Prenatally induced DNA methylation profiles and disease risk at age 60

产前诱导的 DNA 甲基化谱和 60 岁时的疾病风险

• 批准号: 8153701
• 负责人: L H LUMEY
• 金额: $ 36.75万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8153701
• 关键词: Address; Adult; Affect; Age; Agreement; Animals; Assisted Reproductive Technology; Autopsy; Biological Process; Birth; Cadaver; Candidate Disease Gene; Cataloging; Catalogs; Cities; CpG dinucleotide; DNA; DNA Methylation; Data; Development; Diabetes Mellitus; Dietary Intervention; Disease; Disease Outcome; Environment; Epigenetic Process; Exposure to; Family; Family Study; Famines; Fatty acid glycerol esters; Gene Expression Alteration; Genes; Genome; Glucose; Health; Human; Hunger; Hypertension; Individual; Intervention Studies; Interview; Life; Link; Lipids; Liver; Malnutrition; Measurement; Medical; Metabolic; Metabolic Diseases; Methylation; Nazi; Netherlands; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Organ; Outcome; Overnutrition; Pancreas; Participant; Pilot Projects; Plant Roots; Population; Population Study; Pregnancy; Quality Control; Risk; Risk Factors; Sampling; Sampling Studies; Siblings; Site; Skeletal Muscle; Study Subject; Techniques; Technology; Time; Tissue Banking; Tissue Banks; Tissues; Visceral; Whole Blood; Woman; Work; adverse outcome; base; cost effective; disorder risk; follow-up; food shortage; genome-wide; glucose metabolism; innovation; insight; lipid metabolism; medical examination; men; middle age; novel; nutrition; offspring; prenatal; prenatal exposure; sex; subcutaneous; trait

DESCRIPTION (provided by applicant): An epigenetic component of type 2 diabetes and other diseases in humans is widely hypothesized but lacks adequate empirical support. Animal studies show that nutritional interventions during pregnancy can affect gene-specific DNA methylation in the offspring causing obesity and hypertension. We have also described persistent epigenetic changes in humans at age 58 after prenatal exposure to the Dutch Hunger Winter famine of1944-1945 and observed an increase in obesity, diabetes, and other adverse outcomes. This study hopes to clarify the biologic mechanism that can link these observations in a study of 628 men and women with prenatal famine exposure and unexposed controls, arranged in 314 same-sex sibling pairs. First, we will generate a genome-wide catalog of Prenatally-induced Differentially Methylated Regions (P-DMRs), comparing DNA methylation profiles for all study subjects using the novel Illumina high-throughput, high content methylation chip covering over 450k CpG sites. Then we will identify in a human cadaver tissue bank the P-DMRs subsets that mark methylation in metabolically active tissues and organs. These P-DMRs will then be evaluated in relation to prenatal famine exposure and adult disease. This approach will provide further insights into the link between the prenatal environments with adult disease. PUBLIC HEALTH RELEVANCE: Narrative In this study we will utilize the unique quasi-experimental setting of the Dutch Hunger Winter to discover prenatally induced DNA methylation profiles that predict the risk of metabolic disease in humans.

描述（由申请人提供）：2型糖尿病和人类其他疾病的表观遗传成分被广泛假设，但缺乏足够的经验支持。动物研究表明，怀孕期间的营养干预会影响后代基因特异性DNA甲基化，导致肥胖和高血压。我们还描述了在1944 -1945年荷兰饥饿冬季饥荒的产前暴露后，58岁的人类持续的表观遗传变化，并观察到肥胖，糖尿病和其他不良后果的增加。这项研究希望澄清可以将这些观察结果联系起来的生物学机制，该研究涉及628名产前饥饿暴露的男性和女性以及未暴露的对照组，安排在314对同性兄弟姐妹中。首先，我们将生成产前诱导差异甲基化区域（P-DMR）的全基因组目录，使用覆盖超过450 k CpG位点的新型Illumina高通量，高含量甲基化芯片比较所有研究受试者的DNA甲基化谱。然后，我们将在人尸体组织库中鉴定标记代谢活性组织和器官中甲基化的P-DMR子集。然后将评估这些P-DMR与产前饥荒暴露和成人疾病的关系。这种方法将提供进一步的见解产前环境与成人疾病之间的联系。 公共卫生关系：在这项研究中，我们将利用荷兰饥饿冬季的独特准实验环境来发现产前诱导的DNA甲基化谱，预测人类代谢疾病的风险。