AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究

冠心病是2型糖尿病（T2DM）并发症的主要死因，晚期糖基化终末产物（AGEs）及其受体（RAGE）通过调控miRNA影响下游通路，是T2DM并发冠心病的始动因素。本课题组前期发现炎性相关基因与心血管疾病相关，据此推测处于炎性通路上游的AGE/RAGE通路相关miRNA编码基因可能与T2DM并发冠心病相关。本研究采用巢式病例对照研究设计，回顾性收集T2DM患者作为研究基线，2017年起对基线研究对象进行随访，将新发冠心病患者纳入病例组，按年龄、性别、T2DM病程、匹配同期对照；检测AGE、RAGE等的血清学水平，并确定易感基因型，综合应用遗传风险评分及多因子降维法评价AGE/RAGE通路microRNA编码基因多态性与T2DM并发冠心病的关联，并通过多元多重中介效应分析推测遗传因素的致病机制，探讨在miRNA层面选择的基因对疾病作用的新模式，可为T2DM并发冠心病的个体化二级预防提供依据。

Coronary heart disease (CHD) is the major cause of death in type 2 diabetes (T2DM) complications, advanced glycation end products (AGEs) and receptor of AGEs (RAGE) plays important role in the onset of T2DM induced CHD. We have demonstrated that gene polymorphisms of inflammation pathway were related to cardiovascular disease and its intermediate phenotype, which is in the upstream of AGE/RAGE pathway. Thus, we infer that microRNA related to advanced glycation end products (AGEs) and receptor of AGEs (RAGE) pathway may be associated with T2DM induced CHD. The current study is based on nested case control study design, and chooses T2DM patients as baseline population. The incident CHD patients since 2017 in baseline will be selected as cases, and controls will be chosen matched by sex, age, and duration of diabetes. Questionnaire, physical examination and genotyping is carried out to the study subjects. Genetic risk scores is used to evaluate the association between coding genes of microRNA related to AGEs/RAGE and T2DM induced CHD. Generalized multifactor dimensionality reduction (GMDR) will be used to detect gene-gene and gene-environment interaction. Multiple mediation analysis will be used to infer the possible mechanism of genetic determines. Our study will provide necessary scientific basis for personal secondary prevention of T2DM induced CHD.