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）随着年龄的增长而发生，并与死亡率增加有关， 癌症发病率增加，冠状动脉疾病（CAD）和中风增加>2倍。在CH中， 循环白细胞的一部分来源于单一的显性造血干细胞（HSC）谱系。 致癌驱动基因和其他基因的体细胞突变可能是原因。CH也与 缩短白细胞端粒长度（LTL），并伴随生物老化及其影响，独立于 实际年龄早发性CAD家族的健康一级亲属表现出早发性CAD 老年心血管表型和承担的风险事件CAD是2-12倍的一般 人口这些早发性CAD家族在年轻时具有高度可遗传的LTL缩短， 癌症发病率他们的年龄也可能增加CH的患病率，可能导致 CAD的风险。我们认为，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，并且具有较高的临床无症状CH患病率， 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家族是一个非常高的易感人群。我们假设 早期CAD家族史表达了较高的CH患病率和较短的年龄LTL， 从机械上来说，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1610名来自GeneSTAR、健康兄弟姐妹、后代或 CAD先证者的父母年龄< 60岁，使用全基因组测序。我们将决定 CH与缩短的LTL、CAD事件和CAC评分相关，并且CH的患病率是否进一步降低 在人群研究中，来自有和无早发性CAD病史家族的受试者中， （心脏病研究，动脉粥样硬化的多种族研究，杰克逊心脏研究和动脉粥样硬化研究） 在社区研究）在NHLBI的Trans-Omics精准医学（TOPMed）计划，其中 Genstar是会员。我们将鉴定与LTL相关的生殖系和体细胞变异，并确定LTL的基因型。 在某种程度上，这些是早期CAD家族史的函数。已知候选基因的变异 调节LTL的基因，包括端粒酶基因和shelterin基因将在分析中优先考虑。我们也 检查GeneSTAR家族中CH突变的增量和6-20年的LTL损耗率。 对于最高优先级的遗传变异，我们将确定作为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）方法评估其作用 对细胞和体内小鼠模型中增殖和克隆扩增的影响，以及对 Ldlr基因敲除小鼠。这种新的遗传流行病学和功能研究的结合将阐明一个新的基因。 潜在的新机制，过早老化及其早发性心血管疾病的基板。