Prenatally induced DNA methylation profiles and disease risk at age 60

描述(由申请人提供)：人类2型糖尿病和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的基因特异性DNA甲基化，导致肥胖和高血压。我们还描述了在出生前暴露于1944-1945年的荷兰饥饿冬季饥荒后，58岁的人类持续的表观遗传学变化，并观察到肥胖、糖尿病和其他不良后果的增加。这项研究希望在314对同性兄弟姐妹中安排的628名产前暴露于饥荒和未暴露于饥荒的对照组的男性和女性的研究中，阐明将这些观察结果联系起来的生物学机制。首先，我们将生成一个产前诱导的差异甲基化区域(P-DMRS)的全基因组目录，使用覆盖超过45万个CpG位点的新型Illumina高通量、高含量甲基化芯片比较所有研究对象的DNA甲基化图谱。然后，我们将在人类身体组织库中识别P-DMRS亚群，这些亚群标志着代谢活跃的组织和器官中的甲基化。然后将评估这些P-DMR与产前饥荒暴露和成人疾病的关系。这一方法将对产前环境与成人疾病之间的联系提供进一步的见解。 公共卫生相关性：叙述在这项研究中，我们将利用荷兰饥饿冬季独特的准实验环境来发现产前诱导的DNA甲基化特征，这些特征可以预测人类患代谢性疾病的风险。

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.