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

Kristina Pedersen*, Martin Haupt-Jorgensen, Lars Krogvold, Simranjeet Kaur, Ivan C. Gerling, Flemming Pociot, Knut Dahl-Jørgensen, Karsten Buschard

*Corresponding author for this work
18 Citations (Scopus)

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.

Original languageEnglish
JournalDiabetologia
Volume64
Issue number8
Pages (from-to)1805-1815
Number of pages11
ISSN0012-186X
DOIs
Publication statusPublished - Aug 2021

Keywords

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

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