Project 4 - Cardiovascular domain

血管老化(VA)是指血管结构的进行性重塑和改变。 伴随着生物衰老。VA导致动脉僵硬增加，伴随着 内皮再生和白细胞端粒长度缩短(LTL)。早期VA的研究进展 有力地预测了心血管疾病的发生，这是老年死亡的主要原因。这一进展是确定的 在一定程度上是由遗传因素造成的，其影响可以通过接触各种非遗传因素来改变。整体而言 这项建议的目的是确定具有从中等到大的纵向影响的遗传成分 儿童VA的研究进展及其与血液循环的关系 内皮祖细胞和白细胞端粒长度(LTL)代表内皮 再生和生物老化。我们的具体目标是：(1)确定基因组连锁区 以及VA潜在的候选基因。这些假设是一个或多个染色体区域施加 从小到大、可遗传的遗传效应对儿童早期VA表型的影响 基因发挥着从小到大的影响，但缺乏可检测到的遗传性。(2)确定常见效果和罕见效果 基因组链接区的变异和在特定目的1中发现的相关候选基因 与VA、内皮再生和生物老化有关。假设是遗传决定因素 潜在的VA表型与循环内皮祖细胞和LTL有关，5种罕见的功能变异 重要的候选基因与上下部5%的纵向VA表型相关 BHS参与者。(3)在复制样本中验证来自特定目标2的显著发现。这个 假设是常见的和罕见的效应变异的结果将在基于随机种群的情况下重复 样本，并与健康衰老有关。预计效果变种的鉴定 潜在的VA对于以后确定血管老化或健康衰老的遗传易感性将是重要的 生活。

Vascular aging (VA) is the progressive vascular remodeling and alteration of vascular structure that accompanies biological aging. VA results in an increase in artery stiffness, accompanied by impairment of endothelial regeneration and shortening of leukocyte telomere length (LTL). The progress of VA in early age strongly predicts the occurrence of CVD, the leading cause of death in old age. This progress is determined in part by genetic factors, with effects modifiable by exposure to various non-genetic factors. The overall objective of this proposal is to identify genetic components with modest-to-large longitudinal effects on the progress of VA from childhood, and to investigate the association of genetic components with circulating endothelial progenitor cells (EPCs) and leukocyte telomere length (LTL) that represent endothelial regeneration and biological aging respectively. Our specific aims are to: (1) Identify genomic linkage regions and candidate genes underlying VA. The hypotheses are that one or more chromosome regions exert modest-to-large, heritable genetic effects on VA phenotypes from early childhood, and that some candidate genes exert modest-to-large effects but lack detectable heritability. (2) Determine common and rare effect variants at the genomic linkage regions and candidate genes identified in Specific Aim 1 that are associated with VA, endothelial regeneration and biological aging. The hypotheses are that genetic determinants underlying VA phenotypes are related to circulating EPCs and LTL, and rare functional variants in five important candidate genes are associated with longitudinal VA phenotypes in the upper and lower 5% of BHS participants. (3) Validate significant findings from Specific Aim 2 in a replication sample. The hypothesis is that the findings of common and rare effect variants will be repeated in a random populationbased sample and are associated with healthy aging. It is expected that identification of effect variants underlying VA will be important for defining genetic predisposition to vascular aging or healthy aging later in life.