冠心病是一种多因素疾病，其发病机制尚未完全阐明，但遗传基因在其发病机制中具有重要作用。有研究显示家族性早发冠心病是一种单基因遗传病。新近大量全基因组关联研究（GWAS）证实CYP17A1基因多态性和高血压、冠心病以及糖尿病的易感性存在关联。我们前期的研究结果不但证实了CYP17A1基因多态性和新疆维吾尔族、汉族冠心病的易感性有关，而且鉴定出该基因位于第六外显子上的Ins/Del新变异，导致终止密码子提早出现，使后续翻译不能正常进行，形成结构不完整的蛋白，从而影响基因功能。进一步家系连锁分析显示，该突变是早发冠心病家系的致病突变，但具体机制不明。本项目拟在前期研究的基础上，通过人群及家系验证、细胞水平功能研究以及CYP17A1基因敲除小鼠模型等方法进行整体功能研究，以期揭示CYP17A1基因新的变异在早发冠心病发生发展中的作用及其机制，为早期识别易感人群，实现早期个体化干预奠定理论基础。

Coronary heart disease is a multifactorial disease and its pathogenesis has not been fully elucidated up to date, but genetic factors play an important role in its pathogenesis. Previous studies have shown that familial premature coronary heart disease may be a single gene genetic disease. A large number of new genome-wide association studies (GWAS) confirmed that CYP17A1 genetic polymorphisms are associated with hypertension, coronary heart disease, and diabetes. Our previous studies not only demonstrated that the CYP17A1 gene polymorphism was associated with coronary heart disease in Xinjiang Uygur and Han population, but also identified a Ins / Del mutation on the exon 6 of the CYP17A1 gene, leading to premature stop codon, which results in a failure in subsequent protein translation, influencing the formation of P450C17 protein which was encoded by CYP17A1 gene . Further family linkage analysis showed that this novel mutation leading to premature coronary heart disease in a family, but the mechanism was still unknown. In this proposal, based on the previous study, further measures of cell biology, verification in populations and other premature coronary heart disease pedigrees ,animal models using different intervention and other means should be used to reveal the mechanism of the new variation of CYP17A1 gene in the development of premature coronary heart disease ，to identify susceptible populations，and to provide a theoretical basis for the individual intervention.