Using genomic modifiers to mechanistically link clonal hematopoiesis of indeterminate potential penetrance to coronary artery disease

项目摘要/摘要 尽管心血管疾病(CVD)的管理有了进步，但心血管疾病仍然是 全球范围内的过早死亡。由于年龄仍然是心血管疾病风险的主导因素，人口老龄化， 对促进心血管疾病风险的年龄相关因素知之甚少，需要进行紧急调查。本提案使用 利用人体标本进行功能性人类基因组和多组学修饰物分析 不确定潜能克隆性造血(CHIP)与心血管疾病改善的机制联系 临床管理。芯片在老年人中很常见(70岁的人中有十分之一的≥)，最近的数据表明 冠状动脉疾病(CAD)是心血管疾病的主要原因，是#年死亡率增加的主要原因 那些有芯片的。随着在N~37K的发现和N~5K的复制，初步数据显示SNPs在 染色体10q23.32使CHIP携带者的冠心病风险增加10倍，但与 CAD在那些没有芯片的人中。下游分析显示了CPEB3的潜在作用，它调节 IL-6信号通路，与先前的研究表明IL-6通路在 芯片载体中的CAD开发。然而，其确切的机制尚不清楚。进一步的基因组学 功能分子分析将确定新的芯片特异性机制在CAD发病机制和 导致在芯片携带者中制定预防冠心病的策略，这些芯片携带者拥有最可靠的临床前证据。 这项提议的目的将是：发现导致芯片相关的进一步生殖系遗传易感性 CVD，样本量增加(约575k：&gt；是初步研究的10倍)，以构建特定的芯片 冠心病多基因相互作用风险评分(PIRS)，对芯片携带者的心血管疾病风险进行分层(目标1和3)； 通过基因组数据和多组学数据的集成来优先处理芯片相关CAD的原因机制 (目标2)，并结合群体遗传学和分子生物学分析了芯片相关CAD的分子机制。 人体标本的分析(Aim4)。目标的成功完成将为心血管疾病的发展铺平道路 芯片运营商的风险管理：(I)改进风险分层和(Ii)提高我们对 CAD和CHIP的因果基础。 在整个颁奖期内，PI将从导师和顾问委员会成员那里获得宝贵的指导， 这些领域的世界领袖，也参加了由世界级环境提供的丰富的教学课程 哈佛、麻省理工学院和布罗德学院将获得新的知识和技能，以成为具有竞争力的独立人士 调查员，这将直接落实到这项研究。私人投资公司将在以下方面获得丰富的经验 在世界级领军人物Natarajan博士的指导下进行心血管医学的翻译研究 心血管医学基因组学博士，哈佛医学院成员。此外，这一点 研究将为私家侦探成为独立调查员的道路提供重要的职业指导。

Project Summary/Abstract Though cardiovascular disease (CVD) management has advanced, CVD remains the leading cause of premature death worldwide. As age remains the dominant factor in CVD risk and the population ages, the poorly understood age-related factors promoting CVD risk require urgent investigation. This proposal uses functional human genomic and multi-omics modifier analyses with the human specimen to investigate the mechanistic links between clonal hematopoiesis of indeterminate potential (CHIP) and CVD toward improving clinical management. CHIP is common in elders (≥1 in 10 among >70 years), and recent data establish coronary artery disease (CAD), a primary cause of CVD, as the primary cause of the increased mortality in those with CHIP. With the discovery in N~37K and replication in N~5K, preliminary data show that SNPs on chromosome 10q23.32 increase the CAD hazard among those with CHIP 10-fold but are not associated with CAD among those without CHIP. Downstream analyses showed the potential role of CPEB3, which modulates the IL-6 signaling pathway, in line with the previous studies showing the importance of the IL-6 pathway for CAD development in CHIP carriers. However, the exact mechanisms are yet to be elucidated. Further genomic and functional molecular analyses would identify novel CHIP-specific mechanisms in CAD pathogenesis and lead to CAD prevention strategies among CHIP carriers with the most robust preclinical evidence in humans. The aims of this proposal will: discover the further germline genetic predisposition that induces CHIP-related CVD with an increased sample size (~575K: >10-fold from the preliminary study) to construct CHIP specific polygenic interaction risk score (PIRS) for CAD, which stratifies the risk of CVD in CHIP carriers (Aim 1 and 3), prioritize causal mechanisms for CHIP-related CAD with the integration of genomic data and multi-omics data (Aim 2), and dissect the molecular mechanisms for CHIP-related CAD combining population genetics and analyses of human specimens (Aim4). Successful completion of the aims will pave the way for cardiovascular risk management of CHIP carriers by (i) improving risk stratification and (ii) improving our understanding of the causal underpinnings of CAD and CHIP. Through this award period, PI will receive invaluable guidance from mentors and advisory board members, the world leaders in these fields, and also take rich didactic courses provided by the world-class environment of Harvard, MIT, and Broad Institute to gain new knowledge and skills to be a competitive independent investigator, which will be directly implemented to this study. The PI will gain extensive experience in translational research of cardiovascular medicine under the mentorship of Dr. Natarajan, a world-class leader in the genomics of cardiovascular medicine and a member of Harvard Medical School. Furthermore, this research will provide vital career guidance on the PI’s path to becoming an independent investigator.