解析藏族人群高原肺动脉高压的调控机制及其对高原低氧环境适应的遗传效应

High-altitude pulmonary arterial hypertension (haPAH) is a chronic high altitude illness caused by pulmonary vascular remodeling due to chronic exposure to hypoxia, including increased muscularization of distal arterioles, with extension of muscle into previously unmuscularized vessels, and an increase in the collagen and elastin content of the vessel wall. The increased pressure-load on the right ventricle reduces exercise capacity and can lead to right heart failure, however, the molecular mechanism underlying the haPAH remains unclear. One of the key features of physiological adaptation to high altitude hypoxia in Tibetans is relatively low haPAH, however, the current evidences showed that haPAH is not directly regulated by EPAS1, a key gene involving in the genetic adaptation to high altitude hypoxia in Tibetans. There is could be some other genes involved in the regulation of haPAH in Tibetans. Our unpublished clinical data showed a very high incidence (14.21-26.76%) of haPAH in native Tibetans especially those who permanently settled on the higher places with elevation of over 4500 meters. These people will be an ideal natural population for delineating the molecular mechanism of haPAH in Tibetans as well as for deciphering the mechanism of genetic adaptation to high altitude hypoxia in Tibetans. We just generated a large high coverage (30×) whole genome resequencing dataset, including 112 Tibetan haPAHs and 116 Tibetan controls. This project aims to identify new susceptible loci and genes regulating haPAH in Tibetans by performing a GWAS analysis using this haPAH-control dataset and comprehensive physiological traits such as right vascular pressure (RVP), blood NO concentration et al. The identified susceptible loci and gene will not only be very useful for the treatment of haPAH, but also will provide new insights into the mechanism of genetic adaptation to high altitude hypoxia.

高原肺动脉高压是低氧条件下由于肺血管收缩反应增强和肺小动脉中层平滑肌细胞的异常增生导致的一种慢性高原病，但是对其致病机理仍然不甚清楚。藏族人群对高原低氧适应的一个关键生理特征是具有较低的肺动脉压，但现有的肺动脉高压与高原适应关键基因与藏族的高原肺动脉高压没有显著的遗传相关性，提示可能是受其它基因调控。世居高原尤其是4500米以上的高海拔地区的藏族人群中肺动脉高压的发病率很高（14-26%），因而是研究高原肺动脉高压的调控机制以及藏族人群对高原低氧环境长期适应的进化机制的理想人群。本项目中我们将利用前期研究中筛查的112例藏族高原肺动脉高压与116例藏族正常对照人群的全基因组数据的GWAS关联分析，并结合脐带内皮细胞与Cas9基因修饰小鼠的低氧诱导验证实验，以期发现在藏族人群中调控高原肺动脉高压的易感基因。研究结果将为治疗高原肺动脉高压提供分子靶标，还为揭示高原适应的分子机制提供证据。

高原肺动脉高压是低氧条件下由于肺血管收缩反应增强和肺小动脉中层平滑肌细胞的异常增生导致的一种慢性高原病，但是对其致病机理仍然不甚清楚。藏族人群对高原低氧适应的一个关键生理特征是具有较低的肺动脉压，但现有的肺动脉高压与高原适应关键基因与藏族的高原肺动脉高压没有显著的遗传相关性，提示可能是受其它基因调控。世居高原尤其是4500米以上的高海拔地区的藏族人群中肺动脉高压的发病率很高（14-26%），因而是研究高原肺动脉高压的调控机制以及藏族人群对高原低氧环境长期适应的进化机制的理想人群。本项目利用前期研究中筛查的112例藏族高原肺动脉高压与116例藏族正常对照人群的全基因组数据的GWAS关联分析，并结合脐带内皮细胞与Cas9基因修饰小鼠的低氧诱导验证实验，以期发现在藏族人群中调控高原肺动脉高压的易感基因。研究结果将为治疗高原肺动脉高压提供分子靶标，还为揭示高原适应的分子机制提供新的证据。本课题紧紧围绕解析藏族人群中高原肺动脉高原的致病机理及其对高原低氧环境适应的遗传影响这一核心科学问题，按计划高质量完成了原计划的全部研究任务：首次找到14个与高原肺动脉高压相关的基因区域和55个潜在功能位点；提出了一氧化氮在藏族人群对高原低氧环境生理适应的钝化调节机制假说；提出海拔4500米可能是藏族人群对高原低氧环境最佳适应的临界海拔，初步回答了藏族人群究竟能适应多高海拔的低氧环境的问题；初步阐明了低氧通路关键基因EPAS1在高原低氧环境中调控血液血红蛋白的机制；系统分析了高原特有的大型哺乳动物牦牛的8种主要器官的转录组全景图谱。发表研究论文6篇，1篇正在修回中。培养博士毕业生1人、硕士毕业生2人，3人次参加国际学术会议。

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