article/10.3389/fgene.2018.00535/fullType 1 diabetesgenome-wide association studies (GWAS)genetic variationgenome organizationexpression quantitative trait loci (eQTL)autoimmunity |
| spellingShingle | Denis M. Nyaga Mark H. Vickers Craig Jefferies Craig Jefferies Jo K. Perry Justin M. O’Sullivan Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks Frontiers in Genetics Type 1 diabetes genome-wide association studies (GWAS) genetic variation genome organization expression quantitative trait loci (eQTL) autoimmunity |
| title | Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks |
| title_full | Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks |
| title_fullStr | Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks |
| title_full_unstemmed | Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks |
| title_short | Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks |
| title_sort | type 1 diabetes mellitus associated genetic variants contribute to overlapping immune regulatory networks |
| topic | Type 1 diabetes genome-wide association studies (GWAS) genetic variation genome organization expression quantitative trait loci (eQTL) autoimmunity |
| url | https://www.frontiersin.org/article/10.3389/fgene.2018.00535/full |
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