背景:冠状动脉疾病(CAD)是一种多因素复杂的特征,可遗传,尤其是在早发家庭。然而,影响早发性CAD易感性的遗传因素尚未完全表征.
方法:在本研究中,我们在一个中国汉族CAD家族的CYP17A1基因中发现了一个罕见的无义变异。为了验证这种变异对动脉粥样硬化和早发性冠状动脉疾病的影响,我们对人口进行了研究,细胞,和老鼠。
结果:该突变在所有受影响的家庭成员中与临床综合征精确聚集,在未受影响的家庭成员和无关的对照中不存在。类似于人类表型,CYP17A1缺陷小鼠呈现代谢综合征伴高血压的表型,血清葡萄糖浓度升高,以及中心性肥胖和脂肪肝的表现。此外,CYP17A1敲除小鼠或CYP17A1+ApoE双敲除小鼠比野生型(WT)高脂日记发展更多的动脉粥样硬化病变。在细胞模型中,发现CYP17A1通过增加葡萄糖的摄入和利用而参与葡萄糖代谢。通过激活IGF1/mTOR/HIF1-α信号的方式,这与CYP17A1敲除小鼠糖耐量受损和胰岛素抵抗一致。
结论:通过我们对细胞的研究,老鼠和人类,我们将CYP17A1鉴定为参与动脉粥样硬化过程病理生理学的关键蛋白,并揭示了CYP17A1C987X突变诱导动脉粥样硬化和涉及葡萄糖稳态调节的早发性CAD的可能机制.视频摘要。
Coronary artery disease (CAD) is a multi-factor complex trait and is heritable, especially in early-onset families. However, the genetic factors affecting the susceptibility of early-onset CAD are not fully characterized.
In the present study, we identified a rare nonsense variant in the
CYP17A1 gene from a Chinese Han family with CAD. To validate the effect of this variation on atherosclerosis and early-onset coronary artery disease, we conducted studies on population, cells, and mice.
The mutation precisely congregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Similar to the human phenotype, the
CYP17A1-deficient mice present the phenotype of metabolic syndrome with hypertension, increased serum glucose concentration, and presentation of central obesity and fatty liver. Furthermore,
CYP17A1 knockout mice or
CYP17A1 + ApoE double knockout mice developed more atherosclerotic lesions than wild type (WT) with high fat diary. In cell models,
CYP17A1 was found to be involved in glucose metabolism by increasing glucose intake and utilization, through activating IGF1/mTOR/HIF1-α signaling way, which was consistent in CYP17A1 knockout mice with impaired glucose tolerance and insulin resistance.
Through our study of cells, mice and humans, we identified
CYP17A1 as a key protein participating in the pathophysiology of the atherosclerotic process and the possible mechanism of CYP17A1 C987X mutation induced atherosclerosis and early-onset CAD involving glucose homeostasis regulation was revealed. Video Abstract.