Exploring persistent epigenetic changes after prenatal famine exposure in humans

探索人类产前饥荒暴露后持续的表观遗传变化

• 批准号: 7942052
• 负责人: L H LUMEY
• 金额: $ 37.75万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942052
• 关键词: Aberrant DNA Methylation; Address; Adult; Affect; Age; Alcohol consumption; Animals; Area; Biocompatible Materials; Biological; Biological Assay; Birth; Birth Weight; Blood; Blood Glucose; Blood Pressure; Body Size; Body mass index; Breast; Cardiovascular Diseases; Characteristics; Cholesterol; Chromosomal Instability; Chronic; Chronic Disease; Chronic Lymphocytic Leukemia; Clinical; Colon; Colorectal; Critical Pathways; DNA; DNA Methylation; DNA Transposable Elements; Data; Development; Diabetes Mellitus; Disease; Disease Outcome; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Epigenetic Process; Etiology; Event; Exhibits; Exposure to; Family; Famines; Fasting; Funding; Gender; Gene Silencing; Genes; Genetic; Genetic Transcription; Genomic Instability; Genomics; Grant; Growth and Development function; Hand; Head and Neck Cancer; Head and neck structure; Health; Hematopoietic Neoplasms; Histones; Human; Hypermethylation; IGF2 gene; Individual; Infant; Investigation; Laboratory Scientists; Lead; Lesion; Leukocytes; Life; Life Cycle Stages; Link; Lipids; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Malnutrition; Measures; Methodological Studies; Methods; Monozygotic twins; Netherlands; Obesity; Oncogenes; Onset of illness; Outcome; Ovarian; Pattern; Physical environment; Play; Population; Pregnancy; Process; Production; Proteins; Records; Reporting; Reproductive History; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Siblings; Signal Transduction; Smoke; Social Behavior; Socioeconomic Factors; Somatic Cell; Staging; Stomach; Time; Tissues; Tumor Suppressor Genes; Twin Multiple Birth; Vascular Diseases; Waist-Hip Ratio; Weight Gain; Woman; base; cancer type; cardiovascular disorder risk; cohort; critical developmental period; critical period; design; disorder risk; early childhood; early life exposure; experience; fasting glucose; follow-up; genome-wide; health disparity; human disease; medical examination; men; middle age; mother nutrition; multidisciplinary; prenatal; prospective; public health relevance; sex; statistics; tumor

DESCRIPTION (provided by investigator): This application addresses the broad Challenge Area: 08: Genomics, and the specific Challenge Grant Topic: 08-AG-105**: Approaches to study the interactions among individual behaviors, social and physical environments, and genetic/epigenetic processes during critical developmental periods. Project Title: Early Life Exposures before Birth and Adult Epigenetics Extensive epidemiologic evidence has linked many early life and environmental factors to adult- onset diseases. One plausible mechanism how the environment could alter disease risk later in life is through epigenetic effects on somatic cells, leading to activation or silencing of key genes in critical pathways. DNA methylation, one type of epigenetic change, may play an important role in disease causation by altering the proteins that are produced by genes. Thus, people with identical genes, like twins, may have different disease outcomes because of differential changes in DNA methylation that affect the ability of specific genes to produce specific proteins. Human studies have supported that DNA methylation patterns change with age and animal studies have supported that exposures during critical periods can alter epigenetic events. However, until now, there have been few opportunities to link these two lines of evidence in humans by examining exposures during critical periods including the prenatal and early life periods and DNA methylation patterns latter in life. We have recently completed the first study in humans showing associations between early life factors such as birth weight and genomic DNA methylation measured in mid-life among women in a multiethnic birth cohort (1) and also the first study to show that there are persistent epigenetic differences in DNA methylation of the IGF2 gene after exposure to a prenatal famine environment (2). Using resources from an adult follow-up already collected from three birth cohorts in the Netherlands with prenatal famine exposure in born in 1944-1945 and from unexposed time controls and sibling controls (n= 971; 437 men and 537 women), we now propose to examine the associations between maternal famine exposure in the periconceptional period and in different stages of pregnancy on the one hand and DNA methylation patterns in adulthood on the other. We will further examine how the DNA methylation patterns in adulthood are related to disease risk factors for cardio-vascular disease and diabetes such as obesity, elevated blood cholesterol or fasting glucose values. Because some studies suggest that the relation between the early environment and long-term health outcomes may be different in men and women, we will compare these patterns by gender. The field of epigenetics holds great promise in helping us understand the basis of human disease and in particular how environmental exposures can get inside the body to cause disease. Epigenetics may also help explain differences in disease across populations and therefore may be important in understanding how environmental exposures may contribute to health disparities. Conducting large epidemiologic studies with robust measures of exposures based on information already collected in the past during critical periods combined with reliable markers of DNA methylation today are a necessary first step. Such studies can only be conducted by multidisciplinary teams with an understanding of biological mechanisms and methodological issues. Our team has extensive expertise in the design and analysis of life course studies in the US and abroad and is very experienced in dealing with the many methodological issues of critical periods, DNA methylation, and multiple disease outcomes. This challenge grant in addition to accomplishing the scientific aims will support the retention of a senior laboratory scientist with expertise in DNA methylation assays and two Masters level analysts with expertise in statistics and life course methods respectively, as well as provide funding to the investigator team to now include epigenetic approaches in their ongoing analyses of these unique birth cohorts. This will be highly relevant for the continuing investigation of the lifelong impact of even early lifetime exposures on health. A growing body of evidence indicates that epigenetic changes, including DNA methylation, may play an important role in the development of cardiovascular disease, cancer and other chronic conditions. In contrast to genes, epigenetic patterns may be affected by the environment and change over the life course. Further, epigenetic patterns may be reversed through changes in risk factors, as both human and animal studies have reported associations between prenatal and early life exposures and DNA methylation in adulthood. PUBLIC HEALTH RELEVANCE: This study will make use of a prospective birth cohort of women and men born in 1944-1945 to examine in the next two years whether the prenatal environment and specifically maternal nutrition in pregnancy are associated with changes in genomic DNA methylation levels in adulthood. We will further investigate if genomic DNA methylation levels in adulthood are associated with clinical indicators for cardiovascular disease risk such as blood pressure, lipid levels, fasting blood sugar levels, and obesity. The required medical examination records and biological materials for this study have been previously collected and stored and pending funding will be immediately available for analysis.

