Leukocyte Telomere Length and Cardiovascular Disease in Jackson Heart Study

描述(申请人提供)：白细胞中的端粒长度(TL)反映了造血干细胞(HSCs)中的端粒长度，是一种复杂的遗传特征，会受到吸烟和久坐不动的生活方式等环境因素的影响。根据在白人中进行的研究，发现动脉粥样硬化患者的白细胞TL(LTL)相对较短，而左心室肥厚(LVH)患者的白细胞TL(LTL)相对较长。在主要由白人组成的队列中进行的LTL全基因组关联研究(GWAS)破译了LTL调节基因，为LTL动态(出生LTL及其年龄相关缩短)的潜在作用提供了机械性见解，并由此推断HSC-TL动态在心血管疾病(CVD)中的作用。然而，对LTL-CVD的联系和非裔美国人(AFA)的LTL调节基因知之甚少。最近的研究证实，AFA的LTL比白人长。与白蛋白相比，AFAs的动脉粥样硬化程度较轻，但左心室肥厚较多。从理论上讲，AFAs和白人在动脉粥样硬化和LVH的易感性上的差异可能至少部分与HSC-TL动力学的种族差异和决定出生时和以后HSC-TL的变异基因有关。因此，利用杰克逊心脏研究(JHS)中丰富的DNA样本、临床和基因分型数据，该项目的主要目标是：a)更好地了解LTL与AFA中CVD表型的关系；b)扩展LTL的GWAS以确定AFA中的LTL相关基因；以及c)探索这些新发现的AFA LTL相关基因和先前破译的基因(在白色中)在AFA的临床和亚临床CVD表现中的作用。此外，该项目将验证一种新开发的方法，通过斑点印迹分析来测量端粒DNA含量，而不是Southern印迹方法。虽然Southern印迹法是测量TL最可靠和准确的方法，但其复杂性、成本和对大量DNA的要求阻碍了其在临床上的使用。一种有效的斑点印迹方法测量TL将推动人类端粒生物学领域的发展，并促进其结果转化为临床实践。阐明AFA中LTL-CVD的联系将提供对促进动脉粥样硬化和左心室肥厚途径的机械性洞察，并提供新的诊断工具，以便在CVD显性表现之前识别其易感性。

DESCRIPTION (provided by applicant): Telomere length (TL) in leukocytes, which reflects TL in hematopoietic stem cells (HSCs), is a complex genetic trait that is modified by environmental factors such as smoking and sedentary lifestyle. Based on studies performed in whites, leukocyte TL (LTL) has been found to be relatively short in patients with atherosclerosis and relatively long in patients with left ventricular hypertrophy (LVH). Genome-wide association studies (GWAS) of LTL, performed in cohorts comprising mainly whites, have deciphered LTL-regulating genes that provide mechanistic insights into the potential roles of LTL dynamics (birth LTL and its age-dependent shortening thereafter), and by inference HSC-TL dynamics, in cardiovascular disease (CVD). However, little is known about the LTL-CVD connection and LTL-regulating genes in African Americans (AfAs). Recent studies have established that AfAs have a longer LTL than whites. AfAs also display less atherosclerosis but more LVH than whites. In theory, the differences between AfAs and whites in the predilection to atherosclerosis and LVH might relate at least in part to racial differences in HSC-TL dynamics and variant genes that determine HSC-TL at birth and afterward. Accordingly, leveraging the wealth of DNA specimens, clinical and genotypic data in the Jackson Heart Study (JHS), the main goals of this project are to a) gain a better insight into the relation of LTL to CVD phenotypes in AfAs, b) extend GWAS of LTL to identify LTL-associated genes in AfAs, and c) explore the roles of these newly identified AfA LTL-associated genes and previously deciphered genes (in whites) in clinical and subclinical CVD manifestation in AfAs. In addition, the project will validate a newly developed method to measure telomere DNA content by dot-blot analysis against the Southern blot method. Although the Southern blot method is the most reliable and accurate way to measure TL, its complexity, cost and requirement for large quantities of DNA preclude its use in clinical settings. A validated dot-blot method to measure TL will move the field of human telomere biology forward and facilitate the translation of its findings into clinical practice. Elucidating the LTL-CVD links in AfAs will provide mechanistic insight into pathways that promote atherosclerosis and LVH, as well as provide new diagnostic tools to identify susceptibility to CVD before its overt manifestations.