Background Studies have shown that the effects of maternal nutrition exposure during gestation influence metabolic risk in early life through an epigenetic mechanism. Low glycaemic index (GI) diets benefit both maternal and neonatal gestational outcomes. We hypothesize that maternal dietary GI or glycaemic load (GL) changes during pregnancy impact placental DNA methylation, especially in insulin resistance-related genes. Methods From a clinical trial of overweight pregnant women, 12 subjects who successfully reduced their GI and another 12 whose GI increased despite the intervention were selected. A genome-wide differential methylation analysis of placental tissue DNA was conducted, followed by bioinformatic annotation and validation analysis. The distribution of genome-wide differentially methylated regions (DMRs) and CpG sites was described. Six CpG sites in regulatory regions of four insulin-related genes (PLIN1, CPT1B, SSTR4, and CIDEA) were selectively validated by pyrosequencing. Pairwise Spearman correlation analysis was performed to test methylation-phenotype association in an additional 153 subjects from the same trial. Correlation between methylation of significant sites and placental mRNA expression of SSTR4 was also analysed. Results Dietary GI decreased by 24.3 (26.2-20.1) in the group who responded appropriately to the intervention and increased by 19.6 (15.2-29.1) in the comparison group. Epigenome-wide analysis identified 108 DMRs and 365 CpG sites with P < 0.05 adjusted by false discovery rate, distributed over all chromosomes. The methylation level of cg05009389 in the 3' UTR of PLIN1 was negatively correlated with maternal weight gain (ρ = - 0.21, P = 0.027) and increase in insulin levels (ρ = - 0.24, P = 0.015) during gestation. Methylation levels of cg17586860 and cg18197392 in the 5' UTR region of SSTR4 were negatively correlated with changes in dietary carbohydrate intake (ρ = - 0.24, Ps ≤ 0.006) and GL across gestation (ρ = - 0.23, Ps ≤ .008). This correlation survived the adjustment for maternal factors such as dietary GI, body mass index, and gestational diabetes. Up to 89% of cg18197392 methylation was explained by GL change. Cg14631053 methylation correlated positively with mRNA expression of SSTR4 in the placenta (ρ = 0.20, P = 0.037). Conclusions We provide the first evidence that maternal dietary GI changes during gestation may impact placental DNA methylation of insulin regulation genes. This supports the hypothesis that placental methylation may be the epigenetic mechanism through which maternal diet influences the metabolic health of offspring.

中文翻译：

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孕期母体膳食血糖变化影响胎盘组织中胰岛素相关基因甲基化：全基因组甲基化分析。

背景研究表明，孕期母体营养暴露的影响通过表观遗传机制影响生命早期的代谢风险。低血糖指数 (GI) 饮食有益于孕产妇和新生儿的妊娠结局。我们假设怀孕期间母体饮食 GI 或血糖负荷 (GL) 的变化会影响胎盘 DNA 甲基化，尤其是在胰岛素抵抗相关基因中。方法 从一项针对超重孕妇的临床试验中，选择了 12 名成功降低 GI 的受试者和另外 12 名在干预后 GI 增加的受试者。对胎盘组织 DNA 进行全基因组差异甲基化分析，然后进行生物信息学注释和验证分析。描述了全基因组差异甲基化区域 (DMR) 和 CpG 位点的分布。通过焦磷酸测序选择性地验证了四个胰岛素相关基因（PLIN1、CPT1B、SSTR4 和 CIDEA）的调节区域中的六个 CpG 位点。进行配对 Spearman 相关分析以测试来自同一试验的另外 153 名受试者的甲基化-表型关联。还分析了重要位点的甲基化与 SSTR4 的胎盘 mRNA 表达之间的相关性。结果对干预有适当反应的组膳食GI下降24.3（26.2-20.1），对照组增加19.6（15.2-29.1）。表观基因组分析确定了 108 个 DMR 和 365 个 CpG 位点，通过错误发现率调整 P < 0.05，分布在所有染色体上。PLIN1 3' UTR中cg05009389的甲基化水平与母体体重增加呈负相关（ρ = - 0.21，P = 0. 027) 和妊娠期间胰岛素水平的增加 (ρ = - 0.24, P = 0.015)。SSTR4 的 5' UTR 区域中 cg17586860 和 cg18197392 的甲基化水平与膳食碳水化合物摄入量的变化 (ρ = - 0.24, Ps ≤ 0.006) 和妊娠期 GL (ρ = - 0.23, Ps ≤ .008) 的变化呈负相关。这种相关性在调整母体因素（如饮食 GI、体重指数和妊娠糖尿病）后仍然存在。高达 89% 的 cg18197392 甲基化由 GL 变化解释。Cg14631053甲基化与胎盘中SSTR4的mRNA表达呈正相关（ρ = 0.20，P = 0.037）。结论 我们提供的第一个证据表明，孕期母体饮食 GI 的变化可能会影响胰岛素调节基因的胎盘 DNA 甲基化。