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Diabetes. 2017 Sep;66(9):2521-2530. doi: 10.2337/db17-0464. Epub 2017 Jul 6.

A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus.

Author information

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
The Jackson Laboratory for Genomic Medicine, Farmington, CT.
Department of Genetics and Genome Sciences, University of Connecticut Health, Farmington, CT.
Department of Human Genetics, University of Michigan, Ann Arbor, MI.
Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI.
Institute for Systems Genomics, University of Connecticut, Farmington, CT.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC


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.

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