Leukocyte Telomere Length and Cardiovascular Disease in Jackson Heart Study

杰克逊心脏研究中白细胞端粒长度与心血管疾病

• 批准号: 8575407
• 负责人: ABRAHAM AVIV
• 金额: $ 80.51万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575407
• 关键词: Accounting; African American; Age; Aging; Arteries; Atherosclerosis; Biological Markers; Biology; Birth; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cells; Clinical; Complex Genetic Trait; Coronary Arteriosclerosis; DNA; Data; Data Set; Development; Dot Immunoblotting; Elements; Environmental Risk Factor; European; Genes; Genetic; Genetic Polymorphism; Genetic Template; Genetic Variation; Genotype; Goals; Heart; Hematopoietic stem cells; High Prevalence; Human; Hypertension; Individual; Inflammation; Lead; Left Ventricular Hypertrophy; Left Ventricular Mass; Length; Leukocytes; Life; Life Cycle Stages; Life Style; Link; Measurement; Measures; Mediating; Mediation; Metabolic; Methods; Modeling; Oxidative Stress; Participant; Pathway interactions; Patients; Phenotype; Ploidies; Population; Predisposition; Process; Psychosocial Stress; Recording of previous events; Reporting; Research; Risk; Role; Severities; Site; Smoking; Southern Blotting; Specimen; Testing; Thick; Translations; abdominal aorta; age related; angiogenesis; base; calcification; clinical practice; cohort; coronary artery calcification; cost; database of Genotypes and Phenotypes; disease phenotype; genome wide association study; genome-wide; indexing; injury and repair; insight; intima media; life history; novel; novel diagnostics; public health relevance; racial difference; repaired; restriction enzyme; sedentary; sex; telomere; theories; tool; trait

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.

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）中的端粒长度，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。根据对白人进行的研究，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。 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，破译了 LTL 调节基因，这些基因为 LTL 动态（出生 LTL 及其后年龄依赖性缩短）的潜在作用提供了机制见解，并通过推断HSC-TL 动态在心血管疾病 (CVD) 中的应用。然而，人们对非裔美国人 (AfAs) 中的 LTL-CVD 连接和 LTL 调节基因知之甚少。最近的研究表明，非洲人的 LTL 比白人更长。与白人相比，AfAs 的动脉粥样硬化较少，但 LVH 较多。理论上，AfAs 和白人之间在动脉粥样硬化和 LVH 倾向上的差异可能至少部分与 HSC-TL 动态的种族差异以及决定出生时和出生后 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 来识别 AfA 中的 LTL 相关基因，以及 c) 探索这些新识别的 AfA LTL 相关基因和先前破译的基因（在白人中）在临床和治疗中的作用AfAs 的亚临床 CVD 表现。此外，该项目还将验证一种新开发的方法，通过针对 Southern 印迹法的斑点印迹分析来测量端粒 DNA 含量。尽管 Southern 印迹法是测量 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使用。一种经过验证的斑点印迹法测量 TL 将推动人类端粒生物学领域向前发展，并促进其研究结果转化为临床实践。阐明 AfAs 中的 LTL-CVD 联系将为促进动脉粥样硬化和 LVH 的途径提供机制见解，并提供新的诊断工具以在 CVD 明显表现之前识别对 CVD 的易感性。