Leukocyte Telomere Length and Cardiovascular Disease in Jackson Heart Study

描述（由申请人提供）：白细胞的端粒长度（TL）反映了造血干细胞（hsc）的TL，是一个复杂的遗传性状，可受吸烟和久坐生活方式等环境因素的影响。根据对白人的研究，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。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，为LTL动力学（出生后LTL及其年龄依赖性缩短）的潜在作用提供了机制见解，并由此推断HSC-TL动力学在心血管疾病（CVD）中的作用。然而，对非裔美国人（AfAs）的LTL-CVD联系和ltl调节基因知之甚少。最近的研究已经证实，非洲裔美国人的终身寿命比白人更长。与白人相比，afa也表现出较少的动脉粥样硬化，但LVH更高。理论上，AfAs和白人在动脉粥样硬化和LVH倾向上的差异可能至少部分与HSC-TL动力学的种族差异以及出生时和出生后决定HSC-TL的变异基因有关。因此，利用Jackson心脏研究（JHS）中丰富的DNA标本、临床和基因型数据，本项目的主要目标是：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；c)探索这些新鉴定的AfA LTL相关基因和先前破译的基因（白人）在AfAs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，通过点印迹分析来测量端粒DNA含量，与南方印迹方法相比较。尽管Southern blot法是测量TL最可靠、最准确的方法，但其复杂性、成本和对大量DNA的要求阻碍了其在临床环境中的应用。一种经过验证的测量TL的点印迹方法将推动人类端粒生物学领域向前发展，并促进其发现转化为临床实践。阐明AfAs中LTL-CVD的联系将提供促进动脉粥样硬化和LVH通路的机制见解，并提供新的诊断工具，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.