Exploring persistent epigenetic changes after prenatal famine exposure in humans

描述（由研究者提供）：该申请涉及广泛的挑战领域：08：基因组学，以及具体的挑战资助主题：08- ag -105**：研究关键发育时期个体行为、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。大量的流行病学证据表明，许多早期生活和环境因素与成人发病疾病有关。环境如何改变生命后期的疾病风险，一种看似合理的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，可能通过改变基因产生的蛋白质而在疾病病因中发挥重要作用。因此，拥有相同基因的人，如双胞胎，可能会有不同的疾病结果，因为DNA甲基化的不同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甲基化模式随着年龄的变化而变化，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，很少有机会通过检查关键时期的暴露，包括产前和生命早期以及生命后期的DNA甲基化模式，将这两种证据联系起来。我们最近完成了第一项人类研究，表明在多种族出生队列中，早期生活因素（如出生体重）与中年妇女基因组DNA甲基化之间存在关联(1)，也是第一项研究表明暴露于产前饥荒环境后，IGF2基因的DNA甲基化存在持续的表观遗传差异(2)。利用从荷兰的三个出生队列中收集的成人随访资源，这些队列在1944-1945年出生，产前暴露于饥荒，未暴露时间对照和兄弟姐妹对照（n= 971； 437名男性和537名女性），我们现在建议研究母体在围孕期和怀孕不同阶段暴露于饥荒与成年期DNA甲基化模式之间的关系。我们将进一步研究成年期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（如肥胖、血胆固醇升高或空腹血糖值）相关。由于一些研究表明，早期环境与长期健康结果之间的关系在男性和女性中可能有所不同，我们将按性别比较这些模式。表观遗传学领域在帮助我们理解人类疾病的基础，特别是环境暴露如何进入人体导致疾病方面有着巨大的希望。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，结合今天可靠的DNA甲基化标记，对暴露进行强有力的测量，是必要的第一步。这样的研究只能由了解生物学机制和方法问题的多学科小组进行。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广泛的专业知识，并且非常有经验

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.