ADIPOR1基因变异在2型糖尿病合并冠心病中的分子机制研究

We recently identified two variants in ADIPOR1 gene as shared genetic variants that were consistently associated with type 2 diabetes (T2D), coronary artery disease (CAD) and T2D with CAD in a northern Chinese population. This result supported our hypothesis that the etiology of CAD, T2D, and T2D with CAD was partially associated with ADIPOR1 variants. However, molecular mechanism for ADIPOR1 genetic variants contributing to T2D with CAD was not elucidated. Therefore, the present study is designed to investigate whether the effect of ADIPOR1 variants on ADIPOR1 expression in the pathogenesis of T2D with CAD. Firstly, we will construct a larger cohort to confirm this significant association. Secondly, on the one hand, we will make a stratification analysis to assess the relationship of associated variants with clinical phenotypes, adiponectin, and ADIPOR1 expression levels, under different disease status;on the other hand, we will evaluate predictive capacity of risk variants to high risk individuals by follow-up study. Finally, combined with molecular experiment and population study data, the present study will help to clarify the ADIPOR1 variants' contribution to pathogenesis of CAD, T2D, and T2D with CAD.

前期工作识别了脂联素受体1基因（ADIPOR1）相同变异与2型糖尿病（T2D）、冠心病（CAD）及T2D合并CAD易感性关联。我们假设ADIPOR1变异可能影响ADIPOR1表达活性或数量，进而减弱其分子保护作用。本课题拟采用病例-多对照和前瞻性研究设计，比较ADIPOR1变异在T2D合并CAD与正常、T2D及CAD组间的差异，验证不同疾病状态下同时关联的变异，随访基因型与预后的关系；分析ADIPOR1基因分型基础上的临床表型及白细胞表达ADIPOR1水平和外周血脂联素水平的差异。最后综合分子实验和人群数据，阐明ADIPOR1变异对T2D合并CAD的贡献。

研究背景：冠心病（CAD）和2型糖尿病（T2D）均是影响我国居民身体健康的常见慢性病, 两者之间存在着密切的内在联系,可能存在着共同的发病机制。本课题组前期研究发现ADIPOR1基因多态性同时增加CAD、T2D及CAD合并T2D易感风险。故本课题组推测ADIPOR1是2型糖尿病合并冠心病的遗传标记之一。.目的：本课题试图寻找与CAD合并T2D关联的ADIPOR1基因功能区变异，探索功能区变异与疾病严重程度及其预后的关系，并试图揭示可能的机制。.研究内容：首先在100例极端表型病例中测序ADIPOR1基因的外显子、3'UTR及5'UTR，随后在大样本数据中验证与CAD、T2D及CAD合并T2D易感性关联的ADIPOR1功能区变异，分析不同等位基因携带者的ADIPOR1表达水平、冠状动脉病变程度/斑块组成和心血管预后差异的影响，随访基因型与预后的关系。.重要结果：位于3'UTR 的rs7539542 G等位基因同时增加CAD（OR=2.34，P<0.01），T2D（OR=10.66，P<0.01）及CAD合并T2D（OR=1.97，P=0.01）的易感性风险（相关结果未发表）。位于3'UTR的rs10581 T等位基因与T2D的易感性相关（OR=2.18，P=0.039）（未发表）。位于内含子区的rs3737884 G等位基因与CAD的易感性相关，并可提高左前降支病变（OR:6.77，P=0.009）和右冠状动脉病变（OR=4.81，P=0.028）风险（已发表）。位于内含子区的rs16850797 C等位基因与高血压合并T2D合并CAD风险正相关（OR=3.57，P=0.003）（结果未发表）。.科学意义： ADIPOR1基因多态性将来在临床应用中可以作为包括冠心病在内的代谢性疾病个性化一级预防及早期诊断的一部分，以实现对病患进行精确分类，从而进行针对性的预防和治疗。