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

Denis M Nyaga,Mark H Vickers,Justin M O’Sullivan,Craig Jefferies,Jo K Perry

doi:10.3389/fgene.2018.00535

Denis M Nyaga, Mark H Vickers + Show 3 more

Open Access

https://doi.org/10.3389/fgene.2018.00535

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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.

Highlights

Type 1 diabetes (T1D) is a chronic immune-mediated disease characterized by the progressive loss of insulin-secreting pancreatic beta cells, and the incidence is slowly rising worldwide (Insel et al, 2015)
We identified 232 cis- and 66 trans-expression quantitative trait loci (eQTL), at an FDR of q < 0.05 for single nucleotide polymorphisms (SNPs) associated with T1D (Supplementary Table 1)
The functional physical interactions between T1D-associated SNPs and eGenes were represented in a circos plot (Figure 1)

Summary

Introduction

Type 1 diabetes (T1D) is a chronic immune-mediated disease characterized by the progressive loss of insulin-secreting pancreatic beta cells, and the incidence is slowly rising worldwide (Insel et al, 2015). Genetic Variation and Type 1 Diabetes Mellitus polymorphisms (SNPs) (Ram et al, 2016). The major heritable risk (∼50%) for T1D is conferred by SNPs located within the human leukocyte antigen (HLA) region (Ounissi-Benkalha and Polychronakos, 2008). The functional roles of most T1D-associated genetic variants is yet to be determined. 90 percent of these genetic variants fall outside coding regions (Ward and Kellis, 2012), and their biological role in the pathogenesis of diseases is not clear. There is growing evidence supporting a putative role for these non-coding variants in the regulation of gene expression, as the majority of SNPs fall within regulatory loci such as enhancer regions (Guo et al, 2015; Javierre et al, 2016; Ram and Morahan, 2017)

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