Dissect the sex-specific role of the CYP17A1 locus in cardiovascular and metabolic diseases

遗传因素可以调节血压和肥胖，增加冠状动脉疾病(CAD)及其相关危险因素。冠心病是部分可遗传的，我们最近的全基因组关联研究(GWAS)发现了300多个与冠心病风险增加相关的基因座。细胞色素P17A1是冠心病基因座之一，最初被认为与心肌梗死有关。细胞色素P450 17A1基因编码细胞色素P450 17A1酶，是类固醇代谢的决定因素。来自其他小组的研究表明，CYP17A1基因与其他与心血管相关的风险因素有关，包括血压和脂肪分布。最近，心血管疾病的性别分层GWA(仅在男性或女性中)显示出强有力的证据表明，CYP17A1基因座在脂肪分布、血压调节和动脉粥样硬化(冠心病的潜在原因)中具有性别特异性的影响。与人类的数据相似，我们的CYP17A1基因敲除小鼠的结果准确地指出了男性患动脉粥样硬化的风险和女性肥胖的风险。XY CYP17A1 KO小鼠缺乏睾丸素，而XX CYP17A1 KO小鼠缺乏雌激素，并表现出明显的孕酮积累。然而，CYP17A1性别偏向效应与冠心病和其他心血管相关疾病之间联系的功能联系和确切的分子机制尚不清楚。在这项提案中，我们旨在研究CYP17A1及其相关的性类固醇激素以性别方式影响人类和小鼠血压、代谢和动脉粥样硬化(CAD)的确切机制。特别是，我们的目标是1)确定和验证与CYP17A1基因表达变化相关的因果遗传变量在雄性和雌性小鼠中的不同变化，2)测试性激素补充，包括睾酮和雌激素，是否可以防止XY CYP17A1 KO小鼠的动脉粥样硬化和XX CYP17A1 KO小鼠的肥胖，3)测试孕激素受体抑制剂对雌性肥胖的影响；以及4)确定AT1受体阻滞剂在XX和XY CYP17A1 KO小鼠中的重要性，因为已知肾素血管紧张素-醛固酮系统(RAAS)通过CYP17A1调节影响类固醇的生物合成，并且治疗性RAAS干预具有抗脂肪的作用和降低动脉粥样硬化和CAD的风险。所有这些都将有助于为心血管疾病高危男性和女性开发针对性别的治疗和诊断方法。

Genetic factors can modulate blood pressure and obesity and increase coronary artery disease (CAD) and its related risk factors. CAD is partially heritable, and our recent genome-wide association studies (GWAS) identified over 300 loci associated with elevated risk for CAD. CYP17A1 is among the CAD GWAS loci and was initially identified to be associated with myocardial infarction. CYP17A1 gene encodes the cytochrome P450 17A1 enzyme, a determinant in steroid metabolism. Studies from other groups demonstrated the association of the CYP17A1 locus with other cardiovascular-related risk factors, including blood pressure and fat distribution. Recently sex-stratified GWAS (in male or female only) for cardiovascular disease revealed strong evidence of a sex-specific effect of the CYP17A1 locus in fat distribution, blood pressure regulation, and atherosclerosis, the underlying cause of CAD. Similar to the human data, our Cyp17a1 knockout mice results pinpointed a risk of atherosclerosis in males and obesity in females. The XY Cyp17a1 KO mice revealed a lack of testosterone, while the XX Cyp17a1 KO mice lack estrogen and display a marked progesterone accumulation. However, the functional link and exact molecular mechanisms underlying the association between the CYP17A1 sex-biased effect and CAD and other cardiovascular-related diseases are missing. In this proposal, we aim to investigate the exact mechanism by which CYP17A1, and thus its related sex steroid hormones, influence blood pressure, metabolism, and atherosclerosis (CAD) in humans and mice in a sex manner. Especially we aim to 1) identify and validate the causal genetic variants associated with CYP17A1 gene expression changes differently in males and females, 2) test whether sex hormone supplementation, including testosterone and estrogen, can prevent atherosclerosis in XY Cyp17a1 KO and obesity in XX Cyp17a1 KO mice, 3) test the effect of a progesterone receptor inhibitor on obesity in females; and 4) to determine the importance of AT1 receptor blocker therapy in XX and XY Cyp17a1 KO mice, as it is known that the Renin Angiotensin Aldosterone System (RAAS) influences steroid biosynthesis via Cyp17a1 regulation and that therapeutic RAAS intervention has an antiadipose effect and reduces the risk of atherosclerosis and CAD. All these will help to develop sex-specific therapies and diagnostic methods for males and females at high risk for cardiovascular diseases.