冠心病伏寒证的遗传特征及生物学机制研究

A major cause of coronary heart disease is atherosclerosis (AS). There are sufficient evidences proving that hereditary factors play an important, sometimes decisive role in the formation of AS in recent years. Nevertheless, it has not been fully revealed by modern medical science that what are the superficial appearances of people with susceptibility genes and by what means will the biological effects occur. Long-term clinical research has found that a portion of patients with coronary heart disease have an intractable symptom "cold feet only or cold hands and feet," and the formation process of the disease shows the same patterns. The time node tallies with the cycles "Seven years for Women" and "Eight years for Men" which are recorded in The Emperor's Inner Canon. The early stage characteristics or symptoms, "deficiency and retention of vital energy, intermingling of cold and heat" (namely the latent cold syndrome), are found by cluster analysis. The disease is different from the common clinical syndromes and shows familial inheritance. Small samples of proteomics research shows that the disease is associated with complement system and endogenous antioxidant system, such as complement C3C4、complement factor H、 the level of bilirubin. Based on this research, our project intends to set latent cold syndrome from coronary heart disease as a starting point. Through clinical investigation, serum bilirubin and complement quantity measurement as well as protein expression level determination, we will intensively study the hereditary features and biological mechanisms of this category of patients (latent cold syndrome), in order to reveal the nature syndromes and genetic characteristics of this population, moreover, to provide experimental data for the early diagnosis and early warning of coronary heart disease.

冠心病的主要病因是动脉粥样硬化（AS），近年足够的证据证明遗传因素对AS的形成发挥着重要的甚至是决定性的作用。但现代医学并没有完全揭示具有哪些表象的人群具有易感基因，且通过什么途径发生生物学作用。课题组在长期临床中发现部分冠心病人群具有顽固性的“足凉或手足凉”，且疾病形成过程中呈现相同的规律，其时间节点正与《内经》中“女七”“男八”的周期相吻合。前期经聚类分析发现其证候特征是“气虚气滞，寒热错杂”（称伏寒证），有别于临床常见证候，且具有家族遗传性，小样本蛋白质组学研究发现与补体系统及内源性抗氧化系统如补体C3C4、补体因子H及胆红素水平相关。本课题拟在此研究基础上，以冠心病伏寒证为切入点，通过临床调查、血脂、血清胆红素、补体水平测定及蛋白质表达等方面，进一步对这一类人群（伏寒证）的遗传特征及生物学机制深入研究，揭示这类人群的证候本质及遗传特性，为冠心病的早期诊断和预警提供实验数据。

本项目在前期研究基础上，以冠心病伏寒证为切入点，针对临床发病特点及遗传相关性进行了大样本的调查问卷，经统计分析得出结论，先天伏寒证患者的临床表现与前期研究基本一致。将我们判定的伏寒证（气虚气滞寒热错杂证）与冠心病其它不同证候逐一进行血清检测，发现先天伏寒证患者与其他各证候类型间的血清TB、补体C3具有显著差异，且在子代伏寒证的两个年龄节点均表现出相关的差异。同时进一步通过蛋白质组学研究，寻找具有特异表达的差异蛋白，结合生物信息学技术进行深入的体内通路功能分析，发现先天伏寒的各年龄节点的差异蛋白均与补体系统相关，证实这类人群易患冠心病的生物学机制可能与补体系统有关，将对研究冠心病早期预警及早期干预具有重大意义。