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

使用基因组修饰剂将不确定潜在外显率的克隆造血与冠状动脉疾病机械联系起来

• 批准号: 10664184
• 负责人: Tetsushi Nakao
• 金额: $ 16.69万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664184
• 关键词: Address; Affect; Age; Aging; Alleles; Award; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cessation of life; Chromosomes; Clinical Management; Coronary Arteriosclerosis; DNMT3a; Data; Development; Disease; Disease Management; Elderly; Environment; Epidemiology; Etiology; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genomics; Genotype; Heart failure; Hematology; Hematopoiesis; Hematopoietic stem cells; Human; Human Genetics; IL6 Signaling Pathway; Individual; Inflammatory; Interleukin 6 Receptor; Interleukin-1 beta; Interleukin-6; Intervention; Investigation; JAK2 gene; Knowledge; Leukocytes; Link; Mediation; Medicine; Mendelian randomization; Mentors; Mentorship; Molecular; Molecular Analysis; Multiomic Data; Mutation; Pathogenesis; Pathway interactions; Patients; Penetrance; Peripheral arterial disease; Population; Population Analysis; Population Genetics; Prevention strategy; Proliferating; Property; Proteins; Proteome; Quantitative Trait Loci; Research; Research Personnel; Resources; Risk; Risk Assessment; Risk Management; Role; Sample Size; Specificity; Specimen; Stroke; Testing; Training; Transcript; Translational Research; Variant; Vocational Guidance; age related; cardiovascular disorder prevention; cardiovascular disorder risk; cardiovascular risk factor; career; causal variant; disorder risk; efficacious treatment; experience; functional genomics; gene interaction; genetic analysis; genetic variant; genome-wide; genomic data; hazard; human genomics; improved; in silico; large datasets; medical schools; member; mortality; multiple omics; novel; novel strategies; posttranscriptional; pre-clinical; premature; receptor expression; risk stratification; risk variant; single-cell RNA sequencing; skills; transcriptome; translational applications; translational medicine

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.

项目摘要/摘要 尽管心血管疾病（CVD）的管理已经提高，但CVD仍然是 全球过早死亡。随着年龄仍然是CVD风险和人口年龄的主要因素， 促进CVD风险的与年龄相关的因素了解不足需要紧急调查。该建议使用 功能性人类基因组和多态修饰符与人类标本进行研究，以研究 不确定电势（CHIP）的克隆造血与CVD之间的机械联系 临床管理。芯片在长老中很常见（> 70年中的10中≥1），并且最近的数据建立 冠状动脉疾病（CAD）是CVD的主要原因，是导致死亡率增加的主要原因 那些有芯片的人。随着N〜37K的发现和n〜5k中的复制，初步数据显示SNPS on 染色体10q23.32增加了芯片10倍但与不相关的CAD危险 没有芯片的人。下游分析显示了调节CPEB3的潜在作用 IL-6信号通路与先前的研究一致，该研究表明IL-6途径对 芯片载体中的CAD开发。但是，确切的机制尚未阐明。进一步的基因组 功能分子分析将确定CAD发病机理和 在人类中最强大的临床前证据中，导致芯片载体中的CAD预防策略。 该提案的目的将：发现影响与芯片有关的进一步种系遗传易感性 样本量增加的CVD（〜575K：>>> 10倍的初步研究）以构建芯片特异性 CAD的多基因相互作用风险评分（PIRS），这分层了芯片载体中CVD的风险（AIM 1和3）， 优先考虑基因组数据和多摩学数据的芯片相关CAD的因果机制 （AIM 2），并剖析与芯片相关的CAD结合种群遗传学和的分子机制 人类标本的分析（AIM4）。成功完成目标将为心血管铺平道路 通过（i）改善风险分层和（ii）提高我们对芯片承运人的风险管理 CAD和CHIP的因果基础。 在此颁奖期间，PI将获得导师和顾问委员会成员的宝贵指导， 这些领域的世界领导人，也参加世界一流环境提供的丰富教学课程 哈佛，麻省理工学院和广泛研究所，以获得新的知识和技能，成为一个竞争性独立 研究人员将直接实施本研究。 PI将获得丰富的经验 世界一流领导者Natarajan博士的心态下的心血管医学的翻译研究 在心血管医学的基因组学和哈佛医学院的成员中。此外，这个 研究将为PI成为独立调查员的道路提供重要的职业指导。