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

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.

• Authors: Tamara S Roman, Maren E Cannon, Swarooparani Vadlamudi, Martin L Buchkovich, Brooke N Wolford, Ryan P Welch, Mario A Morken, Grace J Kwon, Arushi Varshney, Romy Kursawe, Ying Wu, Anne U Jackson, National Institutes of Health Intramural Sequencing Center (NISC) Comparative Sequencing Program, Michael R Erdos, Johanna Kuusisto, Markku Laakso, Laura J Scott, Michael Boehnke, Francis S Collins, Stephen C J Parker, Michael L Stitzel, Karen L Mohlke
• Journal: Diabetes (Diabetes) Vol. 66 Issue 9 Pg. 2521-2530 (09 2017) ISSN: 1939-327X [Electronic] United States
• PMID: 28684635 (Publication Type: Journal Article)
• Copyright: © 2017 by the American Diabetes Association.

Chemical References

• Insulin
• Adenylyl Cyclases
• adenylyl cyclase type V

Topics

• Adenylyl Cyclases (genetics, metabolism)
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Gene Expression Regulation (physiology)
• Genetic Variation
• Genome-Wide Association Study
• Humans
• Insulin (metabolism)
• Insulin Secretion
• Islets of Langerhans (metabolism)