Biological Sciences, Institute of Developmental Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom.
Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
PLoS Med. 2020 Nov 5;17(11):e1003229. doi: 10.1371/journal.pmed.1003229. eCollection 2020 Nov.
Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia.
We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders.
Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings.
ISRCTN89971375.
即使在妊娠糖尿病（GDM）阈值以下，母体血浆葡萄糖（PG）浓度升高也与后代不良结局有关，DNA 甲基化被提出作为一种中介机制。在这里，我们研究了孕妇 24-28 周时的母体糖代谢异常与新生儿 DNA 甲基化之间的关系，以及肥胖孕妇的饮食和体育活动干预是否改变了与母体糖代谢异常相关的甲基化特征。
我们调查了 557 名女性，她们于 2009 年至 2014 年期间参加了英国怀孕改善饮食和运动试验（UPBEAT），这是一项针对肥胖孕妇（294 名对照组，263 名干预组）的生活方式干预（低升糖指数（GI）饮食加体育活动）的随机对照试验（RCT）。在妊娠 27-28 周时，参与者进行了口服葡萄糖（75g）耐量试验（OGTT），根据国际糖尿病与妊娠研究组（IADPSG）推荐的诊断标准，159 名女性被诊断为 GDM。通过 Infinium Human MethylationEPIC BeadChip 阵列检测婴儿脐带血 DNA 中的全基因组 DNA 甲基化水平。采用稳健回归，调整了母体年龄、吸烟、产次、种族、新生儿性别和预测的细胞类型组成。母体 GDM、空腹血糖、OGTT 后 1 小时和 2 小时血糖浓度与婴儿脐带血 DNA 中 242、1、592 和 17 个差异甲基化胞嘧啶-磷酸-鸟嘌呤（dmCpG）位点相关（假发现率（FDR）≤0.05）。与 GDM 最显著相关的 CpG 是位于富含亮氨酸重复的 G 蛋白偶联受体 6（LGR6）内的 cg03566881（FDR=0.0002）。此外，我们还表明，婴儿脐带血中与 GDM 和 1 小时血糖相关的甲基化特征似乎在怀孕期间通过饮食和体育活动干预得到了减弱；在干预组中，没有 GDM 和两个 1 小时血糖相关的 dmCpG，而在标准护理组中，有 41 个 GDM 和 160 个 1 小时血糖相关的 dmCpG。与标准护理组相比，干预组中 GDM 和 1 小时血糖相关的 dmCpG 中有 87%和 77%的效应大小较小；LGR6 cg03566881 与 GDM 关联的调整 r2 在标准护理组中为 0.317（95%置信区间（CI）0.012，0.022），在干预组中为 0.240（95% CI 0.001，0.015）。研究存在一定局限性，包括脐带血中 DNA 甲基化的测量，目前尚不清楚这种变化的功能意义，而且由于治疗方式和高血糖严重程度之间的强相关性，我们不能排除治疗相关差异可能是潜在的混杂因素。
母体糖代谢异常与婴儿的表观基因组发生显著变化有关。此外，我们发现，妊娠期间不良糖代谢的母体环境的表观遗传影响似乎可以通过生活方式干预来改变。需要进一步研究以探讨这些发现的可能医学意义。
ISRCTN89971375。
