Identifying Targets for Reducing Obesity Caused by Early Life Disadvantage

 描述(申请人提供)：肥胖是许多与老龄化相关的疾病的重要风险因素，如2型糖尿病、心血管疾病、癌症、损伤、身体功能障碍和过早死亡。肥胖风险可以在生命过程的早期确定。社会经济劣势和其他形式的社会逆境发生在产前和儿童早期，大大增加了成年后肥胖的风险。这对减少肥胖相关疾病的发病率的努力具有深远的影响。一个尚未解决的主要问题是，从童年开始的肥胖风险是否可以通过成年干预来改变。如果是这样，那么确定可修改的干预目标是至关重要的。根据定义，可修改的干预目标是位于因果路径链接上的因素 早年的生活逆境与成年后的肥胖(即，在风险和疾病之间起中介作用)。 为了扩大病因学知识，所有这些介体都是有意义的。就公共卫生而言，我们最感兴趣的是效果最强的调节剂，因为对这些调节剂的干预将在扭转早期逆境对成年肥胖症的长期影响的努力中提供最大的影响。令人惊讶的是，关于饮食、体育活动、吸烟、抑郁、教育和表观遗传甲基化模式等主要候选因素是否在早年生活逆境和成年肥胖症之间起中介作用，人们知之甚少。因此，我们提出了以下具体目标，着重于两个主要的临床相关的成年肥胖测量，特别是身体质量指数和腰围：(1)调查社会经济、行为和心理健康因素在儿童经济劣势、社会逆境和成人肥胖之间的关系中的作用。(2)确定是否存在儿童经济困难和社会逆境与中年肥胖症相关的表观遗传DNA甲基化调节因子。建议的目标将使用来自新英格兰家庭研究的独特数据和生物样本来实现，这是一项对出生于1959-1966年间的合作围产期项目的普罗维登斯、国际扶轮社和马萨诸塞州波士顿出生的婴儿进行的长期跟踪研究。世界上很少有产前队列直接评估从怀孕到生命头7年的社会暴露。我们建议对具有表观遗传学特征的68名男性和68名女性样本的储存脂肪和白细胞样本进行Infinium HumanMethylation450珠芯片DNA甲基化阵列。在2005-2011年间，对831名年龄在42-50岁之间的参与者进行了心血管和其他人口统计学变量的直接评估。我们将使用复杂的因果调解分析来估计我们假设为潜在干预目标的条件的比较效果。这项拟议的研究结果将为早期逆境与成年肥胖之间的联系提供新的病因学见解，并将为干预广泛的潜在目标以减少儿童早期逆境对肥胖症的长期后果的预期益处提供证据。

 DESCRIPTION (provided by applicant): Obesity is an important risk factor for many aging-related conditions such as type 2 diabetes, cardiovascular disease, cancer, injuries, physical function disabilities, and premature mortality. Obesity risk can be established early in the life course. Socioeconomic disadvantage and other forms of social adversity occurring prenatally and during early childhood substantially increase risk for obesity in adulthood. This has profound implications for efforts to reduce morbidity associated with obesity-related conditions. A major unresolved question is whether or not obesity risk initiated in childhood can be altered by interventions in adulthood. If so, then it is critical to identify modifiable intervention targes. Modifiable intervention targets are by definition factors that lie along the causal pathway linking early life adversity to obesity in adulthood (i.e. that mediate the link between risk and disease). To expand knowledge of etiology, all such mediators are of interest. For public health purposes, we are most interested in mediators with the strongest effects, as intervening on these mediators will provide the most impact in the effort to reverse the long-term effects of early adversity on adulthood obesity. There is surprisingly little known about whether major candidate factors such as diet, physical activity, smoking, depression, education and epigenetic methylation patterns mediate the links between early life adversity and adulthood obesity. Consequently, we propose the following specific aims, focusing on two primary clinically relevant measures of adiposity in adulthood, specifically body mass index and waist circumference: (1) To investigate the roles of socioeconomic, behavioral, and mental health factors in the associations between childhood economic disadvantage, social adversity and adult adiposity. (2) To determine if there are epigenetic DNA methylation mediators of the associations of childhood economic disadvantage and social adversity with mid-life adiposity. The proposed aims will be achieved using unique data and biosamples from the New England Family Study, a long-term follow-up study of births from the Providence, RI and Boston, MA cohorts of the Collaborative Perinatal Project, born between1959-1966. There are few prenatal cohorts in the world with directly assessed social exposures from pregnancy through the first 7 years of life. We propose to perform Infinium HumanMethylation450 BeadChip DNA methylation arrays on stored adipose and leukocyte samples for a sample of 68 males and 68 females with epigenetic profiles. Cardiovascular and other demographic variables were directly assessed in 831 participants during the years 2005-2011 at age range 42- 50 years. We will employ sophisticated causal mediation analyses to estimate the comparative effects of the conditions we hypothesize to be potential intervention targets. The results of the proposed study will provide new etiologic insights regarding the pathways linking early adversity to obesity in adulthood, and will provide evidence regarding the anticipated benefits of interventions on a wide range of potential targets to reduce the long-term consequences of early childhood adversity on obesity.