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- W2734033274 abstract "Molecular mechanisms remain unknown for most type 2 diabetes genome-wide association study identified loci. Variants associated with type 2 diabetes and fasting glucose levels reside in introns of ADCY5, a gene that encodes adenylate cyclase 5. Adenylate cyclase 5 catalyzes the production of cyclic AMP, which is a second messenger molecule involved in cell signaling and pancreatic β-cell insulin secretion. We demonstrated that type 2 diabetes risk alleles are associated with decreased ADCY5 expression in human islets and examined candidate variants for regulatory function. rs11708067 overlaps a predicted enhancer region in pancreatic islets. The type 2 diabetes risk rs11708067-A allele showed fewer H3K27ac ChIP-seq reads in human islets, lower transcriptional activity in reporter assays in rodent β-cells (rat 832/13 and mouse MIN6), and increased nuclear protein binding compared with the rs11708067-G allele. Homozygous deletion of the orthologous enhancer region in 832/13 cells resulted in a 64% reduction in expression level of Adcy5, but not adjacent gene Sec22a, and a 39% reduction in insulin secretion. Together, these data suggest that rs11708067-A risk allele contributes to type 2 diabetes by disrupting an islet enhancer, which results in reduced ADCY5 expression and impaired insulin secretion." @default.
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- W2734033274 date "2017-07-06" @default.
- W2734033274 modified "2023-10-17" @default.
- W2734033274 title "A Type 2 Diabetes–Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the <i>ADCY5</i> Locus" @default.
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- W2734033274 doi "https://doi.org/10.2337/db17-0464" @default.
- W2734033274 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5860374" @default.
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