Wnt信号通路与2型糖尿病遗传易感性初步探索

Type 2 Diabetes(T2D) is a complex disease affected by many genetic factors. While GWAS have been extremely successful,there is a large proportion of the genetic heritability for T2D that has yet to be uncovered. The imperative problem is "the missing heritability" of T2D. Our previous research showed that gene-gene interaction in certain pathway is associated with the susceptibility of T2D. And Wnt pathway is related to T2D by pathway analysis of T2D GWAS data from WTCCC(Wellcome Trust Case Control Consortium). Previously we established the database for diabetes in Chinese Northern Han population. In this project, we plan to investigate the association between T2D and variants in the Wnt pathway in our database. We will also carry out functional studies to elucidate how the variant(s) participate in mechanism of T2D. The aim is to explore the contribution of the variant(s) and gene-gene interaction from Wnt pathway to genetic mechanism of T2D in the Chinese.

2型糖尿病（T2D）是一种复杂性多基因疾病。目前，全基因组关联研究发现的位点仅能解释约10%的T2D遗传度。因此，寻找T2D"丢失的遗传度"是亟待解决的关键科学问题。我们的前期研究显示信号通路内基因间交互作用可增加T2D遗传易感性，同时对T2D全基因组关联研究数据进行信号通路分析证实，Wnt信号通路与T2D关联。本课题拟在上述工作基础上利用已完成的以人群为基础的T2D样本为研究对象，结合候选基因策略，对Wnt信号通路的相关基因SNP 位点进行基因分型和关联研究，并利用生物信息学工具对突变位点进行与糖代谢相关的功能分析，以期发现我国人群新的糖尿病易感基因突变位点及基因间交互作用对T2D发病机制的作用。

功能相关基因间交互作用可能影响2型糖尿病（T2D）的遗传易感性。文献报道Wnt信号通路在糖尿病的发病机制中起重要作用。我们应用标签SNPs探讨在汉族人群中Wnt通路内基因间交互作用与T2D间的关联性。选择wnt信号通路内十四基因变异，分析其交互作用。在病例对照样本中用广义多因子降维方法（GMDR）确定基因-基因间交互作用。通过Wnt信号通路标签SNPs，我们对1026例T2D和1157例对照病例进行研究。结果发现TCF7L2和WNT2B间交互作用与中国汉族人群中2型糖尿病的易感性关联。该结果与T2D复杂发病机制一致，而这一点在应用传统方法时会被忽略。