The -318 C>G single-nucleotide polymorphism in GNAI2 gene promoter region impairs transcriptional activity through specific binding of Sp1 transcription factor and is associated with high blood pressure in Caucasians from Italy
The -318 C>G single-nucleotide polymorphism in GNAI2 gene promoter region impairs transcriptional activity through specific binding of Sp1 transcription factor and is associated with high blood pressure in Caucasians from Italy
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DOI：
10.1681/asn.2005121340
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发表时间：
2006-04-01
影响因子：
13.6
通讯作者：
Trischitta, Vincenzo
中科院分区：
文献类型：
--
作者：
Menzaghi, Claudia;Paroni, Giulia;Trischitta, Vincenzo
GNAI 2基因编码的抑制性G α亚基2蛋白被认为是原发性高血压和/或胰岛素抵抗的致病因素。本研究的目的是确定GNAI 2变异是否调节这些异常的风险。在GNAI 2基因座的七个单核苷酸多态性（SNP）被确定。由于低等位基因频率或不太可能的生物学相关性（即，同义或内含子），6个SNP未进一步研究。在来自意大利的655名非糖尿病白种人中，研究了启动子区-318 C> G SNP（等位基因频率6%）与肥胖、收缩压（SBP）和舒张压、空腹胰岛素和葡萄糖以及血脂水平的关系。与携带C/C基因型的个体相比，G携带者（即，携带G/G或C/G基因型的个体）具有较高的SBP（117.8 +/- 16对113.6 +/- 12.6 mmHg; P=0.010），并且高血压风险增加（优势比2.2; 95%置信区间1.1至4.5）。与C相比，G等位基因在转染的HEK 293细胞中的转录活性降低了2.5倍。正如TRANSFAC数据库预测的那样，与YY 1或Sp1转录因子的竞争分别特异性地降低了HeLa细胞核蛋白与-318C或-318G等位基因的结合，如移动的电泳迁移率所示。在加入抗Sp1抗体后，观察到核蛋白/-318G等位基因复合物的“超移”，但不加入抗YY 1抗体。GNAI 2 - 318 C > G SNP通过特异性结合Sp1损害转录活性，并与来自意大利的高加索人的高SBP相关。
Inhibiting G alpha subunit 2 protein, which is encoded by the GNAI2 gene, is suggested to be pathogenic for essential hypertension and/or insulin resistance. The aim of this study was to determine whether GNAI2 variations modulate the risk for these abnormalities. Seven single-nucleotide polymorphisms (SNP) at the GNAI2 locus were identified. Because of either low allelic frequency or unlikely biologic relevance (i.e., synonymous or intronic), six SNP were not studied further. The -318C > G SNP (allelic frequency 6%) in the promoter region was studied for association with adiposity, systolic BP (SBP) and diastolic BP, fasting insulin and glucose, and lipids levels in 655 nondiabetic Caucasians from Italy. As compared with individuals who carry the C/C genotype, G carriers (i.e., individuals who carry either the G/G or the C/G genotype) had higher SBP (117.8 +/- 16 versus 113.6 +/- 12.6 mmHg; P=0.010) and were at increased risk for hypertension (odds ratio 2.2; 95% confidence interval 1.1 to 4.5). Compared with the C, the G allele had 2.5-fold reduced transcriptional activity in transfected HEK293 cells. As predicted by the TRANSFAC database, competition with YY1 or Sp1 transcription factors specifically reduced the binding of HeLa cell nuclear proteins to -318C or -318G allele, respectively, as indicated by shifted electrophoretic mobility. A "supershift" of the nuclear proteins/-318G allele complex was observed after anti-Sp1 was added but not anti-YY1 antibody. The GNAI2 -318 C > G SNP impairs transcriptional activity through specific binding of Sp1 and is associated with high SBP in Caucasians from Italy.