Two functional sequence variants of the GATA6 gene promoter in patients with indirect inguinal hernia
Two functional sequence variants of the GATA6 gene promoter in patients with indirect inguinal hernia
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腹股沟斜疝患者 GATA6 基因启动子的两种功能序列变异
DOI：
10.1016/j.gene.2014.06.030
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发表时间：
2014-08-15
期刊：
影响因子：
3.5
通讯作者：
Yan, Bo
中科院分区：
文献类型：
--
作者：
Qiao, Yuangang;Zhang, Zhiping;Yan, Bo
腹股沟疝是一种常见的外科疾病，其中以腹股沟斜疝（IIH）为主。有家族史者提示遗传因素在OH的发生中起重要作用。到目前为止，腹股沟疝的遗传原因和潜在机制仍在很大程度上未知。在胚胎发育过程中，加塔转录因子6（GATA 6）起着至关重要的作用。GATA6基因突变和GATA6水平变化与人类疾病有关。由于GATA6以剂量依赖性方式起作用，我们推测基因调控区内DNA序列变体（DSV）引起的GATA6水平变化可能介导OH的发生。在这项研究中，对IIH患者和种族匹配的对照组中的GATA 6基因启动子进行了遗传和功能分析。在GATA6基因启动子内鉴定了11个DNA序列变体（DSV），包括4个SNP和7个新变体。在两名IIH患者中鉴定出两种杂合DSV，g.22168361C>A和g.22169106C>T，但在对照组中没有。在培养的人成纤维细胞中，这些DSV显着降低GATA 6基因启动子活性。此外，仅在3个对照中发现3个杂合DSV。在IIH患者和对照组中发现了5个DSV，包括4个SNP和1个新变异，频率相似。因此，GATA6基因启动子内的DSV可能通过改变GATA6水平而作为风险因素促进IIH的发展。(C)2014爱思唯尔有限公司版权所有。
Inguinal hernia is a common surgical disease, majority of which are indirect inguinal hernia (IIH). A positive family history has indicated that genetic factors play important roles in the OH development. To date, genetic causes and underlying mechanisms for inguinal hernia remain largely unknown. During the embryonic development, GATA transcription factor 6 (GATA6) plays an essential role. Mutations in GATA6 gene and changed GATA6 levels have been associated with human diseases. As GATA6 acts in a dosage-dependent manner, we speculated that changed GATA6 levels, resulting from DNA sequence variants (DSVs) within the gene regulatory regions, may mediate the OH development. In this study, the GATA6 gene promoter was genetically and functionally analyzed in IIH patients and ethnic-matched controls. Eleven DNA sequence variants (DSVs), including four SNPs and seven new variants, within the GATA6 gene promoter were identified. Two heterozygous DSVs, g.22168361C>A and g.22169106C>T, were identified in two IIH patients, but in none of controls. In cultured human fibroblast, these DSVs significantly reduced the GATA6 gene promoter activities. In addition, three heterozygous DSVs were only found in three controls. Five DSVs, including four SNPs and one new variant, were found in both IIH patients and controls with similar frequencies. Therefore, the DSVs within the GATA6 gene promoter may contribute to the IIH development as a risk factor by changing the GATA6 levels. (C) 2014 Elsevier B.V. All rights reserved.