Roman Tamara S, Cannon Maren E, Vadlamudi Swarooparani, Buchkovich Martin L, Wolford Brooke N, Welch Ryan P, Morken Mario A, Kwon Grace J, 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, Mohlke Karen L
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Diabetes. 2017 Sep;66(9):2521-2530. doi: 10.2337/db17-0464. Epub 2017 Jul 6.
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 , 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 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 , but not adjacent gene , 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 expression and impaired insulin secretion.
对于大多数2型糖尿病全基因组关联研究确定的基因座，其分子机制仍不清楚。与2型糖尿病和空腹血糖水平相关的变异位于一个编码腺苷酸环化酶5的基因的内含子中。腺苷酸环化酶5催化环磷酸腺苷的产生，环磷酸腺苷是一种参与细胞信号传导和胰腺β细胞胰岛素分泌的第二信使分子。我们证明2型糖尿病风险等位基因与人类胰岛中该基因表达降低有关，并研究了候选变异的调控功能。rs11708067与胰腺胰岛中一个预测的增强子区域重叠。与rs11708067-G等位基因相比，2型糖尿病风险rs11708067-A等位基因在人类胰岛中的H3K27ac染色质免疫沉淀测序读数较少，在啮齿动物β细胞（大鼠832/13和小鼠MIN6）的报告基因检测中转录活性较低，且核蛋白结合增加。832/13细胞中同源增强子区域的纯合缺失导致该基因表达水平降低64%，但相邻基因未受影响，胰岛素分泌减少39%。总之，这些数据表明rs11708067-A风险等位基因通过破坏胰岛增强子导致2型糖尿病，这会导致该基因表达降低和胰岛素分泌受损。