描述（由研究者提供）：本申请涉及广泛的挑战领域：08：基因组学，以及特定的挑战资助主题：08-AG-105**：研究关键发育期个体行为，社会和物理环境以及遗传/表观遗传过程之间相互作用的方法。项目名称：早期生活暴露在出生前和成人表观遗传学广泛的流行病学证据已链接到许多早期生活和环境因素成人发病的疾病。环境如何改变晚年疾病风险的一个合理机制是通过对体细胞的表观遗传效应，导致关键途径中关键基因的激活或沉默。DNA甲基化是一种表观遗传变化，通过改变基因产生的蛋白质，在疾病的致病中起重要作用。因此，具有相同基因的人，如双胞胎，可能会有不同的疾病结果，因为DNA甲基化的差异变化会影响特定基因产生特定蛋白质的能力。人类研究支持DNA甲基化模式随年龄而变化，动物研究支持关键时期的暴露可以改变表观遗传事件。然而，到目前为止，通过检查关键时期（包括产前和生命早期）的暴露以及生命后期的DNA甲基化模式，很少有机会将人类的这两条证据联系起来。我们最近完成了第一项人类研究，显示了多种族出生队列中妇女的早期生命因素（如出生体重和中年妇女的基因组DNA甲基化）之间的关联（1），也是第一项研究，表明暴露于产前饥荒环境后IGF 2基因的DNA甲基化存在持续的表观遗传差异（2）。使用的资源来自于已经收集的来自于1944-1945年出生于荷兰的三个出生队列的产前饥荒暴露以及来自于未暴露时间对照和兄弟姐妹对照的成人随访（n= 971; 437名男性和537名女性），我们现在建议一方面检查围受孕期和怀孕不同阶段的母亲饥饿暴露之间的联系，另一方面是成年期的DNA甲基化模式。我们将进一步研究成年期的DNA甲基化模式如何与心血管疾病和糖尿病的疾病风险因素相关，如肥胖，血胆固醇升高或空腹血糖值。因为一些研究表明，早期环境和长期健康结果之间的关系可能在男性和女性中是不同的，我们将按性别比较这些模式。表观遗传学领域在帮助我们了解人类疾病的基础，特别是环境暴露如何进入体内导致疾病方面有很大的希望。表观遗传学也可能有助于解释不同人群之间的疾病差异，因此对于理解环境暴露如何导致健康差异可能很重要。开展大型流行病学研究，根据过去在关键时期收集的信息，结合可靠的DNA甲基化标志物，对暴露进行强有力的测量，是必要的第一步。此类研究只能由了解生物机制和方法问题的多学科团队进行。我们的团队在美国和国外的生命历程研究的设计和分析方面拥有丰富的专业知识， 在处理关键时期，DNA甲基化和多种疾病结果的许多方法学问题方面经验丰富。除了实现科学目标之外，这项挑战补助金还将支持保留一名具有DNA甲基化检测专业知识的高级实验室科学家和两名分别具有统计学和生命过程方法专业知识的硕士级分析师，并为研究人员团队提供资金，现在将表观遗传方法纳入他们对这些独特出生队列的持续分析中。这对于继续调查即使是生命早期的接触对健康的终身影响也具有高度相关性。越来越多的证据表明，包括DNA甲基化在内的表观遗传变化可能在心血管疾病、癌症和其他慢性疾病的发展中发挥重要作用。与基因相反，表观遗传模式可能会受到环境的影响，并在生命过程中发生变化。此外，表观遗传模式可以通过风险因素的变化而逆转，因为人类和动物研究都报告了产前和生命早期暴露与成年期DNA甲基化之间的关联。 公共卫生相关性：这项研究将利用1944-1945年出生的女性和男性的前瞻性出生队列，在未来两年检查产前环境，特别是妊娠期母体营养是否与成年期基因组DNA甲基化水平的变化相关。我们将进一步研究成年期基因组DNA甲基化水平是否与心血管疾病风险的临床指标相关，如血压，血脂水平，空腹血糖水平和肥胖。本研究所需的医学检查记录和生物材料先前已收集和储存，待拨款将立即用于分析。