母亲妊娠早期糖脂代谢对胎儿先天性心脏病的作用及相关机制研究

Congenital heart diseases (CHD) are the most common birth defects in China. Although previous studies have confirmed that the risk of CHD was associated with maternal diabetes mellitus and obesity, it is still unknown for the impact of maternal glycolipid metabolism in early pregnancy on congenital heart disease in offspring and its related mechanisms. The only effect method to answer this question is cohort study of early pregnancy. This program, based on our previous cohort of early pregnancy, will explore the impact of maternal glycolipid metabolism abnormality in early pregnancy on CHD and its related mechanisms, which include: 1) to assess whether glycolipid metabolic indicators in early pregnancy are early diagnosis markers of CHD; 2) to assess the relationship between glycolipid metabolism in early pregnancy and single nucleotide polymorphisms of currently validated major susceptibility genes for CHD such as cardiac transcription factors (NKX2.5, TBX5, and GATA4); 3) to assess gene(cardiac transcription factor)-environment(maternal glycolipid metabolism in early pregnancy) and gene-gene interactions on the development of CHD. This study will pay attention to etiology, prediction and early diagnosis of CHD. The results of this study can not only identify the levels of glycolipid metabolic as early biomarkers for the diagnosis of CHD, but also as a potential therapeutic target for reducing the incidence of CHD. Additionally, the results are expected to reveal the mechanism of glycolipid metabolism on CHD. So this study will have very important significance both in theory and in practice.

先天性心脏病（CHD）是我国最常见的出生缺陷。虽然发现CHD发病与母亲患糖尿病、肥胖有关，但在妊娠早期（心脏发育的关键期）糖脂代谢对CHD的影响及相关机制仍不明确。解决这个问题的有效方法就是做妊娠早期队列研究。本研究拟在已构建的妊娠早期队列的基础上，研究妊娠早期糖脂代谢对CHD的作用和相关机制，主要包括：（i）评估妊娠早期糖脂代谢指标能否作为CHD的早诊标志；（ii）评估妊娠早期糖脂代谢与已经证实的关于CHD的主要易感基因如心脏转录因子（NKX2.5、TBX5、GATA4）基因多态性的相关性；（iii）评估心脏转录因子基因之间以及这些基因与妊娠早期糖脂代谢之间在CHD发病中的联合效应。本研究既关注病因，又关注预测和早期诊断；糖脂代谢水平既可作为早期诊断CHD的生物标记物，又可将其作为减少CHD发病风险的潜在治疗靶点；结果有望揭示糖脂代谢对CHD的作用机制。因此，本研究有重要理论和实际意义。

先天性心脏病（CHD）是我国最常见的出生缺陷。虽然发现CHD发病与母亲患糖尿病、肥胖有关，但在妊娠期糖脂代谢对CHD的影响及相关机制仍不明确。本研究在已构建的妊娠早期队列的基础上，研究妊娠期糖脂代谢（表现为糖尿病和肥胖）对CHD的作用和相关机制，包括：（i）全面评估妊娠期糖尿病/肥胖与胎儿CHD及亚型的相关性；（ii）评估妊娠期糖尿病/肥胖与胎儿心脏特异性转录因子（NKX2.5、TBX5、GATA4）基因多态性的相关性；（iii）评估心脏转录因子基因之间以及这些基因与妊娠期糖尿病/肥胖之间在CHD发病中的联合效应。结果显示：（i）母亲孕前糖尿病（OR=3.18）、妊娠期糖尿病（OR=1.98）均增加胎儿CHD的风险；（ii）母亲患糖尿病不管是孕前糖尿病还是妊娠期糖尿病几乎与胎儿CHD各种亚型的发病风险有关，其中右心室双出口（OR=10.89）、房室间隔缺损（OR=5.74）、动脉干分隔不均（OR=5.06）是与母亲糖尿病关联最强的三种CHD亚型；（iii）母亲孕前超重（OR=1.04）、I级肥胖（OR=1.15）、II级肥胖（OR=1.26）、III级肥胖（OR=1.42）均增加胎儿CHD的发病风险，胎儿CHD的风险与母亲BMI存在剂量效应关系（P=0.000）；（iv）母亲肥胖或重度肥胖几乎与胎儿CHD各种亚型的发病风险有关，尚未发现母亲低体重与胎儿CHD各种亚型的发病风险有关；（v）NKX2.5基因两个位点rs118026695（TC vs TT：OR=2.15；CC vs TT：OR=4.97）和rs2277923（CT vs CC：OR=1.61；TT vs CC：OR=1.74）的遗传变异与CHD发生有关；（vi）妊娠期糖尿病与NKX2.5基因两个位点rs118026695（OR=2.32）和rs2277923（OR=1.52）在CHD发病中存在联合效应，共同影响心脏的发育。本研究既关注病因，又关注预测和早期诊断；糖脂代谢水平既可作为早期诊断CHD的生物标记物，又可将其作为减少CHD发病风险的潜在治疗靶点；结果有望揭示糖脂代谢对CHD的作用机制。