Genetic predisposition in the 2'-5'A pathway in the development of type 1 diabetes: potential contribution to dysregulation of innate antiviral immunity

Abstract

Aims/hypothesis: The incidence of type 1 diabetes is increasing more rapidly than can be explained by genetic drift. Viruses may play an important role in the disease, as they seem to activate the 2'-5'-linked oligoadenylate (2'-5'A) pathway of the innate antiviral immune system. Our aim was to investigate this possibility.

Methods: Innate antiviral immune pathways were searched for type 1 diabetes-associated polymorphisms using genome-wide association study data. SNPs within ±250kb flanking regions of the transcription start site of 64 genes were examined. These pathways were also investigated for type 1 diabetes-associated RNA expression profiles using laser-dissected islets from two to five tissue sections per donor from the Diabetes Virus Detection (DiViD) study and the network of Pancreatic Organ Donors (nPOD).

Results: We found 27 novel SNPs in genes nominally associated with type 1 diabetes. Three of those SNPs were located upstream of the 2'-5'A pathway, namely SNP rs4767000 (p = 1.03 × 10^-9, OR 1.123), rs1034687 (p = 2.16 × 10^-7, OR 0.869) and rs739744 (p = 1.03 × 10^-9, OR 1.123). We also identified a large group of dysregulated islet genes in relation to type 1 diabetes, of which two were novel. The most aberrant genes were a group of IFN-stimulated genes. Of those, the following distinct pathways were targeted by the dysregulation (compared with the non-diabetic control group): OAS1 increased by 111% (p < 1.00 × 10^-4, 95% CI -0.43, -0.15); MX1 increased by 142% (p < 1.00 × 10^-4, 95% CI -0.52, -0.22); and ISG15 increased by 197% (p = 2.00 × 10^-4, 95% CI -0.68, -0.18).

Conclusions/interpretation: We identified a genetic predisposition in the 2'-5'A pathway that potentially contributes to dysregulation of the innate antiviral immune system in type 1 diabetes. This study describes a potential role for the 2'-5'A pathway and other components of the innate antiviral immune system in beta cell autoimmunity.

Keywords: 2′-5′ Oligoadenylate synthetase; 2′-5′A pathway; Interferon α; RNase L; Ribonuclease L; Toll-like receptor 7; Type 1 diabetes; Type 1 interferon; Type 2 diabetes; Virus.

Fig. 1

Overview of the OAS family of genes on chromosome 12 and the location of SNPs rs1034687, rs4767000 and rs739744

Fig. 2

Heatmap of RNA expression in the analysed genes. Genes were normalised to the non-diabetic control group by calculating the ratio of the means in each group. Blue indicates lower RNA expression compared with the control group and red indicates higher RNA expression level. A total of 21 genes showed significantly (*) dysregulated RNA expression levels in either autoantibody-positive (Ab+), new-onset type 1 diabetes (T1D, New), longstanding type 1 diabetes (T1D, Long) or longstanding type 2 diabetes (T2D, Long) compared with controls

Fig. 3

Genes involved in PAMP recognition and IFN induction. The RNA expression levels of TLR4 (a), TLR7 (b), IRF7 (c), IFNAR1 (d), IFNA1 (e), IFNA10 (f), IFNB (g), IFNG (h) and IL6 (i) were transformed, and a mean was calculated. The ratio between the mean expression level in each group (autoantibody-positive [Ab+], new-onset type 1 diabetes [T1D, New], longstanding type 1 diabetes [T1D, Long], longstanding type 2 diabetes [T2D, Long]) and the non-diabetic control group was graphed. *p < 0.05, **p < 0.01 and ***p < 0.001 vs control group

Fig. 4

Cytokine genes and ISGs that were upregulated by IFN induction. The RNA expression levels of ADAR (a), IFIH1 (b), OAS1 (c), OAS2 (d), OAS3 (e), OASL (f), MX1 (g), MX2 (h) and ISG15 (i) were transformed, and a mean was calculated. The ratio between the mean expression level in each group (autoantibody-positive [Ab+], new-onset type 1 diabetes [T1D, New], longstanding type 1 diabetes [T1D, Long], longstanding type 2 diabetes [T2D, Long]) and the non-diabetic control group was graphed. *p < 0.05 and ***p < 0.001 vs control group

Fig. 5

The activation and the feedback loop of the innate antiviral immune system during a viral infection. The RNA dysregulated genes/proteins where SNPs were also found in the GWAS study are highlighted in red. Genes/proteins that were only dysregulated at the RNA level are highlighted in green. SP1 is highlighted in yellow because we only found SNPs in this gene associated with type 1 diabetes. The figure illustrates the multitude of genes involved in the potential overactivation in response to an infection in type 1 diabetes. LPS, lipopolysaccharide