TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic Beta Cells.

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Comparison of methods for transcriptome imputation through application to two common complex diseases

Transcriptome imputation has become a popular method for integrating genotype data with publicly available expression data to investigate the potentially causal role of genes in complex traits. Here, we compare three approaches (PrediXcan, MetaXcan and FUSION) via application to genome-wide association study (GWAS) data for Crohn's disease and type 1 diabetes from the Wellcome Trust Case Control Consortium. We investigate: (i) how the results of each approach compare with each other and with those of standard GWAS analysis; and (ii) how variants in the models used by the prediction tools compare with variants previously reported as eQTLs. We find that all approaches produce highly correlated results when applied to the same GWAS data, although for a subset of genes, mostly in the major histocompatibility complex, the approaches strongly disagree. We also observe that most associations detected by these methods occur near known GWAS risk loci. PrediXcan and MetaXcan's models for predicting expression more consistently recapitulate known effects of genotype on expression, suggesting they are more robust than FUSION. Application of these transcriptome imputation approaches to summary statistics from meta-analyses in Crohn's disease and type 1 diabetes detects 53 significant expression-Crohn's disease associations and 154 significant expression-type 1 diabetes associations, providing insight into biology underlying these diseases. We conclude that while current implementations of transcriptome imputation typically detect fewer associations than GWAS, they nonetheless provide an interesting way of interpreting association signals to identify potentially causal genes, and that PrediXcan and MetaXcan generally produce more reliable results than FUSION

Abnormal islet sphingolipid metabolism in type 1 diabetes

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.AIMS/HYPOTHESIS: Sphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis of human type 1 diabetes and whether increasing the levels of the sphingolipid sulfatide would prevent models of diabetes in NOD mice. METHODS: We examined the amount and distribution of sulfatide in human pancreatic islets by immunohistochemistry, immunofluorescence and electron microscopy. Transcriptional analysis was used to evaluate expression of sphingolipid-related genes in isolated human islets. Genome-wide association studies (GWAS) and a T cell proliferation assay were used to identify type 1 diabetes related polymorphisms and test how these affect cellular islet autoimmunity. Finally, we treated NOD mice with fenofibrate, a known activator of sulfatide biosynthesis, to evaluate the effect on experimental autoimmune diabetes development. RESULTS: We found reduced amounts of sulfatide, 23% of the levels in control participants, in pancreatic islets of individuals with newly diagnosed type 1 diabetes, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. Next, we discovered eight gene polymorphisms (ORMDL3, SPHK2, B4GALNT1, SLC1A5, GALC, PPARD, PPARG and B4GALT1) involved in sphingolipid metabolism that contribute to the genetic predisposition to type 1 diabetes. These gene polymorphisms correlated with the degree of cellular islet autoimmunity in a cohort of individuals with type 1 diabetes. Finally, using fenofibrate, which activates sulfatide biosynthesis, we completely prevented diabetes in NOD mice and even reversed the disease in half of otherwise diabetic animals. CONCLUSIONS/INTERPRETATION: These results indicate that islet sphingolipid metabolism is abnormal in type 1 diabetes and suggest that modulation may represent a novel therapeutic approach. DATA AVAILABILITY: The RNA expression data is available online at https://www.dropbox.com/s/93mk5tzl5fdyo6b/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%2C%20RNA%20expression.xlsx?dl=0 . A list of SNPs identified is available at https://www.dropbox.com/s/yfojma9xanpp2ju/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%20SNP.xlsx?dl=0 .The DiViD study was funded by the South-Eastern Norway Regional Health Authority (grant to KD-J), the Novo Nordisk Foundation (grant to KD-J), and through the PEVNET (Persistent Virus Infection in Diabetes Network) Study Group funded by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 261441 PEVNET. Additional grant support from National Institutes of Health, UC4 DK104155, the JDRF (47-2013- 520), Dutch Diabetes Research Foundation, and Stichtin

Viral infections in type 1 diabetes mellitus-why the beta cells?

Type 1 diabetes mellitus (T1DM) is caused by progressive autoimmune-mediated loss of pancreatic β-cell mass via apoptosis. The onset of T1DM depends on environmental factors that interact with predisposing genes to induce an autoimmune assault against β cells. Epidemiological, clinical and pathology studies in humans support viral infection-particularly by enteroviruses (for example, coxsackievirus)-as an environmental trigger for the development of T1DM. Many candidate genes for T1DM, such as MDA5, PTPN2 and TYK2, regulate antiviral responses in both β cells and the immune system. Cellular permissiveness to viral infection is modulated by innate antiviral responses that vary among different tissues or cell types. Some data indicate that pancreatic islet α cells trigger a more efficient antiviral response to infection with diabetogenic viruses than do β cells, and so are able to eradicate viral infections without undergoing apoptosis. This difference could account for the varying ability of islet-cell subtypes to clear viral infections and explain why chronically infected pancreatic β cells, but not α cells, are targeted by an autoimmune response and killed during the development of T1DM. These issues and attempts to target viral infection as a preventive therapy for T1DM are discussed in the present Review.SCOPUS: re.jinfo:eu-repo/semantics/publishe