Significant progress was achieved with the development of TIGER. Datasets provided by partners allowed the development of the database. This included the development dataset storage including, addressing specific issues associated with ownership and use of the data. Analysis of the datasets and pipeline development together with database functionality was developed. The database is publicly available at
http://tiger.bsc.es/(öffnet in neuem Fenster). Development will continue to increase the datasets available within TIGER and seek collaborations with other, similar European databases to provide an integrated research resource in the area of T2D. We will continnue to organise events to increase the visibility, profile and potential utilisation of TIGER.
Partners Intomics, ULB, and BSC worked on the development of a range of tools and pipelines for analysis of the TIGER datasets. The tools allow TIGER dataset analysis of RNA sequencing and protein-protein interaction studies. RNA-seq and genotype data were harmonized, quality controlled, genotypes phased and imputed. T2DSystems partners then assembled a) genetic variation effects from T2D genome wide association studies (GWAS) meta-analyses, GWAS Catalog, Variant Effect Predictor and Gnomad, b) epigenomic marks from islet DNA-methylation sites, chromatin accessibility and CHiP-seq profiles, c) annotation from Gene Ontology, lncRNAs and islet regulome, d) gene expression from normalised islet RNA-seq counts, microarrays and the Genotype-Tissue Expression database, and e) computed eQTL and allelic specific expression and created the largest regulatory variation database from human pancreatic islets. The development of additional tools will continue to allow functional and biological inter-relationships to be investigated.
Partners are characterizing the transcriptome, regulome and metabolome of human islets exposed to metabolic stresses and therapeutic agents which modify insulin secretion. Predicted molecular mechanisms of human islet dysfunction are being validated using authentic human ß cell models, including human induced pluripotent stem cells (iPSCs) that are differentiated into ß cells, coupled with state of the art genome editing technologies and cellular phenotyping. Based on these transcriptomic and cellular studies, candidate biomarkers are being selected for assay development and investigation in patient datasets. Significant and collaborative progress continues to be made with respect to the objectives in this area. Furthermore, the partners have pursued a range of activities to identify potential genetic and circulating biomarkers, including microRNAs, associated with islet cell dysfunction in humans. This has involved studies using clinically available data generated by the partner organisations and other data repositories.
The identification of rare loss of function gene variants associated with dysfunction of transcription factors, ion channels, enzymes and incretin secretion and incretin response, all essential for insulin secretion and/or response to glucose-lowering treatments, has also been investigated. The association of rare mutations with the onset of diabetes continues to be actively investigated at the present time and this work will continue. Investigation of national registers in Denmark associated with diabetes has been accessed and the data will be used to investigate inter-relationships between single gene variants and biological functionality associated with pancreatic ß cell insulin secretion during future investigations.
The consortium has been very active in the dissemination of project results with more than 60 scientific publications and presentations arising from the research that has been performed during the project. In addition, the exploitation of project results and planning for the continued support of TIGER following the end of the project has been significantly progressed to maintain the TIGER scientific and clinical resource after the end of the project.
