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，这些变化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、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甲基化衡量）之间的关联方面，存在着相当大的重要知识差距。我们的目标是评估3000名出生于1959-1966年的围产期合作项目（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。具体的分析目标包括：（a）研究皮下脂肪细胞中的DNA甲基化是否与来自DEXA扫描、CT腰椎区域扫描的肥胖测量相关（评估内脏脂肪）、腰围和BMI;（B）鉴定产前状况是否与肥胖和相关DNA甲基化模式相关;（c）评估脐带血清中的DNA甲基化是否与0岁、4岁、7岁和中年时的肥胖相关;（d）研究产前状况是否与脐带血清中的肥胖相关DNA甲基化相关。该研究将从罗得岛和马萨诸塞州招募3000名CPP参与者。将对宫内生长受限不一致的同胞集合进行过采样，目标是获得500个同胞集合。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）和心血管风险因素（如血脂）。将进行皮下脂肪细胞活检和颊细胞采集。将从库存血清样本中测量妊娠期间（约50年前）的母体皮质醇水平。脐带血清DNA和脂肪细胞DNA将使用已建立的方案获得，并通过深度测序DNA甲基化测定作为表观遗传特征的生物标志物。分析方法将包括对每个26，486个常染色体CpG进行逐基因座分析，评估平均甲基化与a）肥胖和B）产前/早期生命风险状况的关联，校正错误发现率。将进行兄弟姐妹内分析，以说明共同家庭和环境作为潜在混杂因素。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的理解，以及围产期和早期生活因素如何成为衰老的重要决定因素。它是全世界关于产前、生命早期和中年健康决定因素的少数数据来源之一。这项研究提供了潜力，使重大进展，了解整个生命过程中，在产前和生命早期开始的衰老的可修改的决定因素。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并预防疾病后果。 公共卫生相关性：对健康老龄化和与老龄化有关的疾病的可改变影响的研究导致人们对怀孕和幼儿期条件的潜在健康影响产生了相当大的兴趣（例如，宫内生长受限、母亲吸烟、妊娠期间的母亲压力、经济窘迫、母亲认知功能、儿童认知功能、儿童血压、儿童身体生长和肥胖，儿童期忽视和孕产妇心理健康）。这些信息可能有助于关键和有效的新的替代方案，以加强健康老龄化和预防以后的疾病，在生命早期的公共卫生干预措施。该项目将增加对产前和生命早期因素可能影响健康的生物机制的科学理解，包括可能发现生物标志物作为治疗和预防工作的目标。总的来说，这项研究是世界范围内产前，早期生活和中年健康决定因素和健康结果的极少数可用来源之一，并提供了在更充分地了解产前和早期生活健康决定因素方面取得重大进展的潜力。

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.