Genetic predisposition in the 2'-5'A pathway in the development of type 1 diabetes: potential contribution to dysregulation of innate antiviral immunity.
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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DOI：
10.1007/s00125-021-05469-5
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发表时间：
2021-08
期刊：
影响因子：
8.2
通讯作者：
Buschard K
中科院分区：
文献类型：
--
作者：
Pedersen K;Haupt-Jorgensen M;Krogvold L;Kaur S;Gerling IC;Pociot F;Dahl-Jørgensen K;Buschard K
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. 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). 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). 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. The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05469-5.
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影响因子：
30.8
作者：
Westra, Harm-Jan;Peters, Marjolein J.;Esko, Tonu;Yaghootkar, Hanieh;Schurmann, Claudia;Kettunen, Johannes;Christiansen, Mark W.;Fairfax, Benjamin P.;Schramm, Katharina;Powell, Joseph E.;Zhernakova, Alexandra;Zhernakova, Daria V.;Veldink, Jan H.;Van den Berg, Leonard H.;Karjalainen, Juha;Withoff, Sebo;Uitterlinden, Andre G.;Hofman, Albert;Rivadeneira, Fernando;'t Hoen, Peter A. C.;Reinmaa, Eva;Fischer, Krista;Nelis, Mari;Milani, Lili;Melzer, David;Ferrucci, Luigi;Singleton, Andrew B.;Hernandez, Dena G.;Nalls, Michael A.;Homuth, Georg;Nauck, Matthias;Radke, Doerte;Voelker, Uwe;Perola, Markus;Salomaa, Veikko;Brody, Jennifer;Suchy-Dicey, Astrid;Gharib, Sina A.;Enquobahrie, Daniel A.;Lumley, Thomas;Montgomery, Grant W.;Makino, Seiko;Prokisch, Holger;Herder, Christian;Roden, Michael;Grallert, Harald;Meitinger, Thomas;Strauch, Konstantin;Li, Yang;Jansen, Ritsert C.;Visscher, Peter M.;Knight, Julian C.;Psaty, Bruce M.;Ripatti, Samuli;Teumer, Alexander;Frayling, Timothy M.;Metspalu, Andres;van Meurs, Joyce B. J.;Franke, Lude
通讯作者：
Franke, Lude
影响因子：
30.8
作者：
Onengut-Gumuscu, Suna;Chen, Wei-Min;Burren, Oliver;Cooper, Nick J.;Quinlan, Aaron R.;Mychaleckyj, Josyf C.;Farber, Emily;Bonnie, Jessica K.;Szpak, Michal;Schofield, Ellen;Achuthan, Premanand;Guo, Hui;Fortune, Mary D.;Stevens, Helen;Walker, Neil M.;Ward, Lucas D.;Kundaje, Anshul;Kellis, Manolis;Daly, Mark J.;Barrett, Jeffrey C.;Cooper, Jason D.;Deloukas, Panos;Todd, John A.;Wallace, Chris;Concannon, Patrick;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
7.7
作者：
Lundberg, Marcus;Krogvold, Lars;Skog, Oskar
通讯作者：
Skog, Oskar
DOI：
10.1073/pnas.1519657113
发表时间：
2016-02-23
影响因子：
11.1
作者：
Li, Yize;Banerjee, Shuvojit;Weiss, Susan R.
通讯作者：
Weiss, Susan R.