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: 10011313
• 负责人: Leslie J Baier
• 金额: $ 24.52万
• 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/10011313
• 关键词: Affect; Age; American Indians; Beta Cell; Biological; Blood specimen; CYP1A1 gene; Cardiovascular Diseases; Cell Proliferation; Cell physiology; Child; Cytosine; DNA Methylation; Data Set; Development; Diabetes Mellitus; Disease; Embryonic Development; Environment; Epigenetic Process; Ethnic group; Exposure to; Future; Gene Expression Regulation; Genes; Genetic Enhancer Element; Genomics; Guanine; Hypermethylation; Impairment; Individual; Inflammation; Insulin; Intercistronic Region; Leukocytes; Life; Literature; Maps; Measures; Metabolic Diseases; Methylation; Modification; Mothers; Native Americans; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Pima Indian; Population; Pregnancy; RRAS2 gene; Reporting; Risk; Role; STC1 gene; Sampling; Siblings; Signal Transduction; Site; Source; Testing; Time; Weight Gain; bead chip; cohort; diabetes risk; diabetic; epigenetic regulation; epigenome-wide association studies; genome-wide; genome-wide analysis; glucose tolerance; hazard; high risk; in utero; inorganic phosphate; insulin secretion; logarithm; maternal diabetes; novel; offspring; peripheral blood; transmission process

Individuals exposed to maternal diabetes in utero are more likely to develop metabolic and cardiovascular diseases later in life. This may be partially attributable to epigenetic regulation of gene expression. To examine whether differential DNA methylation, a major source of epigenetic regulation, can be observed in offspring of mothers with type 2 diabetes (OMD) during the pregnancy as compared to offspring of mothers with no type 2 diabetes(OMND) during the pregnancy, we performed an epigenome-wide association study. A total of 423,311 cytosine-phosphate-guanine (CpG) sites were analyzed in 388 Native Americans, of which 187 were OMD and 201 were OMND. Forty-eight differentially methylated CpG sites (with empirical false discovery rate < 0.05), mapping to 29 genes and 10 intergenic regions, were identified. The gene with the strongest evidence was LHX3, where 6 CpG sites were hyper-methylated in OMD (P 1.1 10-5). Similarly, a CpG near PRDM16 was hyper-methylated in OMD (1.1% higher, P = 5.6 10-7), where hyper-methylation also predicted future diabetes risk (hazard ratio = 2.12, P = 9.7 10-5). Hyper-methylation near AK3L1 and hypo-methylation at PCDHGA4 and STC1 associated with exposure to diabetes in utero and decreased insulin secretory function among offspring with normal glucose tolerance. Analysis of all 29 genes in aggregate did not shown enrichment for any biologic pathway; however, literature searches provided evidences that several of these genes have a role in embryonic development and/or beta cell function. We conclude that intrauterine exposure to diabetes can affect methylation at multiple genomic sites. Methylation status at some of these sites can impair insulin secretion, increase body weight and increase risk of type 2 diabetes. We have also conducted a genome-wide analysis to identify CpG sites at which methylation associates with BMI in Pima Indians. DNA methylation in 399 peripheral blood leukocyte samples was measured on the Illumina Infinium HumanMethylation450 BeadChip, and 423,311 CpG sites were analyzed. Each subject's BMI (measured at the time of blood sampling) was natural logarithm transformed and tested for association with DNA methylation with adjustments for appropriate covariates. CpG sites that achieved genome-wide significance in the discovery cohort (FDR p 0.05) were analyzed for replication in two existing datasets of Pima Indians (N = 320, age = 35; N = 183, age = 53). Among 263 CpG sites that associated with BMI in the discovery cohort, 9 replicated (p 0.05 and consistent direction of effect) in both replication cohorts. These were located in 6 genes and 2 enhancer elements. Three of these CpG sites map to genes (AHRR, RPS6KA2 and LGALS3BP) where DNA methylation has previously been reported to associate with BMI in other populations. The epigenetic associations at the remaining genes (DUSP5, RRAS2, APOBR) and enhancer elements are novel. Several of these genes have known roles in inflammation (DUSP5, LGALS3BP, APOBR, RPS6KA2) or cell proliferation (RRAS2 and AHRR). Thus, the present study has validated that DNA methylation at some genes associates with obesity in different ethnic groups, and it identifies other genes that may have a larger effect in American Indians.

在子宫中暴露于母亲糖尿病的人更有可能在以后的生活中患上代谢和心血管疾病。这可能部分归因于基因表达的表观遗传调控。为了检验是否可以观察到怀孕期间患有2型糖尿病(OMD)的母亲的后代与怀孕期间非2型糖尿病(OMND)母亲的后代相比，是否可以观察到不同的DNA甲基化，这是表观遗传调控的主要来源，我们进行了一项表观基因组范围的关联研究。共分析了388名美洲印第安人的423,311个胞嘧啶-磷酸-鸟嘌呤(CpG)位点，其中187个为OMD，201个为OMND。共鉴定出48个差异甲基化的CpG位点(经验假发现率为0.05)，定位于29个基因和10个基因间隔区。证据最充分的基因是LHX3，在OMD中有6个CpG位点高甲基化(P1.1 10-5)。类似地，在OMD中，靠近PRDM16的CpG高甲基化(1.1%，P=5.6 10-7)，其中高甲基化也预测未来的糖尿病风险(危险比=2.12，P=9.7 10-5)。在糖耐量正常的后代中，AK3L1附近的高甲基化和PCDHGA4和STC1的低甲基化与宫内糖尿病暴露和胰岛素分泌功能降低有关。对所有29个基因的分析没有显示出任何生物途径的丰富；然而，文献搜索提供了证据，表明其中几个基因在胚胎发育和/或β细胞功能中发挥作用。我们得出结论，宫内暴露于糖尿病会影响多个基因组位置的甲基化。其中一些位点的甲基化状态可能会损害胰岛素的分泌，增加体重，增加患2型糖尿病的风险。 我们还进行了全基因组分析，以确定在皮马印第安人中甲基化与BMI相关的CpG位点。在Illumina Infinium Human Mylation450型微珠芯片上检测了399例外周血白细胞DNA甲基化情况，分析了423,311个CpG位点。每个受试者的BMI(在采血时测量)被自然对数转换，并通过调整适当的协变量来测试与DNA甲基化的关联。在发现队列中获得全基因组意义的CpG位点(FDR p0.05)被分析在两个现有的PIMA印第安人数据集中(N=320，年龄=35；N=183，年龄=53)中复制。在发现队列中与BMI相关的263个CpG位点中，有9个在两个复制队列中重复(p0.05，作用方向一致)。这些基因定位于6个基因和2个增强子元件。其中三个CpG位点映射到基因(AHRR、RPS6KA2和LGALS3BP)，此前已有报道称DNA甲基化与其他人群的BMI有关。其余基因(DUSP5、RRAS2、APOBR)和增强子元件的表观遗传关联是新的。这些基因中有几个已知在炎症(DUSP5、LGALS3BP、APOBR、RPS6KA2)或细胞增殖(RRAS2和AHRR)中起作用。因此，本研究证实了一些基因的DNA甲基化与不同种族群体中的肥胖有关，并确定了可能对美洲印第安人有更大影响的其他基因。