糖尿病易感基因的microRNA结合位点多态性与妊娠期糖尿病发病关系研究

Women who experience gestational diabetes mellitus (GDM) and their offsprings have increased risk of developing type 2 diabetes in their later lives, and if the appropriate method is developed to predict and intervene the onset of GDM at the beginning of pregnancy, the prevalence of type 2 diabetes will probably decrease. There is a plenty of evidence suggesting that heritability takes an improtant role in GDM. Although recent advances in the genetics of GDM have been exciting, the variants thus far detected only explain a very small fraction (less than 10%) of the heritability of GDM. Since miRNAs are wide and key regulators of gene expression,miRNA-related SNPs including SNPs in miRNA genes and target sites may function as regulatory SNPs through modifying miRNA regulation to affect the phenotypes and disease susceptibility.To date, a number of studies have demonstrated that SNPs in target sites are associated with diseases,such as cancer, cardiovascular disease and osteoporosis. However, the effect of miRNA binding site SNP on GDM is unknown．In the present study，we try to explore the association of 60 miRNA binding sits involving in the development of islet cell,beta-cell fuction,insulin resistance, MODY with GDM, the level of plasma glucose and inslin,to construct a simple points model for predicting incident of GDM among Chinese people.

妊娠期糖尿病（GDM）患者及其后代是2型糖尿病(DM)的重要潜在人群，早期对其预测干预，是减少DM发病的有效措施之一。遗传因素在GDM发病中作用显著，可以作为GDM的重要预测指标，但与GDM相关的遗传机制尚不完全清楚。MicroRNA(miRNA)调控是近年发现的参与转录后调控的重要机制，其作用的结构基础是靶基因的3'UTR区有其结合位点。研究表明靶基因上miRNA结合位点SNP多态性与肿瘤、心血管疾病、骨质疏松症等多基因遗传病的发生密切相关，但其与GDM发病的关系尚未见报道。因此本研究将以我们前期建立的大样本GDM资源库为基础，以TaqMan SNP基因分型系统为技术平台，全面分析与胰岛发育、胰岛beta细胞功能、胰岛素抵抗和青少年糖尿病相关的基因的60个miRNA结合位点SNP等位基因和基因型分布频率，探讨它们与GDM及血糖和胰岛素等数量性状的相关关系，为早期预测GDM发生提供重要依据

近年来发现miRNA及其靶基因的单核苷酸多态性在疾病的发生发展过程中起着重要作用。本项目着重研究了糖脂代谢相关基因miRNA结合位点、转录因子结合位点多态性与妊娠期糖脂水平的关系。研究结果如下：全面筛选GWAS中与T2DM相关,且已在汉族人群中验证的基因,18个microRNA结合位点多态性中有6个与GDM相关,分别是rs2466293、rs1051295, rs1063192, rs1042842, rs1366600和rs712699。其中rs2466293C等位基因与HOMA-B相关,rs1802295T等位基因与空腹血糖相关,rs10802502C等位基因与HOMA-B和AUC相关;Has-miR-27a基因rs895819与GDM低风险相关,其CC基因型孕妇空腹血糖低于CT+TT基因型孕妇。说明部分T2DM相关基因的miRNA结合位点与GDM相关,且可能通过改变胰岛beta细胞功能发挥作用,主要对空腹血糖造成影响。对于4个GDM相关基因miRNA结合多态位点与特异miRNA的结合及miRNA对靶基因的表达调控进行的功能实验验证结果发现,hsa-miR-223模拟物明显降低含有PAX4基因3'UTR区rs721699少见等位基因AA纯合型的荧光素酶基因及mRNA的表达,表明其可能通过与hsa-miR-223结合下调PAX4的表达。另外,炎性标记物孕早期WBC、ALT、AST和孕中期hsCRP与GDM及相关指标的关联研究发现,孕早期WBC升高是GDM发病的独立危险因素,ALT、AST和孕中期hsCRP水平与GDM及其相关指标有关,炎症指标可能作为GDM预测标记。妊娠期血脂研究表明,26个SNP位点中有rs3764261,rs1883025,rs4225和rs16851339与妊娠期HDL-C水平相关；rs1367117,rs174561,rs2278356和rs2280826与妊娠期LDL-C水平相关；rs2278356与妊娠期TC水平相关；rs2278356,rs1059611,rs2280826和rs3201475与妊娠期TG水平相关,说明部分GWAS发现的血脂相关基因SNP位点及microRNA结合位点、转录因子结合位点与中国汉族人群妊娠期的血脂水平相关。上述研究为妊娠期糖脂代谢异常的临床诊疗提供了遗传学依据,并初步探讨了炎症指标与GDM发生的关系。