UGT1A1基因启动子多态及表观遗传学修饰在新生儿高胆红素血症发病中的作用研究

UGT1A1 variation, including promoter TATA box variation and coding region 211 G to A (Gly71Arg) variation, has been shown to be associated with an increased incidence and severity of neonatal hyperbilirubinemia. However, our previous study has found that there were more heterozygotes of the (TA)7 repeat variant in the control group.The promoter TATA box variation in the UGT1A1 gene seem to may not contribute, and may even have a protective effect to neonatal hyperbilirubinemia in Asian population.This finding is in contrast to previous reports in Caucasian population. The contradicted role of (TA)7 repeat variant in neonatal hyperbilirubiemia merit further study. The aim of the present study is to firgure our the following scientific issues. Firstly,we will to define the effect of promoter TATA box variation in neonatal hyperbilirubinemia susceptibility . Secondly, we will investigate the features of methylation in the promoter region of UGT1A1 gene and the association between gene promoter methylation and neonatal hyperbilirubilinemia. At last, we will explore the possible mechanism of DNA methylation and neonatal hyperbilirubiem .This will lay a foundation for develop new drug in use of lowing TSB level in neonatal with severe hyperbilirubinemia。

胆红素代谢关键酶的编码基因UGT1A1基因多态是新生儿黄疸高发的重要遗传因素。我们前期的研究提示着UGT1A1基因启动子区TATA盒（UGT1A1*28）的变异与新生儿黄疸的临床表现并不一致，不同种族人群的研究结果存在很大的差异，具体机制不明。我们推测表观遗传学修饰可能是背后的机制。本课题拟以UGT1A1启动子多态为切入点，从基因多态和表观遗传学两个角度对新生儿黄疸发病的分子机制进行探讨：首先，病例-对照研究，探寻UGT1A1启动子区UGT1A1*28的变异和CpG岛甲基化与新生儿黄疸易感性的关联；其次，研究不同种族新生儿UGT1A1启动子多态的分布、CPG甲基化、转录因子水平及新生儿黄疸的发生率差异，明确该差异在人群新生儿黄疸易感性中所发挥的作用。最后，细胞水平研究UGT1A1启动子甲基化修饰在新生儿黄疸发生中的作用及机制。为阐明新生儿黄疸易感性的种族差异及个体化治疗提供理论依据。

高胆红素血症或黄疸是新生儿时期最常见的症状，大多数是良性的，但少数新生儿黄疸会发展为严重的胆红素脑病。不同地区，不同种族人群黄疸发生差异很大，亚洲人群是黄疸的高发人群，其黄疸及严重黄疸的发生率显著高于其他人群。尿苷二磷酸葡萄糖醛酸转移酶(UGT1A1)是胆红素代谢通路上的关键酶, 编码该酶的UGT1A1基因突变被认为是新生儿高胆红素血症的重要遗传基础。 本项目获取了112例维族和108例汉族足月健康新生儿出生一周内胆红素水平，UGT1A1启动子，增强子和外显子编码区基因序列。发现汉族新生儿胆红素水平明显高于维族新生儿胆红素水平，且黄疸高危儿的比例也高于维族新生儿。观察到UGT1A1启动子（TA）n重复序列突变的频率维、汉族存在显著的差异。相关性分析发现UGT1A1外显子突变（c.211 G>A ）显著升高汉维族新生儿经皮胆红素值且黄疸发生风险也增高。同时我们还详细分析了69例ABO溶血新生儿UGT1A1启动子，增强子和外显子编码区基因序列，结果显示UGT1A1基因突变增加ABO溶血新生儿发生严重黄疸的风险。我们的研究结果，一方面支持了以往关于UGT1A1启动子多态在调控不同人群胆红素水平差异的重要作用的假说，同时，进一步明确UGT1A1基因突变对我国不同地区及种族新生儿出生胆红素水平的影响及该基因突变，尤其是c.211G>A的突变，是我国新生儿非病理性黄疸的重要原因，提示UGT1A1基因分型在黄疸高危人群早期诊断和干预的必要性。