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.
This project will measure leukocyte telomere length in approximately 3,400 African Americans from the Jackson Heart Study (JHS). We will investigate the relationship between leukocyte telomere length and various measures of subclinical cardiovascular disease in JHS. Using available genome-wide genotype data, we will also discover and validate new and previously identified telomere length-regulating genes. Finally, telomere length-regulating genes will be further tested for association with clinical and subclinical cardiovascular phenotypes in a much larger data set of African Americans available through dbGaP and various GWAS consortia and collaborative networks.
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