4.7 Article

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

期刊

DIABETOLOGIA
卷 64, 期 8, 页码 1805-1815

出版社

SPRINGER
DOI: 10.1007/s00125-021-05469-5

关键词

2 '-5 ' Apathway; Interferona alpha,2 '-5 ' Oligoadenylate synthetase; Ribonuclease L; RNaseL; Toll-like receptor7; Type 1 diabetes; Type 1 interferon; Type 2 diabetes; Virus

资金

  1. South-Eastern Norway Regional Health Authority
  2. Novo Nordisk Foundation
  3. PEVNET (Persistent Virus Infection in Diabetes Network) Study Group - European Union's Seventh Framework Program (FP7/2007-2013) [261441]
  4. National Institutes of Health [UC4 DK104155]
  5. JDRF [47-2013-520, 25-2013-268, 25-2012-380, 25-2007-874]
  6. Bagger-Sorensen Foundation

向作者/读者索取更多资源

The study 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, revealing a potential role of the immune mechanism in the development of the disease.
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 x 10(-9), OR 1.123), rs1034687 (p = 2.16 x 10(-7), OR 0.869) and rs739744 (p = 1.03 x 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 x 10(-4), 95% CI -0.43, -0.15); MX1 increased by 142% (p < 1.00 x 10(-4), 95% CI -0.52, -0.22); and ISG15 increased by 197% (p = 2.00 x 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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据