PROCR基因功能性遗传变异影响凝血酶水平促发心梗的机制研究

Arterial thrombosis caused by unregulated thrombin generation is a key step in the pathogenesis of acute myocardial infarction. Recent genome-wide association studies (GWAS) identified that SNP in PROCR is associated with prothrombin time and is related to the risk of coronary heart disease in European ancestry. We re-sequenced the coding region of the PROCR gene in 500 cases of myocardial infarction and 500 healthy controls, discovered several new functional variations (S88P, T174I, R179W, R236W), which may be associated with thrombin levels and myocardial infarction. This study intends to clarify the molecular mechanism that functional variations in PROCR gene affect thrombin levels and relate to the incidence and prognosis of myocardial infarction, using bioinformatics, site-directed mutagenesis, affinity detection, reporter gene, CHIP and other technology. This study will provide a new theoretical basis of potential target for anticoagulation therapy and secondary prevention of coronary heart disease.

凝血酶生成失控致动脉血栓形成是急性心梗发病的关键步骤。新近的全基因组关联分析（GWAS）发现PROCR基因变异与凝血酶原时间个体差异相关，且与欧裔冠心病风险相关。我们通过对500例心梗患者和500例健康对照PROCR基因编码区进行再测序，发现多个新的功能性变异位点（S88P、T174I、R179W、R236W），可能与凝血酶水平及心梗相关。本课题拟在前期工作基础上综合应用生物信息学、定点突变、亲和力检测、报告基因、CHIP等技术系统阐明PROCR基因功能性新突变致凝血酶水平异常的分子机制，探索其与心梗发病及预后的关系，为深入理解遗传变异在凝血/纤溶个体差异中的作用、寻求抗凝治疗潜在靶点及冠心病的二级预防提供新的理论和实验依据。