Department of Cardiology, Children's Hospital of Fudan University, Shanghai, China.
Institute of Cardiovascular Disease, General Hospital of Jinan Military Command, Jinan, China.
Pediatr Res. 2019 Feb;85(3):378-383. doi: 10.1038/s41390-018-0181-y. Epub 2018 Sep 18.
Tbx2 plays a critical role in determining fates of cardiomyocytes. Little is known about the contribution of TBX2 3' untranslated region (UTR) variants to the risk of congenital heart defect (CHD). Thus, we aimed to determine the association of single-nucleotide polymorphisms (SNPs) in TBX2 3' UTR with CHD susceptibility.
We recruited 1285 controls and 1241 CHD children from China. SNPs identification and genotyping were detected using Sanger Sequencing and SNaPshot. Stratified analysis was conducted to explore the association between rs59382073 polymorphism and CHD subtypes. Functional analyses were performed by luciferase assays in HEK-293T and H9c2 cells.
Among five TBX2 3'UTR variants identified, rs59382073 minor allele T carriers had a 1.89-fold increased CHD risk compared to GG genotype (95% CI = 1.48-2.46, P = 4.48 × 10). The most probable subtypes were right ventricular outflow tract obstruction, conotruncal, and septal defect. G to T variation decreased luciferase activity in cells. This discrepancy was exaggerated by miR-3940 and miR-708, while their corresponding inhibitors eliminated it.
T allele of rs59382073 in TBX2 3'UTR contributed to greater CHD risk in the Han Chinese population. G to T variation created binding sites for miR-3940 and miR-708 to inhibit gene expression.
Tbx2 在决定心肌细胞命运方面发挥着关键作用。关于 TBX2 3' 非翻译区（UTR）变异体对先天性心脏病（CHD）风险的贡献知之甚少。因此，我们旨在确定 TBX2 3'UTR 中单核苷酸多态性（SNP）与 CHD 易感性的关联。
我们从中国招募了 1285 名对照者和 1241 名 CHD 患儿。使用 Sanger 测序和 SNaPshot 检测 SNP 鉴定和基因分型。进行分层分析以探讨 rs59382073 多态性与 CHD 亚型之间的关系。通过在 HEK-293T 和 H9c2 细胞中进行荧光素酶测定进行功能分析。
在所鉴定的五个 TBX2 3'UTR 变异体中，与 GG 基因型相比，rs59382073 次要等位基因 T 携带者的 CHD 风险增加了 1.89 倍（95%CI=1.48-2.46，P=4.48×10）。最可能的亚型是右心室流出道梗阻、圆锥动脉干和室间隔缺损。G 到 T 的变异降低了细胞中的荧光素酶活性。这种差异被 miR-3940 和 miR-708 放大，而它们相应的抑制剂则消除了这种差异。
TBX2 3'UTR 中的 rs59382073 T 等位基因导致汉族人群 CHD 风险增加。G 到 T 的变异为 miR-3940 和 miR-708 创造了结合位点，以抑制基因表达。
