Clonal Hematopoiesis in Healthy Individuals from Families with Early OnsetCoronary Artery Disease

早发冠状动脉疾病家族的健康个体的克隆性造血

• 批准号: 9760677
• 负责人: Lewis C Becker
• 金额: $ 85.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760677
• 关键词: Age; Age-Years; Aging; Arteries; Atherosclerosis; Biological Aging; Blood Vessels; Blood specimen; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Cell Lineage; Cell model; Cells; Chronology; Clinical; Clonal Expansion; Communities; Coronary Arteriosclerosis; Coronary heart disease; Cultured Cells; DNA Sequence Alteration; Disease; Event; Exhibits; Family; Family history of; First Degree Relative; Framingham Heart Study; Gene Silencing; General Population; Genes; Genetic Predisposition to Disease; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic stem cells; Heritability; High Prevalence; In Vitro; Incidence; Individual; Jackson Heart Study; Knockout Mice; Length; Leukocytes; Malignant Neoplasms; Mus; Mutation; National Heart, Lung, and Blood Institute; Oncogenic; Parents; Phenotype; Population; Population Study; Premature aging syndrome; Prevalence; Process; Race; Recording of previous events; Risk; Risk Factors; Siblings; Somatic Mutation; Stroke; TERF1 gene; TINF2 gene; Telomerase; Telomere Shortening; Time; Trans-Omics for Precision Medicine; Ursidae Family; Variant; atherosclerosis risk; cancer risk; cardiovascular risk factor; cohort; coronary calcium scoring; density; design; disorder risk; early onset; exome sequencing; gain of function; genetic epidemiology; genetic variant; genome sequencing; in vivo; loss of function; member; mortality; mouse model; novel; offspring; overexpression; pre-clinical; premature; proband; programs; prospective; sex; telomere; whole genome

Clonal hematopoiesis (CH) occurs with aging and is associated with increased mortality, a 10-fold increase of incident cancers, and a >2 fold increase in coronary artery disease (CAD) and stroke. In CH a significant proportion of circulating leukocytes are derived from a single dominant hematopoietic stem cell (HSC) lineage. Somatic mutations in oncogenic driver and other genes may be responsible. CH is also associated with shortened leukocyte telomere length (LTL) and accompanies biological aging and its effects, independent of chronological age. Healthy first degree relatives from families with early-onset CAD demonstrate premature aging cardiovascular phenotypes and bear a risk for incident CAD that is 2-12 times that of the general population. These early-onset CAD families have highly heritable shortened LTL at young ages, and higher rates of cancer. They may also have an increased prevalence of CH for their age, possibly contributing mechanistically to CAD risk. We posit that populations with increased genetic susceptibility to early CAD and shorter telomeres exhibit early-onset biological aging and have a higher prevalence of clinically silent CH, which in turn may contribute to both atherosclerosis and cancer risk. No studies have investigated this hypothesis in families with early-onset CAD, a putatively highly susceptible population. Our hypothesis is that a family history of early CAD conveys a higher prevalence of CH and shorter LTL for age, contributing mechanistically to a potent atherosclerosis substrate, with greater CAC score and higher rates of incident CAD. We will determine the prevalence of CH in 1610 subjects from GeneSTAR, healthy siblings, offspring or parents of probands with CAD < 60 years of age, using whole genome sequencing. We will determine whether CH is related to shortened LTL, to CAD events, and to CAC scores, and further whether the prevalence of CH is greater by age in subjects from families with and without early-onset CAD history in population studies (Framingham Heart Study, Multiethnic Study of Atherosclerosis, Jackson Heart Study, and the Atherosclerosis in Communities Study) in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program, of which GeneSTAR is a member. We will identify germline and somatic variants associated with LTL and determine the extent to which these are a function of family history of early CAD. Variants in candidate genes known to regulate LTL, including telomerase genes and shelterin genes will be given priority in the analysis. We are also examining increments in CH mutations and the LTL attrition rate over 6-20 years in the GeneSTAR families. For the highest priority genetic variants, we will ascertain functional significance as potential drivers of CH using gain-of-function (over-expression) and loss-of-function (gene silencing) approaches to assess their effect on proliferation and clonal expansion in cellular and in vivo murine models, and effects on atherosclerosis in Ldlr knockout mice. This novel combination of genetic epidemiology and functional studies will elucidate a potentially new mechanism for premature aging and its early-onset cardiovascular disease substrate.

克隆性造血（CH）随着衰老而发生，并与死亡率增加相关，死亡率增加 10 倍 癌症发病率增加 2 倍以上，冠状动脉疾病 (CAD) 和中风的发病率增加 2 倍以上。在 CH 中，显着 部分循环白细胞源自单一显性造血干细胞 (HSC) 谱系。 致癌驱动基因和其他基因的体细胞突变可能是造成这种情况的原因。 CH 还与 白细胞端粒长度 (LTL) 缩短并伴随生物衰老及其影响，与 实际年龄。来自患有早发性 CAD 家族的健康一级亲属表现出早发性 心血管表型老化，发生 CAD 的风险是一般人的 2-12 倍 人口。这些早发 CAD 家族在年轻时具有高度遗传性的缩短 LTL，并且更高 癌症的发生率。与他们的年龄相比，他们的 CH 患病率也可能有所增加，这可能导致 机械地降低CAD风险。我们假设早期 CAD 遗传易感性增加的人群 较短的端粒表现出早发性生物衰老，并且临床无症状 CH 的患病率较高， 这反过来又可能导致动脉粥样硬化和癌症风险。没有研究对此进行调查 早发性 CAD 家族（被认为是高度易感人群）的假设。我们的假设是 早期 CAD 家族史表明 CH 患病率较高，LTL 较短，这有助于 从机制上讲，它是一种有效的动脉粥样硬化底物，具有更高的 CAC 评分和更高的 CAD 发病率。 我们将确定来自 GeneSTAR 的 1610 名受试者、健康兄弟姐妹、后代或 使用全基因组测序，对年龄 < 60 岁患有 CAD 先证者的父母进行研究。我们将确定是否 CH 与缩短的 LTL、CAD 事件和 CAC 评分相关，并且进一步确定 CH 的患病率是否与 在人口研究中，来自有或没有早发 CAD 家族史的受试者的年龄更大 （弗雷明汉心脏研究、动脉粥样硬化多种族研究、杰克逊心脏研究和动脉粥样硬化 社区研究博士）在 NHLBI 精准医学跨组学 (TOPMed) 计划中，其中 GeneSTAR 是会员。我们将鉴定与 LTL 相关的种系和体细胞变异，并确定 这些在多大程度上是早期 CAD 家族史的函数。已知候选基因的变异 调控LTL的基因，包括端粒酶基因和shelterin基因将被优先分析。我们也是 检查 GeneSTAR 家族 6-20 年间 CH 突变的增量和 LTL 损耗率。 对于最优先的遗传变异，我们将确定其作为 CH 潜在驱动因素的功能意义 使用功能获得（过度表达）和功能丧失（基因沉默）方法来评估其效果 对细胞和体内小鼠模型中增殖和克隆扩张的影响，以及对动脉粥样硬化的影响 Ldlr 基因敲除小鼠。这种遗传流行病学和功能研究的新颖结合将阐明 过早衰老及其早发性心血管疾病的潜在新机制。