The G/G genotype of a resistin single-nucleotide polymorphism at-420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3
The G/G genotype of a resistin single-nucleotide polymorphism at-420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3
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DOI：
10.1086/424761
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发表时间：
2004-10-01
影响因子：
9.8
通讯作者：
Makino, H
中科院分区：
文献类型：
--
作者：
Osawa, H;Yamada, K;Makino, H
胰岛素抵抗是2型糖尿病(T2 DM)的主要原因。抵抗素是一种脂肪细胞分泌的激素，能拮抗胰岛素。在脂肪组织中过度表达抵抗素基因(Retn)的转基因小鼠是胰岛素抵抗的，而Retn(-/-)小鼠的空腹血糖较低，这表明Retn启动子功能的改变可能会导致糖尿病。为了确定RETN在人类T2 DM中的作用，我们分析了其5‘侧翼区的多态性。我们发现-420G/G基因型与T2 DM(397例患者和406例对照)相关(P=0.008；调整优势比=1.97[Logistic回归分析])，并且可以将疾病的发病时间提前4.9年(P=0.006[多元回归分析])。对1,888个病例和1,648个对照的荟萃分析证实了这种关联(P=.013)。连锁不平衡分析显示，-420G/G基因本身是决定T2 DM易感性的主要变异。在功能上，Sp1和Sp3转录因子与包括-420G在内的敏感DNA元件特异结合。在缺乏内源性Sp家族成员的果蝇Schneider株2细胞中，过表达Sp1或Sp3可增强带有-420G的RETN启动子活性。与这些发现一致的是，携带-420G/G基因型的T2 DM患者的空腹血清抵抗素水平更高。因此，Sp1/3对-420G的特异性识别增加了RETN启动子的活性，导致血清抵抗素水平升高，从而诱发人类T2 DM。
Insulin resistance is a major cause of type 2 diabetes mellitus (T2DM). Resistin, an adipocyte-secreted hormone, antagonizes insulin. Transgenic mice that overexpress the resistin gene (Retn) in adipose tissue are insulin-resistant, whereas Retn (-/-) mice show lower fasting blood glucose, suggesting that the altered Retn promoter function could cause diabetes. To determine the role of RETN in human T2DM, we analyzed polymorphisms in its 5' flanking region. We found that the -420G/G genotype was associated with T2DM (397 cases and 406 controls) (P = .008; adjusted odds ratio = 1.97 [by logistic regression analysis]) and could accelerate the onset of disease by 4.9 years (P = .006 [by multiple regression analysis]). Meta-analysis of 1,888 cases and 1,648 controls confirmed this association (P = .013). Linkage disequilibrium analysis revealed that the -420G/ G genotype itself was a primary variant determining T2DM susceptibility. Functionally, Sp1 and Sp3 transcription factors bound specifically to the susceptible DNA element that included -420G. Overexpression of Sp1 or Sp3 enhanced RETN promoter activity with -420G in Drosophila Schneider line 2 cells that lacked endogenous Sp family members. Consistent with these findings, fasting serum resistin levels were higher in subjects with T2DM who carried the -420G/G genotype. Therefore, the specific recognition of -420G by Sp1/3 increases RETN promoter activity, leading to enhanced serum resistin levels, thereby inducing human T2DM.