Project 4 - Cardiovascular domain

血管老化（vascular aging，VA）是指血管结构的进行性重塑和改变， 伴随着生物老化。VA导致动脉僵硬度增加，伴随着 内皮再生和白细胞端粒长度（LTL）缩短。早发VA的研究进展 强烈预测CVD的发生，CVD是老年人死亡的主要原因。这一进展是确定的 部分是由遗传因素造成的，其影响可以通过暴露于各种非遗传因素来改变。整体 这项建议的目的是确定遗传成分与中度到大的纵向影响， 从儿童期VA的进展，并调查遗传成分与循环的关联， 内皮祖细胞（EPCs）和白细胞端粒长度（LTL），代表内皮细胞 再生和生物老化。我们的具体目标是：（1）确定基因组连锁区域 和VA潜在的候选基因。假设是一个或多个染色体区域发挥 从儿童早期开始，对VA表型的中等到大的可遗传效应， 基因发挥中等至大的影响，但缺乏可检测的遗传性。(2)确定常见和罕见效应 特异性目的1中鉴定的基因组连锁区的变异体和候选基因， 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EPCs和LTL有关，在5个基因组中罕见的功能变异 重要的候选基因与纵向VA表型在上和下5%的 BHS参与者(3)在重复样本中验证特定目标2的显著发现。的 假设常见和罕见效应变异的发现将在随机人群中重复， 与健康的衰老有关。预期效应变体的鉴定 潜在的VA对于确定血管老化或健康老化的遗传易感性很重要， 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.