De-coding genetic risk variants in type 1 diabetes

Abstract

The conceptual basis for a genetic predisposition underlying the risk for developing type 1 diabetes (T1D) predates modern human molecular genetics. Over half of the genetic risk has been attributed to the human leukocyte antigen (HLA) class II gene region and to the insulin (INS) gene locus - both thought to confer direction of autoreactivity and tissue specificity. Notwithstanding, questions still remain regarding the functional contributions of a vast array of minor polygenic risk variants scattered throughout the genome that likely influence disease heterogeneity and clinical outcomes. Herein, we summarize the available literature related to the T1D-associated coding variants defined at the time of this review, for the genes PTPN22, IFIH1, SH2B3, CD226, TYK2, FUT2, SIRPG, CTLA4, CTSH and UBASH3A. Data from genotype-selected human cohorts are summarized, and studies from the non-obese diabetic (NOD) mouse are presented to describe the functional impact of these variants in relation to innate and adaptive immunity as well as to β-cell fragility, with expression profiles in tissues and peripheral blood highlighted. The contribution of each variant to progression through T1D staging, including environmental interactions, are discussed with consideration of how their respective protein products may serve as attractive targets for precision medicine-based therapeutics to prevent or suspend the development of T1D.

Keywords: coding variant; human; precision medicine; risk gene; single nucleotide polymorphism; type 1 diabetes.

Figure 1.

Expression profiles of genes containing T1D-associated coding variants. (a) Heatmap depicting relative gene expression by organ. Rows are organ classifications utilized in The Human Protein Atlas (HPA), and columns are individual genes containing T1D-associated coding variants. Depicted are the consensus normalized expression (NX) values summarized from HPA, Genotype-Tissue Expression (GTEx), and Functional Annotation of Mammalian Genomes 5 (FANTOM5) transcriptomics datasets. (b) Heatmap of gene expression within immune cell subsets. Data are population averaged gene expression from the Human Cell Atlas Census of Immune Cells, an ultra-low-input (ULI) RNA-Seq dataset. Blue represents high expression, while white represents low expression levels. Cells indicated as natural killer (NK), mucosal-associated invariant T (MAIT), regulatory T cell (Treg), and dendritic cell (DC).

Figure 2.

Coding gene variants converge on signaling and activation pathways to impact autoimmunity. (a) Disruption of FUT2 function and the resulting lack of ABO blood group antigen secretion in the intestinal mucosa can result in impaired barrier function and immunity by increasing susceptibility to some viral infections and altering microbiome composition as well as the microbial metabolites (such as short-chain fatty acids). IFIH1 variants may augment innate responses against enteroviruses. (b) Antiviral or other pro-inflammatory responses in the gut may result in trafficking of APCs to the pancreatic lymph node (pLN), where autoantigen-specific T cells are activated. (c) Activation and function of autoreactive T cells may be exacerbated by T1D-risk variants expressed either in the APC or in the T cell itself. The risk variant of PTPN22 (LYP) abolishes CSK binding, which could result in decreased phosphatase activity and increased TCR signaling. The CTLA4 risk variant results in reduced CTLA4 expression on the T-cell surface, reducing regulation of T-cell activation. Variants in co-stimulatory molecules CD226 and SIRPγ may contribute to pro-inflammatory T-cell skewing by promoting activation of the MAPK/ERK pathway and enhancing the production of inflammatory and cytotoxic molecules, respectively. Treg function may be negatively impacted by a UBASH3A variant, which inhibits NFκB activation and downstream IL-2 production. APCs may contribute to the generation of this pro-inflammatory milieu, as altered LNK function results in enhanced NOD2 signaling, activation of NFκB and production of IL-6 and IL-1β. APC peptide repertoire for presentation may be influenced by a CTSH variant. Variants in TYK2 and IFIH1 may also contribute to innate inflammation through increased induction of IFN stimulated genes (ISGs). (d) Genetic variants may impact β-cell susceptibility to death via sensing of viral or self dsRNA in the case of IFIH1, while a variant within CTSH seems to play a role in TLR3 activation, downstream IFN production and susceptibility to cytokine-induced damage. T1D-associated TYK2 variants may enhance β-cell expression of ISGs, including MHC I and CXCL10. Created with BioRender.