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. Graphical abstract

Identification and validation of key biomarkers for the early diagnosis of diabetic kidney disease

“… Field et al (2005) proposed that OAS1 activation may promote β-cell apoptosis, thereby enhancing susceptibility to T1DM. Pedersen et al (2021 ) showed upregulation of OAS1 in the islets of T1DM. OAS1 is also relevant in multiple sclerosis, and hepatitis C virus infection ( García-Álvarez et al, 2017 ; O'Brien et al, 2010 ).…”

Proteomic analysis of tear film in canine diabetic patients with and without retinopathy

“…multiple sclerosis or lupus erythematosus ( 6 ). It was reported to play a pivotal role in the development of both type 1 and type 2 diabetes in humans ( 6 , 20 , 24 , 30 ). Although the natural course of canine diabetes and its aetiopathogenesis are not exactly the same as in humans, there are numerous reports suggesting its similarity to type 1 diabetes, with the autoimmune response playing a significant role.…”

Redox Regulation of m6A Methyltransferase METTL3 in Human β-cells Controls the Innate Immune Response in Type 1 Diabetes

“…Sustained activation of OAS or RNAse L may lead to protein translation arrest and cell apoptosis (Hornung et al, 2014). Indeed, polymorphisms in the OAS gene cluster have been associated with increased OAS enzymatic activity and susceptibility to T1D (Field et al, 2005;Pedersen et al, 2021;Tessier et al, 2006). Intriguingly, β-cells are unique among pancreatic islet cells with the ability to upregulate OAS expression in response to interferon-α or poly(I:C) (a dsRNA mimetic) (Bonnevie-Nielsen et al, 1996;Li et al, 2009b).…”