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

描述（由申请人提供）：关于怀孕和生命早期的条件如何影响表观遗传改变和衰老过程，这些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、肥胖和认知能力下降，目前知之甚少。特别是，在产前条件（如宫内生长受限、母体血清皮质醇水平、母体吸烟和社会经济逆境）与表观遗传过程（通常以DNA甲基化衡量）之间的关联方面，存在相当大且重要的知识空白，表观遗传过程可能改变基因表达和疾病结果。我们的目标是评估3000名出生于1959-1966年的合作围产期项目（CPP）参与者的衰老过程，这些参与者在生命的前8年进行了详细的产前评估、生物样本收集和表型评估。具体分析目标包括：(a)调查皮下脂肪细胞DNA甲基化是否与DEXA扫描、CT腰椎扫描（评估内脏脂肪）、腰围和BMI得出的肥胖测量结果相关；(b)确定产前条件是否与肥胖和相关的DNA甲基化模式相关；(c)评估脐带血清DNA甲基化是否与0岁、4岁、7岁和中年肥胖相关；(d)研究产前条件是否与脐带血清中与肥胖相关的DNA甲基化有关。这项研究将从罗德岛州和马萨诸塞州招募3000名CPP参与者。不符合宫内生长限制的同胞集将进行过采样，目标是获得500个同胞集。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检和颊细胞收集。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，并通过深度测序DNA甲基化分析作为表观遗传特征的生物标志物。分析方法将包括对每26,486个常染色体CpG进行逐位点分析，评估平均甲基化与a)肥胖和b)产前/早期生活风险状况的关联，纠正错误发现率。将进行同胞内部分析，以解释共同的家庭和环境作为潜在的混杂因素。本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的理解，以及围产期和早期生活因素如何可能是衰老的重要决定因素。它是全世界关于产前、早期生活和中年健康决定因素的为数不多的数据来源之一。这项研究为理解从产前和生命早期开始的整个生命过程中可改变的衰老决定因素提供了重大进展。这可能有助于扩大公共卫生战略的补充，从而促进健康老龄化和预防疾病后果。

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.