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

我们在Affymetrix Human Tabling 2.0R阵列上使用MeDIP芯片分析初步探索了DNA甲基化作为表观遗传信号从母亲传递给后代的机制的可能性。比较了14名糖尿病母亲的非糖尿病子女和14名非糖尿病母亲的非糖尿病子女外周血白细胞DNA甲基化情况。使用Partek基因组套件中实现的基于模型的平铺阵列分析(MAT)算法对数据进行分析。对差异甲基化的启动子(N=5,975)进行KEGG通路分析，结果显示最主要的通路结果是II型糖尿病(p&lt；0.003)和青年成熟期糖尿病(p&lt；0.005)。这些初步发现支持一种假设，即已知的参与胰腺发育和胰岛素分泌的基因的表观遗传失调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。受试者被选为T2D母亲的子女(母亲在孩子出生前9个月的检查中发现高血糖)或非T2D母亲的子女(母亲在孩子出生前9个月内血糖正常，并在孩子出生后1年进行了非糖尿病检查)。来自388个人的423,343个CpG点的数据(N=187个暴露于宫内糖尿病和201个不暴露于宫内糖尿病)通过了所有质量控制措施。经过适当调整的Logistic回归模型被用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假发现率(FDR)后具有表观基因组意义。对有糖尿病状况随访数据的个体进行的Cox比例风险模型表明，基因间CpG位点(位于FLJ42875和PRDM16之间)显著增加了T2D风险(P值=9.7E-5)。 这项研究首次在表观基因组的意义上确定了宫内糖尿病暴露的差异甲基化基因。对受这些不同甲基化基因影响的生物途径的详细研究正在进行中，这将导致对代谢变化的了解，这些变化是流行病学观察的基础，即母亲糖尿病影响后代患糖尿病的风险。

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.