Dataset Information

Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks.

ABSTRACT: 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.

SUBMITTER: Nyaga DM

PROVIDER: S-EPMC6258722 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks.

Nyaga Denis M DM Vickers Mark H MH Jefferies Craig C Perry Jo K JK O'Sullivan Justin M JM

Frontiers in genetics 20181121

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 ...[more]

PMID: 30524468

Similar Datasets

Project description:SIRT1 has been demonstrated in nutrient-sensing and insulin-signaling pathways in in vivo and in vitro experiments, but there is minimal information concerning the association between gene polymorphisms of SIRT1 and type 2 diabetes mellitus (T2DM) in a Chinese Han population. Using case-control design, we recruited 310 unrelated T2DM patients from inpatients at Shanghai Jiao Tong University Affiliated Sixth People's Hospital, while 301 healthy controls were volunteers from the community for regular medical checkup. All participants were genotyped within the SIRT1 region. The following five SNPs rs10509291, rs12778366, rs10997870, rs10823112, and rs4746720 cover 100% of common genetic variations (minor allele frequency≥0.05) within the SIRT1 gene (r2≥0.8). The genotypes of SIRT1 gene polymorphisms were analyzed by the Snapshot assay and DNA sequencing. The resulting data show that there was significant genetic differentiation in rs10823112 [p=0.003; OR (95% CI)=1.515 (1.152-1.994) for genotype], rs4746720 [p=0.024; OR (95% CI)=1.37 (1.037-1.674) for genotype], and rs10509291 [p=0.002; OR (95% CI)=1.551 (1.179-2.04) for genotype] between T2DM and control subjects. However, the result of rs4746720 was no longer significant after correction for multiple testing (p after Bonferroni correction=0.12); the results of rs10509291and rs10823112 were still significantly different between the two groups (p after Bonferroni correction=0.01 and 0.015, respectively). Linear regression analyses adjusting for age, gender, and body mass index (BMI) showed that HbA1c and HOMA-IR in subjects with rs10509291 AA genotype were higher than those with TT genotype in T2DM group (p=0.045, p=0.035, respectively). Together, our data show that genetic variation of the SIRT1 gene is related to insulin resistance and increase risk of T2DM in Chinese Han population. The risk allele A at SIRT1 rs10509291 was closely associated with T2DM, and subjects who were homozygous of the A allele were more likely to develop T2DM.

Dataset Information

Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks.

Publications

Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets