宫内高血糖环境下胰岛素生长因子2/H19基因表达及甲基化水平的变化

Macrosomia is one of the most common complications in diabetes mellitus with pregnancy, which has been associated with higher risk of obesity, type 2 diabetes (T2D) and cardiovascular disease (CVD) in the adult life. The cause of macrosomia includes hereditary、nutrition、endocrine and other factors. Intrauterine life is now considered a critical period associated with long-term programming of energy balance regulation. Events during this critical window are believed to play an important role in the fetal development and growth and in determining children's susceptibility to energy metabolism-related diseases over the long-term. In fact, detrimental fetal and perinatal environments have been repeatedly associated with obesity, T2D and CVD. Genomic imprinting is known to impact genes important in placental and fetal growth and development. Insulin-like growth factor 2 (IGF2)/H19 is one of the key players being involved in fetal growth and development. Taken together, the clinical features of three human syndromes highly suggest that IGF2/H19 DNA methylation is important for fetal growth and development as well as for children's health. However, the role of DNA methylation at the IGF2/H19 locus in macrosomia induced by intrauterine hyperglycemia has not yet been established. Accordingly, we tested whether IGF2/H19 DNA expression and methylation levels in placenta and umbilical blood are correlated with fetal growth and development and whether intrauterine hyperglycemia environment is affecting IGF2/H19 epigenetic profile.

巨大胎儿是妊娠合并糖尿病最常见的并发症，其成年期高血压、2型糖尿病、心脏病等代谢性疾病的发生风险明显增加。巨大胎儿的发生机制可能与遗传、营养及内分泌等多种因素相关，研究显示，母亲孕期的营养状态对胎儿基因组和印迹基因的表达存在影响，胚胎发育过程中某些基因组甲基化可能对其后续的发育产生重要影响，而印迹基因更容易受到外源性因素和营养因素变化的影响。胰岛素生长因子2（insulin-like growth factor 2, IGF2）/H19基因是调节胎儿生长发育的重要的印迹基因，已有研究已经表明IGF2/H19的甲基化与胎儿体重和儿童早期的超重和肥胖相关，本研究将分析宫内高血糖环境与IGF2和H19基因的甲基化的关系，进而分析宫内高血糖环境下巨大胎儿的发生是否与IGF2和H19基因的甲基化水平的变化存在因果关系。

项目从2014年1月开始进行，已基本按照计划执行。共完成了237例标本：包括脐血，胎盘（母面、子面）的收集。通过对糖尿病组及非糖尿病组胎盘和脐血中IGF2/H19基因表达水平的检测，验证了母亲高血糖环境对胎儿印记基因的表达存在影响，其中宫内高血糖暴露环境下胎盘和脐血中IGF2基因高表达，H19基因低表达。根据胎儿出生体重不同进行亚组分析，结果发现与胎儿生长发育密切相关的IGF2/H19基因表达出现明显组间差异，其中IGF2基因在巨大儿组明显增高，H19基因明显降低，宫内高血糖暴露进一步增加了基因表达差异程度。.对脐血中IGF2/H19甲基化程度进行检测，验证了宫内高血糖暴露会改变胚胎发育过程中印迹基因的甲基化程度，这一个改变可能对其后续胎儿的发育产生重要影响。本研究发现宫内高血糖暴露IGF2多数位点出现低甲基化改变，H19多数位点出现高甲基化改变，多元线性回归分析发现IGF2/H19基因甲基化程度与新生儿体重密切相关，其中IGF2 CpG10和CpG 12与新生儿体重明显负相关。而且IGF2/H19基因甲基化水平与基因表达水平也有相关性。.目前本研究培养博士2名，共撰写4篇论文（SCI 3篇，核心期刊1篇），其中1篇核心期刊论文已接收，2篇SCI论文已投出，1篇SCI论文在撰写中。通过对糖尿病及非糖尿病孕妇胎盘和脐血中IGF2/H19进行基因表达及甲基化水平的检测，探讨宫内高血糖环境对胎儿印迹基因表达的影响，为临床孕期宫内高血糖环境对子代的远期影响及机制探讨奠定基础，为巨大胎儿及其儿童期肥胖和超重的远期预防提供一定的科学研究基础。