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.

我们使用 Affymetrix Human Tiling 2.0R 阵列上的 MeDIP 芯片检测初步探索 DNA 甲基化作为表观遗传信号从母亲传递到后代的机制的可能性。对糖尿病母亲的 14 个非糖尿病后代和非糖尿病母亲的 14 个非糖尿病后代的外周血白细胞 DNA 甲基化进行了比较。使用 Partek Genomic Suite 中实施的基于模型的平铺阵列分析 (MAT) 算法对数据进行分析。对差异甲基化启动子（N=5,975）进行KEGG通路分析，排名靠前的通路结果是II型糖尿病（p<0.003）和青少年发病的成年糖尿病（MODY）（p<0.005）。这些初步发现支持这样的假设：已知参与胰腺发育和胰岛素分泌的基因的表观遗传失调会导致糖尿病母亲的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 甲基化阵列对 450,000 个单独的 CpG 位点进行表观基因分型。使用 Illumina Infinium 甲基化阵列对 420 名非糖尿病皮马印第安人的外周血白细胞进行表观基因分型。受试者被选择为 T2D 母亲的后代（母亲在孩子出生前 9 个月的检查中记录有高血糖）或非 T2D 母亲的后代（母亲在孩子出生前 9 个月期间记录有正常血糖）。孩子出生后并在孩子出生后 1 年以上进行过非糖尿病检查）。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）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逻辑回归模型来估计暴露与甲基化状态之间的关联。在校正错误发现率 (FDR) 后，39 个差异甲基化基因达到了表观基因组范围内的显着性。具有糖尿病状况随访数据的个体的 Cox 比例风险模型确定，基因间 CpG 位点（FLJ42875 和 PRDM16 之间的图谱）显着增加 T2D 风险（P 值 = 9.7E-5）。 这项研究首次在表观基因组范围内鉴定出响应宫内糖尿病暴露的差异甲基化基因。对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，这将导致了解代谢变化，这些变化是流行病学观察中母亲糖尿病影响后代糖尿病风险的基础。