Prenatally induced DNA methylation profiles and disease risk at age 60

摘要 2型糖尿病和人类其他疾病的表观遗传成分广泛存在于 假设，但缺乏足够的实证支持。动物研究表明， 怀孕期间的干预可以影响后代的基因特异性DNA甲基化 导致肥胖和高血压。我们还描述了持续的表观遗传变化， 出生前暴露于1944 -1945年荷兰饥饿冬季饥荒的58岁人类， 观察到肥胖和糖尿病以及其他不良后果的增加。本研究希望 在一项对628名男性进行的研究中， 产前饥饿暴露的妇女和未暴露的对照组，安排在314个同性 兄弟姐妹 首先，我们将生成一个产前诱导的差异甲基化的全基因组目录， 区域（P-DMR），比较使用新方法的所有研究受试者的DNA甲基化谱 Illumina高通量、高含量甲基化芯片，覆盖超过450 k CpG位点。然后我们 将在人类尸体组织库中鉴定标记甲基化的P-DMR子集， 代谢活跃的组织和器官。然后，将根据以下方面对这些P-DMR进行评价： 产前饥荒暴露和成人疾病。这种方法将进一步深入了解 产前环境与成人疾病之间的联系。

Abstract 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 impact 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 and 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 environment with adult disease.