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Distillation of potential drug targets for type 2 diabetes by overlaying TCF7L2 ChIP-seq and pancreatic islet open chromatin maps

AuthorsSainz, Jesús
Issue Date28-May-2011
PublisherEuropean Society of Human Genetics
CitationEuropean Human Genetics Conference (2011)
AbstractVariation in TCF7L2 is strongly associated with type 2 diabetres(T2D). We previously mapped the genomic regions bound by TCF7L2 using ChIP-seq. The list of genes bound by TCF7L2 harbor a highly significant over-representation of loci uncovered in GWAS of T2D. Further support for our conclusions came from a subsequent VDR ChIP-seq study that gave a similar enrichment of GWAS-discovered genes. Therefore, it is our hypothesis that a substantial portion of the reminder of genes bound by TCF7L2 on our list, not previously implicated in disease, also harbor genetic variants associated with T2D. We aimed at distilling down genes bound by TCF7L2 that encode proteins that would be considered attractive drug targets. We analyzed the overlap of loci between our TCF7L2 ChiP-seq gene list and the published open chromatin map for pancreatic islets in order to get an indirect measure of relevant sites in this key tissue. We found that 94 genes overlapped, and interestingly, 36% of the gene products fall in to drug target classes. Attempting to distill this gene list further, we also carried out ChIP-seq in HepG2 cells where TCF7L2 is abundantly expressed. 24 genes remained of which 7 encode what would be considered druggable targets. In summary, we have distilled down loci that are both bound by TCF7L2 across two cell lines and coincide with open chromatin in human pancreatic islets, of which a number encode potentially attractive drug targets that are also likely candidates to be genetically validated when sequenced in a T2D cohort.
DescriptionTrabajo presentado a: "European Human Genetics Conference" celebrada en Amsterdam del 28 al 31 de mayo de 2011.-- et al.
Appears in Collections:(IBBTEC) Comunicaciones congresos
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