The New England Family Study: Fifty Year Post-Perinatal Follow-Up for Life Course

描述(由申请人提供)：关于怀孕和早期生活条件如何影响表观遗传改变和衰老过程，随后可能在中年表现为动脉粥样硬化、2型糖尿病、肥胖症和认知能力下降，目前知之甚少。特别是，关于产前状况(例如宫内生长受限、产妇血清皮质醇水平、产妇吸烟和社会经济逆境)与可能改变基因表达和疾病结果的表观遗传过程(通常以DNA甲基化来衡量)之间的关系，存在着相当大和重要的知识差距。我们的目标是评估出生于1959-1966年的3000名合作围产期项目(CPP)参与者的衰老过程，他们在出生后8年内进行了详细的产前评估、生物样本收集和表型评估。具体的分析目标包括：(A)调查皮下脂肪细胞中的DNA甲基化是否与DEXA扫描、腰部CT扫描(以评估内脏脂肪)、腰围和BMI得出的肥胖症指标相关；(B)确定产前状况是否与肥胖症及相关的DNA甲基化模式有关；(C)评估脐带血清中的DNA甲基化是否与0、4、7岁和中年的肥胖症有关；(D)探讨产前状况是否与脐带血清中脂肪相关的DNA甲基化有关。这项研究将从罗德岛和马萨诸塞州招募3000名CPP参与者。不符合宫内生长受限的兄弟姐妹集将被过度抽样，目标是获得500个兄弟姐妹集。临床评估包括肥胖、动脉粥样硬化(冠状动脉钙化CT扫描)、认知功能、糖尿病(空腹血糖)和心血管危险因素(如血脂)。将进行皮下脂肪细胞活组织检查和口腔细胞采集。孕妇在怀孕期间(大约50年前)的皮质醇水平将从储存的血清样本中测量。脐带血清DNA和脂肪细胞DNA将使用既定的方案获得，并进行深度测序DNA甲基化分析，作为表观遗传学特征的生物标志物。分析方法将包括对每个26,486个常染色体CpG进行逐个位点分析，评估平均甲基化与a)肥胖症的关联，以及b)产前/早期生命危险状况，修正错误发现率。将进行兄弟姐妹内部分析，以说明共同的家庭和环境是潜在的混杂因素。这项研究提供了创新的信息，以促进对表观遗传过程如何参与衰老，以及围产期和早期生命因素如何可能是衰老的重要决定因素的理解。它是世界上为数不多的关于产前、早期生命和中年健康决定因素的数据来源之一。这项研究为从产前和生命早期开始了解整个生命过程中衰老的可改变的决定因素提供了重要的进展。这可能有助于扩大可能促进健康老龄化和预防疾病后果的公共卫生战略的补充。 公共卫生相关性：寻找对健康老龄化和与衰老相关的疾病的可改变影响，导致人们对怀孕和儿童早期状况(例如宫内发育迟缓、母亲吸烟、母亲怀孕期间的压力、经济困难、母亲认知功能、儿童认知功能、儿童血压、儿童身体发育和肥胖、儿童忽视和母亲心理健康)的潜在健康影响产生了相当大的兴趣。这些信息可能有助于通过生命早期的公共卫生干预，为促进健康老龄化和预防后来的疾病提供关键和有效的新替代方案。该项目将增加对产前和早期生命因素可能影响健康的生物学机制的科学理解，包括可能发现生物标记物作为治疗和预防努力的目标。总体而言，这项研究是世界范围内为数不多的产前、早期和中年健康决定因素和健康结果的可用来源之一，并为更充分地了解产前和早期健康决定因素提供了重大进展。

DESCRIPTION (provided by applicant): Little is known regarding how conditions during pregnancy and early life may impact epigenetic alterations and aging processes that could subsequently manifest in midlife as atherosclerosis, type 2 diabetes, adiposity and cognitive decline. In particular, there are sizeable and important knowledge gaps regarding associations of prenatal conditions (e.g. intrauterine growth restriction, maternal serum cortisol levels, maternal smoking and socioeconomic adversity) with epigenetic processes (often measured as DNA methylation) that could alter gene expression and disease outcomes. Our goal is to assess aging processes in 3000 of the Collaborative Perinatal Project (CPP) participants born in 1959-1966 who had detailed prenatal assessments, biosample collection and phenotypic assessments during the first 8 years of life. Specific analytic objectives include: (a) to investigate if DNA methylation in subcutaneous adipocytes is associated with measures of adiposity derived from DEXA scans, CT lumbar region scans (to assess visceral fat), waist circumference and BMI; (b) to identify whether prenatal conditions are associated with adiposity and relevant DNA methylation patterns; (c) to evaluate whether DNA methylation in umbilical cord serum is associated with adiposity at ages 0, 4, 7 years and middle age; (d) to investigate whether prenatal conditions are associated with adiposity-related DNA methylation in umbilical cord serum. The study will recruit 3000 CPP participants from Rhode Island and Massachusetts. Sibling sets discordant for intrauterine growth restriction will be oversampled, with a goal of obtaining 500 sibling sets. Clinical assessments include adiposity, atherosclerosis (coronary artery calcium CT scans), cognitive function, diabetes (fasting glucose), and cardiovascular risk factors (e.g. lipids). Subcutaneous adipocyte biopsies and buccal cell collection will be performed. Maternal cortisol levels during pregnancy (approximately 50 years ago) will be measured from banked serum samples. Umbilical cord serum DNA and adipocyte DNA will be obtained using established protocols, and run through deep sequencing DNA methylation assays as biomarkers of epigenetic characteristics. The analytic approach will include a locus-by- locus analysis for each 26,486 autosomal CpG, assessing the association of average methylation with a) adiposity, and b) prenatal/early life risk conditions, correcting for false discovery rate. Within-sibling analyses will be performed to account for shared family and environment as potential confounders. This study offers to provide innovative information to advance understanding of how epigenetic processes are involved in aging, and how perinatal and early life factors may be important determinants of aging. It is one of the very few data sources available worldwide regarding prenatal, early life and middle-age determinants of health. This study offers potential to make major inroads towards understanding modifiable determinants of aging across the lifecourse, beginning during prenatal and early years of life. This could serve to expand the complement of public health strategies that may enhance healthy aging and prevent disease outcomes. PUBLIC HEALTH RELEVANCE: The search for modifiable influences on healthy aging and aging-related disease has led to considerable interest in the potential health impact of conditions during pregnancy and early childhood (e.g. intrauterine grown restriction, maternal smoking, maternal stress during pregnancy, economic distress, maternal cognitive function, childhood cognitive function, childhood blood pressure, childhood body growth and obesity, childhood neglect and maternal mental health). Such information may contribute to critical and effective new alternatives to enhance healthy aging and prevent later disease, by public health interventions early in life. This project will add to the scientific understanding of biological mechanisms by which prenatal and early life factors may influence health, including the potential discovery of biomarkers as targets for treatment and prevention efforts. Overall, this study is one of the very few available sources of prenatal, early life and middle-aged health determinants and health outcomes worldwide, and offers the potential to make major inroads in more fully understanding prenatal and early life determinants of health.