A single-nucleotide polymorphism in a methylatable Foxa2 binding site of the G6PC2 promoter is associated with insulin secretion in vivo and increased promoter activity in vitro.
A single-nucleotide polymorphism in a methylatable Foxa2 binding site of the G6PC2 promoter is associated with insulin secretion in vivo and increased promoter activity in vitro.
复制标题
G6PC2启动子的甲基化FOXA2结合位点中的单核苷酸多态性与体内胰岛素分泌有关，体外启动子活性增加。
作者：
Dos Santos C;Bougnères P;Fradin D
G6 PC 2基因编码胰岛特异性葡萄糖-6-磷酸酶相关蛋白（IGRP），有一个共同的启动子变体rs 573225（− 231 G/A），位于Foxa结合位点。我们测试了rs 573225对启动子活性的顺式调节作用及其与胰岛素对口服葡萄糖的反应的关系。研究设计和方法-rs 573225在转染的INS-1和HIT-T β细胞系中的功能作用。共有734名欧洲血统的年轻肥胖受试者进行了rs 573225基因分型。测量胰岛素和葡萄糖水平对口服葡萄糖的反应，并计算胰岛素分泌的胰岛素生成指数（IGI）。在体外，G等位基因表现出更高的亲和力结合Foxa 2转录因子和增加G6 PC 2启动子活性。如果邻近G等位基因的C被甲基化，则Foxa 2结合被修饰。通过线性回归分析，IGI与rs 573225相关，AA或AG肥胖儿童的IGI比GG肥胖儿童高30%。rs 573225也与空腹血糖相关。结论rs 573225是一个功能性顺式调节（epi）单核苷酸多态性（SNP）的G6 PC 2与葡萄糖-胰岛素稳态肥胖儿童，可能解释最近的结果在非糖尿病成人全基因组关联研究。
OBJECTIVE—The G6PC2 gene encoding islet-specific glucose-6-phosphatase related protein (IGRP) has a common promoter variant, rs573225 (−231G/A), located within a Foxa binding site. We tested the cis-regulatory effects of rs573225 on promoter activity and its association with insulin response to oral glucose. RESEARCH DESIGN AND METHODS—Functional effects of rs573225 were explored in transfected INS-1 and HIT-T β-cell lines. A total of 734 young obese subjects of European ancestry were genotyped for rs573225. Insulin and glucose levels were measured in response to oral glucose, and the insulinogenic index (IGI) of insulin secretion was calculated. RESULTS—In vitro, the G allele showed a higher affinity for binding Foxa2 transcription factor and increased G6PC2 promoter activity. Foxa2 binding is modified if the C adjacent to the G allele is methylated. IGI was associated with rs573225 by linear regression analysis and was 30% greater in AA or AG than in GG obese children. rs573225 was also associated with fasting glucose. CONCLUSIONS—rs573225 is a functional cis-regulatory (epi)-single-nucleotide polymorphism (SNP) of G6PC2 associated with glucose-insulin homeostasis in obese children, likely to explain the results of recent genome-wide association studies in nondiabetic adults.