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

克隆性造血(CH)随着年龄的增长而发生，并与增加的死亡率相关，增加10倍 发生癌症，冠状动脉疾病(CAD)和中风的发病率增加了2倍。在Cha中有重要意义 循环中的白细胞比例来自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之一。CH还与 白细胞端粒长度(LTL)缩短并伴随着生物衰老及其影响，独立于 按时间顺序排列的年龄。早发性冠心病家族中健康的一级亲属表现出早产儿 心血管表型老化，发生冠心病的风险是普通人群的2-12倍 人口。这些早发性CAD家系在年轻时有高度可遗传的LTL缩短，以及更高 癌症发病率。与他们的年龄相比，他们也可能有更高的CH患病率，可能是 机械地降低了CAD风险。我们假设，遗传易感性增加的人群对早期冠心病和 较短的端粒表现出较早的生物衰老，并具有较高的临床静止性CH的患病率， 这反过来可能会导致动脉粥样硬化和癌症风险。目前还没有研究对此进行研究 早发性冠心病家族中的假说，推测这是一个高度敏感的人群。我们的假设是一个 早期冠心病的家族史表明CH的患病率更高，年龄的LTL更短，这在 从机制上讲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发生率。 我们将从GeneSTAR、健康的兄弟姐妹、后代或 60岁冠心病先证者的父母，使用全基因组测序。我们将确定是否 CH与LTL缩短、CAD事件和CAC评分有关，而且CH的患病率 在人群研究中，来自有和没有早发性冠心病病史的家庭的受试者的年龄更大 弗雷明翰心脏研究、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 在社区研究中)在NHLBI精密医学(TOPMed)计划中，其中 Genestar是成员之一。我们将鉴定与LTL相关的种系和体细胞变异，并确定 这在多大程度上是早期CAD家族史的作用。已知的候选基因的变异 调控LTL的基因，包括端粒酶基因和丝裂原基因将在分析中优先考虑。我们也是 检查GeneSTAR家族6-20年内CH突变的增量和LTL磨损率。 对于最高优先级的基因变异，我们将确定其作为慢性肝炎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)方法来评估它们的效果 小鼠细胞和体内模型的增殖和克隆性扩增及其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组合将阐明一种 早衰的潜在新机制及其早发性心血管疾病的基础。

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.