Evolution of Cardiovascular Risk with Normal Aging

描述(由申请人提供)：心血管(C-V)老化在动脉和心脏结构/功能(心血管指数)方面反映了内在衰老效应、遗传背景下心血管风险因素的负担和包括子宫内在内的早期生命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控制的，部分是由表观遗传机制介导的。在博加卢萨心脏研究中，这项续签申请集中在以社区为基础的黑人和白人队列中的这些方面，他们进入中年，并从童年开始跟踪调查。拟议研究的具体目标是：1)继续描述儿童时期心脏代谢危险变量的轨迹和家族性长寿特征 这些研究包括：1)检验DNA甲基化与心脏和动脉结构/功能(C-V指数)的关系；2)检验出生体重影响DNA甲基化(全基因组和候选基因)在成年期按种族发生纵向变化的假设；3)检验DNA甲基化模式(全局的和基因特有的)与C-V风险变量之间存在时间关系的假设；4)确定全球和基因特异性DNA甲基化与候选基因变异和出生体重联合对亚临床C-V指数的影响。拟议的研究队列包括800名白人和550名黑人，年龄29-52岁，他们的C-V风险因素变量从童年、出生体重、成年C-V指数、基因数据(38个候选基因)和储存的血样(基线和随访，相隔12-20年)连续测量6-15次。C-V指标包括左心室重量和几何重构、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。整个基因组和38个基因的DNA甲基化将使用Illumina Human Methylation450微珠芯片进行测量。多变量回归分析将被用来检验出生体重-甲基化、基因-甲基化和甲基化-结局的关联。这项研究的发现将进一步了解影响中年混血人群中C-V衰老的易感因素，即 对预防战略有影响。

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.