Genetic predisposition in the 2′-5′A pathway in the development of type 1 diabetes: potential contribution to dysregulation of innate antiviral immunity
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- Pedersen2021_Article_GeneticPredispositionInThe2-5A
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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: [Figure not available: see fulltext.]
Original language | English |
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Journal | Diabetologia |
Volume | 64 |
Issue number | 8 |
Pages (from-to) | 1805-1815 |
Number of pages | 11 |
ISSN | 0012-186X |
DOIs | |
Publication status | Published - Aug 2021 |
Bibliographical note
Funding Information:
The authors thank N. Lenchik from the Department of Medicine, University of Tennessee, Memphis, TN, USA for technical support in collecting gene expression data. The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. KP, MHJ and KB contributed to the conception and design of the study. KP, LK, SK, ICG, FP and KDJ acquired the data. KP analysed and interpreted data and drafted the manuscript. All authors revised the article critically and approved the final version. KP is the guarantor of the work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding Information:
The DiViD study was funded by the South-Eastern Norway Regional Health Authority, the Novo Nordisk Foundation, and through the PEVNET (Persistent Virus Infection in Diabetes Network) Study Group funded by the European Union’s Seventh Framework Program (FP7/2007-2013) under grant agreement no. 261441 PEVNET. Additional grant support was from the National Institutes of Health (UC4 DK104155) and the JDRF (47-2013-520). nPOD, a collaborative type 1 diabetes research project, is sponsored by the JDRF (grant no. 25-2013-268, 25-2012-380 and 25-2007-874). Lastly, the study was supported by Bagger-Sørensen Foundation.
Publisher Copyright:
© 2021, The Author(s).
- 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
Research areas
ID: 284193042