绝经后女性冠心病患者芳香化酶的变异与功能

After menopause, the cardiovascular risk of woman increases rapidly and eventually is equivalent to that of men when reach the age of 60. The longer time of menopause, the more serious damage to the coronary artery, as a result is more common complex lesions, high incidence of cardiovascular events with poor clinic prognosis. That might well be related to the lost function of follicles secreting estrogen in postmenopausal women, imbalance of estrogen/androgen and the loss of estrogen protection. Estrogen is mainly produced by aromatase conversion androgen to estrogen in postmenopausal women, we highly speculate the variation and function of aromatase is associated with coronary artery disease in postmenopausal women. In our study, we will determine the aromatase levels, screen the non-synonymous mutation of aromatase (CYP19A1) single nucleotide variation, for the higher frequency variations in CYP19A1, examine the association between aromatase as well as the level of sex hormone and coronary artery disease, meanwhile, for lower frequencies of rare mutation, to count the frequencies of functional variations and observe the difference in the case and control, and continue to make the clinical verifications by adding the sample size. We will do the further experiment to investigate the functional and molecular mechanisms in the field of cell and animals, establish gene mutation/function test, correlation analysis/disease phenotype research system, clarify molecular mechanism of aromatase functional SNV in the development of coronary artery disease in postmenopausal women.

女性绝经后冠心病的发生迅速增加，至60岁时男女患病率已无明显差别，且距离绝经期时间越长，冠脉病变程度严重，复杂病变多见，心血管事件发生率高，临床预后差，其原因与绝经后卵泡分泌雌激素功能丧失、雌/雄激素比例失调、失去雌激素保护有关。绝经后女性体内雌激素主要由芳香化酶转化雄激素而来，因而推测芳香化酶功能变异可能与绝经后女性冠心病发病有关。本研究将在绝经后女性冠心病患者中检测血清芳香化酶水平、筛查芳香化酶（CYP19A1）单核苷酸非同义变异（SNV），对频率较高的SNV进行基因分型与血清芳香化酶、雌/雄激素水平、冠心病的关联研究；对频率较低或稀有变异，统计功能性变异出现频率、考察其在冠心病组和对照组中分布、扩大样本量进行临床验证；并通过细胞、动物水平功能和分子机制研究，建立基因变异/功能测定、关联分析/疾病表型的研究系统，阐明芳香化酶功能性SNV在绝经后女性冠心病发生发展中的意义及其分子机制。

女性绝经后冠心病的发生迅速增加，至60岁时男女患病率已无明显差别，且距离绝经期时间越长，冠脉病变程度严重，复杂病变多见，心血管事件发生率高，临床预后差，其原因与绝经后卵泡分泌雌激素功能丧失、雌/雄激素比例失调、失去雌激素保护有关。绝经后女性体内雌激素主要由芳香化酶转化雄激素而来，因而推测芳香化酶功能变异可能与绝经后女性冠心病发病有关。本研究通过对绝经后女性冠心病患者中检测血清芳香化酶水平、筛选芳香化酶（CYP19A1）单核苷酸非同义变异（SNV），对4个(rs2236722,rs2304463,rs4275794,rs4646)频率较高的SNV进行基因分型与血清芳香化酶、雌/雄激素水平、冠心病的关联研究，研究发现CYP19A1 基因 rs2236722 多态性可能和新疆维族群体冠心病的发生相关性。rs4646 可能是一种与中国维吾尔族人群冠心病相关的新的遗传标记。rs4646 的 CA 基因型携带者发生冠心病的风险性较高，而携带CC 基因的人发生冠心病的风险性降低。初步阐明了CYP19A1功能性SNV在绝经后女性冠心病发生发展中的意义及其分子机制。此外，通过对绝经后女性冠心病进行全转录组测序，从转录水平的角度来阐明绝经后女性冠心病基因组的结构与功能，为绝经后女性冠心病的研究和治疗提供新的思路和方法。发表研究成果6篇（SCI论文4篇），培养学生5人，圆满完成各项考察指标。

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