Leukocyte Telomere Length and Cardiovascular Disease in Jackson Heart Study

描述（由申请人提供）：白细胞中的端粒长度（TL）反映了造血干细胞（HSC）中的TL，是一种复杂的遗传性状，会受到吸烟和久坐生活方式等环境因素的影响。基于在白人中进行的研究，已发现动脉粥样硬化患者的白细胞TL（LTL）相对较短，而左心室肥大（LVH）患者的LTL相对较长。LTL的全基因组关联研究（GWAS）在主要由白人组成的队列中进行，已经破译了LTL调节基因，这些基因提供了对LTL动态（出生LTL及其年龄依赖性缩短）的潜在作用的机制见解，并通过推断HSC-TL动态，在心血管疾病（CVD）中。然而，对非裔美国人（AfAs）的LTL-CVD连接和LTL调节基因知之甚少。最近的研究表明，非洲裔美国人的LTL比白人长。与白人相比，AFA也显示出较少的动脉粥样硬化，但更多的LVH。从理论上讲，AfAs和白人之间在动脉粥样硬化和LVH偏好方面的差异可能至少部分与HSC-TL动力学的种族差异以及在出生时和出生后决定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标本、临床和基因型数据，该项目的主要目标是a）更好地了解AfAs中LTL与CVD表型的关系，B）扩展LTL的GWAS以鉴定AfAs中LTL相关基因，和c）探索这些新鉴定的AfA LTL相关基因和先前破译的基因（在白人中）在AfA的临床和亚临床CVD表现中的作用。此外，该项目还将验证一种新开发的方法，即通过斑点印迹分析与Southern印迹方法相比较来测量端粒DNA含量。虽然Southern印迹法是测量TL的最可靠和准确的方法，但其复杂性、成本和对大量DNA的要求排除了其在临床环境中的使用。一个有效的斑点印迹方法来测量TL将推动人类端粒生物学领域的发展，并促进其研究结果转化为临床实践。阐明AFAs中LTL-CVD的联系将为促进动脉粥样硬化和LVH的途径提供机制性见解，并提供新的诊断工具，以在其明显表现之前识别CVD的易感性。

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.