Haplotypes of the Mutated SIRT2 Promoter Contributing to Transcription Factor Binding and Type 2 Diabetes Susceptibility
Haplotypes of the Mutated SIRT2 Promoter Contributing to Transcription Factor Binding and Type 2 Diabetes Susceptibility
复制标题
有助于转录因子结合和 2 型糖尿病易感性的突变 SIRT2 启动子的单倍型
DOI：
10.3390/genes11050569
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发表时间：
2020-05-01
期刊：
影响因子：
3.5
通讯作者：
Xu, Yao
中科院分区：
文献类型：
--
作者：
Zheng, Xiao;Li, Jiajun;Xu, Yao
遗传变异是2型糖尿病（T2 D）易感性和发病机制的重要致病因素。组蛋白去乙酰化酶，sirtuin 2（SIRT 2），在葡萄糖代谢和胰岛素敏感性中起调节作用。然而，SIRT 2变体或单倍型是否有助于T2 D风险仍有待阐明。在本研究中，我们首次在中国人群中检测到SIRT 2启动子区的三个新的多态性（P-MU 1，P-MU 2和P-MU 3）。这三个位点的所有成对组合都处于强烈的连锁不平衡状态。其次，我们构建了单倍型块结构，发现H1-GGC和H2-CCA在T2 D中占最多（共91.8%）。单倍型组合H1-H1-GGGGCC显示T2 D的高风险（OR = 2.03，95%CI = 1.12-3.72）。经关联分析发现H1-H1-GGGGCC携带者空腹血糖和糖化血红蛋白显著升高。单倍型H1-GGC的启动子活性是H2-CCA的6.74倍，这与相关性结果一致。此外，我们阐明了P-MU 1和P-MU 2基因座的C等位基因破坏信号转导和转录激活因子1（STAT 1）结合位点，导致SIRT 2转录减弱的机制。总之，这些数据表明，连锁单倍型GGC可以被认为是T2 D诊断和治疗评估的有希望的标志物。
Genetic variability is an important causative factor for susceptibility and pathogenesis of type 2 diabetes (T2D). Histone deacetylase, sirtuin 2 (SIRT2), plays regulatory roles in glucose metabolism and insulin sensitivity. However, whether the SIRT2 variants or haplotypes contribute to T2D risk remain to be elucidated. In this study, we first detected three novel polymorphisms (P-MU1, P-MU2, and P-MU3) in the promoter of SIRT2 in the Chinese population. All pairwise sets of the three loci were strongly in linkage disequilibrium. Next, we constructed the haplotype block structure, and found H1-GGC and H2-CCA accounted for the most (total 91.8%) in T2D. The haplotype combination H1-H1-GGGGCC displayed a high risk for T2D (OR = 2.03, 95% CI = 1.12–3.72). By association analysis, we found the individuals carrying H1-H1-GGGGCC had significantly higher fasting plasma glucose and glycated hemoglobin. The haplotype H1-GGC presented a 6.74-fold higher promoter activity than H2-CCA, which was consistent with the correlation results. Furthermore, we clarified the mechanism whereby the C allele of both the P-MU1 and P-MU2 loci disrupted the signal transducer and activator of transcription 1 (STAT1) binding sites, leading to the attenuation of the SIRT2 transcription. Together, these data suggest that the linked haplotype GGC could be considered as a promising marker for T2D diagnosis and therapy assessment.