Identifying Targets for Reducing Obesity Caused by Early Life Disadvantage

 描述（由申请人提供）：肥胖是许多衰老相关疾病的重要风险因素，如2型糖尿病、心血管疾病、癌症、损伤、身体功能残疾和过早死亡。肥胖风险可以在生命过程的早期建立。产前和幼儿期发生的社会经济劣势和其他形式的社会逆境大大增加了成年后肥胖的风险。这对减少与肥胖相关疾病相关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，儿童时期引发的肥胖风险是否可以通过成年后的干预措施来改变。如果是这样，那么确定可修改的干预目标至关重要。根据定义，可修改的干预目标是沿着因果路径的因素， 早期生活逆境与成年期肥胖的关系（即介导风险与疾病之间的联系）。 为了扩大病因学的知识，所有这些介质都是感兴趣的。出于公共卫生的目的，我们最感兴趣的是具有最强影响的介质，因为对这些介质进行干预将在扭转早期逆境对成年肥胖的长期影响方面产生最大影响。令人惊讶的是，对于饮食、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介导了早期生活逆境和成年肥胖之间的联系，人们知之甚少。因此，我们提出了以下具体目标，重点是两个主要的临床相关措施的肥胖在成年期，特别是体重指数和腰围：（1）调查的社会经济，行为和心理健康因素之间的关联儿童经济劣势，社会逆境和成人肥胖。(2)确定是否有表观遗传DNA甲基化介导的儿童经济劣势和社会逆境与中年肥胖症的关联。通过使用来自新英格兰家庭研究的独特数据和生物样本，将实现所提出的目标，该研究是一项对出生于1959 -1966年之间的普罗维登斯、RI和马萨诸塞州波士顿的围产期合作项目队列的长期随访研究。世界上很少有产前队列能够直接评估从怀孕到生命头7年的社会暴露。我们建议对储存的脂肪和白细胞样本进行Infinium HumanMethylation 450 BeadChip DNA甲基化阵列，样本为68名男性和68名女性，具有表观遗传学特征。在2005-2011年期间，直接评估了831名年龄在42- 50岁之间的参与者的心血管和其他人口统计学变量。我们将采用复杂的因果中介分析来估计我们假设为潜在干预目标的条件的比较效果。拟议研究的结果将提供有关将早期逆境与成年肥胖联系起来的途径的新病因学见解，并将提供有关干预措施对广泛潜在目标的预期益处的证据，以减少儿童早期逆境对肥胖的长期后果。

 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.