Epigenetic modifications associated with intrauterine exposure to maternal type 2 diabetes.

与子宫内暴露于母亲 2 型糖尿病相关的表观遗传修饰。

• 批准号: 9148968
• 负责人: Leslie J Baier
• 金额: $ 130.99万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9148968
• 关键词: Affect; Algorithms; Birth; Child; Cox Proportional Hazards Models; DNA Methylation; Data; Development; Diabetes Mellitus; Diabetic mother; Disease; Environment; Epidemiology; Epigenetic Process; Exposure to; Genes; Genomics; Human; Hyperglycemia; Individual; Knowledge; Lead; Leukocytes; Logistic Regressions; Maps; Measures; Mediating; Metabolic; Methylation; Modeling; Modification; Mothers; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pathway Analysis; Pathway interactions; Pima Indian; Pregnancy; Quality Control; Reporting; Risk; Siblings; Signal Transduction; Site; Techniques; base; chromatin immunoprecipitation; diabetes risk; diabetic; epigenome; follow-up; high risk; in utero; insulin secretion; maternal diabetes; non-diabetic; offspring; peripheral blood; promoter; response; transmission process

We preliminarily exploring the possibility of DNA methylation as a mechanism through which epigenetic signals are passed from mother to offspring using a MeDIP-chip assay on the Affymetrix Human Tiling 2.0R Array. DNA methylation in peripheral blood leukocytes was compared between 14 non-diabetic offspring of diabetic mothers and 14 non-diabetic offspring of nondiabetic mothers. Data were analyzed using the model based analysis of tiling arrays (MAT) algorithm implemented in the Partek Genomic Suite. Differentially methylated promoters (N=5,975) were subjected to KEGG pathway analysis and the top pathway results were Type II Diabetes (p<0.003) and maturity onset diabetes of the young (MODY) (p<0.005). These preliminary findings support the hypothesis that epigenetic dysregulation of genes known to be involved in pancreatic development and insulin secretion mediate the increased risk for diabetes in offspring of diabetic mothers. Recent advances in genomic techniques now allows for epigenotyping of 450,000 individual CpG sites using the Illumina Infinium Methylation Array.Peripheral blood leukocytes from 420 non-diabetic Pima Indians were epigenotyped using the Illumina Infinium Methylation Array. Subjects were selected as being either the offspring of a T2D mother (mother had documented hyperglycemia at an exam during the 9 months preceding the child's birth) or the offspring of a non-T2D mother (mother had documented normoglycemia during the 9 months prior to the child's birth and had a non-diabetic exam >1 year after the childs birth). Data from 423,343 CpG sites in 388 individuals (N= 187 with exposure and 201 without exposure to intrauterine diabetes) passed all quality control measures. A Logistic Regression model with appropriate adjustments was used to estimate the association between exposure and methylation status. Thirty-nine differentially methylated genes achieved epigenome-wide significance after correction for false discovery rate (FDR). A Cox Proportional Hazard model in individuals with follow-up data on diabetes status determined that an intergenic CpG site (maps between FLJ42875 and PRDM16) significantly increased T2D risk (P value = 9.7E-5). This study is the first to identify differentially methylated genes in response to intrauterine diabetes exposure at the epigenome-wide significance. Detailed studies of the biologic pathways affected by these differentially methylated genes are ongoing, which will lead to knowledge of the metabolic changes that underlie the epidemiologic observation that maternal diabetes affects diabetes risk in offspring.

我们初步探讨了DNA甲基化作为一种机制的可能性，通过这种机制，表观遗传信号从母亲传递给后代使用的MeDIP芯片检测的Affyphase人类Tiling 2.0R阵列。比较了14名糖尿病母亲的非糖尿病后代和14名非糖尿病母亲的非糖尿病后代外周血白细胞DNA甲基化。使用Partek Genomic Suite中实现的基于模型的平铺阵列分析（MAT）算法分析数据。对不同甲基化的启动子（N= 5，975）进行KEGG途径分析，最高途径结果是II型糖尿病（p<0.003）和青年成熟型糖尿病（MODY）（p<0.005）。这些初步研究结果支持这样的假设，即已知参与胰腺发育和胰岛素分泌的基因的表观遗传失调介导了糖尿病母亲后代患糖尿病的风险增加。 基因组技术的最新进展现在允许使用Illumina Infinium Methylation Array对450，000个单独的CpG位点进行表观基因分型。受试者被选择为T2 D母亲的后代（母亲在孩子出生前9个月的检查中记录了高血糖症）或非T2 D母亲的后代（母亲在孩子出生前9个月的检查中记录了正常血糖症，并且在查尔兹出生后>1年进行了非糖尿病检查）。来自388名个体（N= 187名暴露于宫内糖尿病，201名未暴露于宫内糖尿病）的423，343个CpG位点的数据通过了所有质量控制措施。使用经过适当调整的Logistic回归模型来估计暴露与甲基化状态之间的关联。39个差异甲基化基因在校正错误发现率（FDR）后达到表观基因组范围的显著性。在具有糖尿病状态随访数据的个体中，考克斯比例风险模型确定基因间CpG位点（FLJ 42875和PRDM 16之间的映射）显著增加T2 D风险（P值= 9.7 E-5）。 这项研究是第一个确定差异甲基化基因在宫内糖尿病暴露在表观基因组的意义。受这些差异甲基化基因影响的生物学途径的详细研究正在进行中，这将导致对代谢变化的了解，这些代谢变化是母亲糖尿病影响后代糖尿病风险的流行病学观察的基础。