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

项目总结/摘要 尽管心血管疾病（CVD）的管理已经取得了进展，但CVD仍然是导致心血管疾病的主要原因。 全球过早死亡由于年龄仍然是CVD风险的主导因素，人口老龄化， 对促进CVD风险的年龄相关因素知之甚少，需要进行紧急调查。该提案使用 使用人类样本进行功能性人类基因组和多组学修饰物分析，以研究 不确定潜能的克隆造血（CHIP）和CVD之间的机制联系， 临床管理CHIP在老年人中很常见（在>70岁的人群中，≥1/10），最近的数据表明， 冠状动脉疾病（CAD）是CVD的主要原因，是死亡率增加的主要原因， 那些与芯片。随着在N~ 37 K中的发现和在N~ 5 K中的复制，初步数据表明， 染色体10q23.32使CHIP患者的CAD风险增加10倍，但与CHIP无关。 没有芯片的人中的CAD。下游分析显示了CPEB 3的潜在作用， IL-6信号通路，与先前的研究一致，表明IL-6通路对 CHIP载体的CAD开发。然而，确切的机制尚未阐明。其他基因组 和功能分子分析将识别CAD发病机制中新的CHIP特异性机制， 在CHIP携带者中导致CAD预防策略，在人类中具有最强大的临床前证据。 该提案的目的是：发现诱导CHIP相关的进一步生殖系遗传易感性。 CVD具有增加的样本量（~ 575 K：从初步研究的>10倍）以构建CHIP特异性 CAD的多基因相互作用风险评分（PIRS），对CHIP携带者的CVD风险进行分层（目标1和3）， 通过整合基因组数据和多组学数据，优先考虑CHIP相关CAD的因果机制 (Aim 2）结合群体遗传学和分子生物学方法， 人体样本分析（Aim 4）。成功完成目标将为心血管疾病铺平道路 CHIP携带者的风险管理，通过（i）改善风险分层和（ii）提高我们对 CAD和CHIP的因果基础。 在此期间，PI将获得导师和顾问委员会成员的宝贵指导， 在这些领域的世界领导者，并采取丰富的教学课程，由世界一流的环境， 哈佛，麻省理工学院和广泛的研究所获得新的知识和技能，是一个有竞争力的独立 研究者，将直接实施本研究。PI将获得以下方面的丰富经验： 在世界级领导者Natarajan博士的指导下进行心血管医学的转化研究 他是心血管医学基因组学专家，也是哈佛医学院的一员。而且这 研究将为PI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.