Mild decrease in TBX20 promoter activity is a potentially protective factor against congenital heart defects in the Han Chinese population.
Mild decrease in TBX20 promoter activity is a potentially protective factor against congenital heart defects in the Han Chinese population.
复制标题
TBX20启动子活性轻度降低是汉族人群先天性心脏病的潜在保护因素
DOI：
10.1038/srep23662
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发表时间：
2016-04-01
影响因子：
4.6
通讯作者：
Wang HY
中科院分区：
文献类型：
--
作者：
Yu LW;Wang F;Yang XY;Sun SN;Zheng YF;Li BB;Gui YH;Wang HY
先天性心脏病是世界上最常见的人类出生缺陷之一。TBX20是胚胎心血管系统发育的关键转录因子。以往的研究表明，TBX20编码区的突变有助于家族性和散发性CHD的发生。然而，TBX20调控区的变异是否也与CHD相关仍是未知数。在这项研究中，我们测序了228例CHD患者和292名对照的TBX20转录起始位点上游的2 kb区域。在所鉴定的8个单核苷酸多态性（SNP）中，6个SNP处于强连锁不平衡，并且次要等位基因与较低的CHD风险相关（对于rs10235849选择为标签SNP，p = 0.0069，OR（95%CI）= 0.68（0.51 - 0.90））。功能分析表明，在人类心脏组织和三种细胞系中，次要等位基因的转录活性低于主要等位基因。电泳迁移率变动分析表明，TBX20次要等位基因可能表现出较高的结合亲和力与某些转录抑制因子。我们的研究结果表明，在中国汉族人群中，TBX20活性适度降低可能降低CHD风险，为CHD病因学研究提供了新的见解。
Congenital heart defects (CHDs) are one of the most common human birth defects worldwide. TBX20 is a crucial transcription factor for the development of embryonic cardiovascular system. Previous studies have demonstrated that mutations in the TBX20 coding region contribute to familial and sporadic CHD occurrence. However, it remains largely unknown whether variants in the TBX20 regulatory region are also related to CHDs. In this study, we sequenced the 2 kb region upstream of the TBX20 transcription start site in 228 CHD patients and 292 controls in a Han Chinese population. Among the 8 single nucleotide polymorphisms (SNPs) identified, six SNPs are in strong linkage disequilibrium and the minor alleles are associated with lower CHD risk (for rs10235849 chosen as tag SNP, p = 0.0069, OR (95% CI) = 0.68 (0.51–0.90)). Functional analysis showed that the minor alleles have lower transcriptional activity than major alleles in both human heart tissues and three cell lines. The electrophoretic mobility shift assay suggested that TBX20 minor alleles may exhibit higher binding affinity with certain transcription repressors. Our results indicate that a moderately lower TBX20 activity potentially reduces CHD risk in the Han Chinese population, providing new insight in the study of CHD etiology.