Evolution of Cardiovascular Risk with Normal Aging

描述（由申请方提供）：动脉和心脏结构/功能（CV指数）方面的心血管（C-V）老化反映了内在老化效应、遗传背景中CV风险因素负担和生命早期（包括子宫内）开始的环境变化之间的复杂相互作用。这种相互作用是由基因表达部分介导的表观遗传机制。本更新申请的重点是以社区为基础的、进入中年的黑人白色队列中的这些方面，并在博加卢萨心脏研究中从童年开始进行随访。拟议研究的具体目的是：1）继续描述儿童时期以来心脏代谢风险变量的轨迹和家族长寿特征， 与动脉和心脏结构/功能的关系（C-V指数）; 2）检验出生体重影响DNA甲基化纵向变化的假设（全基因组和候选基因）; 3）检验DNA甲基化模式之间存在时间关系的假设（总体和基因特异性）和C-V风险变量;和4）确定总体和基因特异性DNA甲基化与候选基因变体和出生体重结合对亚临床C-V指数的影响。拟议的研究队列由800名白色和550名黑人无关的成年人组成，年龄29-52岁，他们具有从儿童期连续测量6-15次的C-V风险因素变量、出生体重、成年C-V指数、基因型数据（38个候选基因）和储存的血液样本（基线和随访，间隔12-20年）。C-V指标包括左心室质量和几何重构、颈动脉壁厚度和顺应性;候选基因包括与C-V风险、胎儿生长和一碳代谢相关的基因。将使用Illumina HumanMethylation 450 BeadChip测量全基因组和38个基因的DNA甲基化。多变量回归分析将用于检查出生体重甲基化，基因甲基化和甲基化结果的关联。这项研究的结果将进一步了解影响中年人C-V老化的诱发因素， 对预防策略有影响。

DESCRIPTION (provided by applicant): The cardiovascular (C-V) aging in terms of arterial and cardiac structure/function (CV indices) reflects complex interplay between the intrinsic aging effect, burden of CV risk factors in a genetic background and environmental changes beginning in early life, including in utero. This interplay is governed by gene expression mediated in part by epigenetic mechanisms. This renewal application focuses on these aspects in a community-based, black white cohort entering midlife and followed since childhood in the Bogalusa Heart Study. The Specific Aims of the proposed research are: 1) to continue characterizing the trajectories of cardio-metabolic risk variables since childhood and the familial longevity trait in relation to the arterial and cardiac structure/function (C-V indices); 2) to test the hypothesis tht birth weight affects longitudinal changes of DNA methylation (genome-wide and in candidate genes) during adulthood by race; 3) to test the hypothesis that there is a temporal relationship between DNA methylation patterns (global and gene-specific) and C-V risk variables measured over 12-20 years; and 4) to determine effect of global and gene-specific DNA methylation in conjunction with candidate gene variants and birth weight on subclinical C-V indices. The proposed study cohort consists of 800 white and 550 black unrelated adults, aged 29-52 years, who have C-V risk factor variables measured serially 6-15 times from childhood, birth weight, adulthood C-V indices, genotype data (38 candidate genes) and stored blood samples (baseline and follow-up, 12-20 years apart). The C-V indices include left ventricular mass and geometric remodeling, carotid artery wall thickness and compliance; candidate genes include those related to C-V risk, fetal growth and one-carbon metabolism. DNA methylation will be measured for the whole genome and 38 genes using Illumina HumanMethylation450 BeadChip. Multivariable regression analyses will be used to examine the birth weight-methylation, gene-methylation and methylation-outcome associations. Findings from this research will further the understanding of the predisposing factors that influence C-V aging in a biracial population reaching mid-life, which have implications for preventive strategies.