A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the Adcy5 Locus.
Diabetes 2017 Jul 6. [Epub ahead of print]
Molecular mechanisms remain unknown for most type 2 diabetes genome-wide association study (GWAS) 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 beta 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 beta cells (rat 832/13 and mouse MIN6) and increased nuclear protein binding compared to 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.
Roman, Tamara S; Cannon, Maren E; Vadlamudi, Swarooparani; Buchkovich, Martin L; Wolford, Brooke N; Welch, Ryan P; Morken, Mario A; Kursawe, Romy; Varshney, Arushi; Kursawe, Romy; Wu, Ying; Jackson, Anne U; Erdos, Michael R; Kuusisto, Johanna; Laakso, Markku; Scott, Laura J; Boehnke, Michael; Collins, Francis S; Parker, Stephen C J; Stitzel, Michael L.; and Mohlke, Karen L, "A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the Adcy5 Locus." (2017). Faculty Research Ahead of Print. 7.
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