Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial.
Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial.
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DOI：
10.1371/journal.pmed.1003229
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发表时间：
2020-11
期刊：
影响因子：
15.8
通讯作者：
UPBEAT Consortium
中科院分区：
文献类型：
--
作者：
Antoun E;Kitaba NT;Titcombe P;Dalrymple KV;Garratt ES;Barton SJ;Murray R;Seed PT;Holbrook JD;Kobor MS;Lin DT;MacIsaac JL;Burdge GC;White SL;Poston L;Godfrey KM;Lillycrop KA;UPBEAT Consortium
较高的母体血糖（PG）浓度，甚至低于妊娠期糖尿病（GDM）阈值，与不良的后代结局相关，DNA甲基化被认为是一种介导机制。在这里，我们研究了妊娠24至28周的母体血吸虫病与新生儿DNA甲基化之间的关系，以及肥胖孕妇的饮食和体力活动干预是否改变了与母体血吸虫病相关的甲基化特征。我们调查了2009年至2014年期间从英国孕妇更好饮食和活动试验（UPBEAT）招募的557名妇女，这是一项随机对照试验（RCT），对肥胖孕妇进行生活方式干预（低血糖指数（GI）饮食加体力活动）（294对照，263干预）。在妊娠27至28周之间，参与者进行口服葡萄糖（75 g）耐受试验（OGTT），GDM诊断基于国际糖尿病和妊娠研究组协会（IADPSG）推荐的诊断标准，其中159名女性被诊断为GDM。使用Infinium Human MethylationEPIC BeadChip阵列对来自婴儿的脐带血DNA样本进行全基因组DNA甲基化水平的询问。进行稳健回归，调整母亲年龄，吸烟，产次，种族，新生儿性别和预测的细胞类型组成。母亲GDM、空腹血糖、OGTT后1小时和2小时血糖浓度分别与婴儿脐带血DNA中242、1、592和17个差异甲基化胞嘧啶-磷酸-鸟嘌呤（dmCpG）位点（错误发现率（FDR）≤ 0.05）相关。最显著的GDM相关CpG是位于富含亮氨酸重复序列的G蛋白偶联受体6（LGR 6）内的cg 03566881（FDR = 0.0002）。此外，我们发现，婴儿脐带血中的GDM和1小时葡萄糖相关甲基化特征似乎通过妊娠期间的饮食和体力活动干预而减弱;在干预组中，没有GDM和2个1小时葡萄糖相关dmCpG，而在标准护理组中，有41个GDM和160个1小时葡萄糖相关dmCpG。与标准治疗组相比，干预组中共有87%的GDM和77%的1小时葡萄糖相关dmCpG的效应量较小; LGR 6 cg 03566881与GDM相关性的校正r2为0.317（95%置信区间（CI）0.012，0.022），标准治疗和0.240（95% CI 0.001，0.015）。局限性包括测量脐带血中的DNA甲基化，这种变化的功能意义尚不清楚，由于治疗方式和高血糖症严重程度之间存在强共线性，我们不能排除治疗相关差异是潜在的混杂因素。母亲的营养不良与婴儿表观基因组的显著变化有关。此外，我们发现，表观遗传的影响，一个异常的产前母体环境似乎是修改的生活方式干预怀孕。需要进一步的研究来调查这些发现可能的医学意义。ISRCTN89971375。Karen Lillycrop及其同事调查了肥胖孕妇的饮食和体力活动干预是否改变了与母体代谢异常相关的甲基化特征。妊娠期糖尿病的发病率在全球范围内不断增加，同时肥胖症也在增加，患有妊娠期糖尿病（GDM）的母亲所生的孩子患肥胖症和代谢疾病的风险更高，从而使代谢疾病的代际循环持续下去。GDM母亲的高循环葡萄糖水平被认为会在胎儿发育期间引发表观遗传变化（影响基因活性和从中产生的蛋白质量的化学修饰），导致晚年对代谢疾病的易感性增加。由于对肥胖母亲（GDM的高危人群）中由母体GDM诱导的表观遗传变化知之甚少，我们研究了患有GDM的肥胖母亲和未患GDM的肥胖母亲所生婴儿的DNA甲基化与母亲血糖浓度之间的关系。然后，我们研究了在怀孕期间的饮食和体力活动干预，旨在改善产妇高血糖症，修改与母亲GDM暴露相关的婴儿的DNA甲基化变化。我们使用来自英国孕妇更好饮食和活动试验（UPBEAT）的样本，这是一项针对肥胖孕妇的生活方式干预（低血糖指数（GI）饮食加体力活动）与标准护理的随机对照试验（RCT），我们调查了脐带血DNA甲基化水平来自557名新生儿。母亲GDM状态和母亲高循环葡萄糖水平与婴儿DNA甲基化的适度变化相关。在婴儿中观察到的与母亲GDM暴露相关的甲基化变化似乎通过妊娠生活方式干预而减少。这些研究结果表明，母亲循环葡萄糖水平高对婴儿DNA甲基化的影响可以通过怀孕期间的生活方式干预来改变。需要进行后续研究，以确定在接受生活方式干预的GDM母亲的婴儿中观察到的DNA甲基化变化的减少是否伴随着儿童晚年健康状况的改善。
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. Karen Lillycrop and colleagues investigate whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia. The incidence of gestational diabetes is increasing worldwide, concurrent with a rise in obesity with children born to mothers with gestational diabetes mellitus (GDM) having a heightened risk of obesity and metabolic disease, perpetuating an intergenerational cycle of metabolic disease. High circulating levels of glucose in mothers with GDM have been suggested to trigger epigenetic changes (chemical modifications that affect gene activity and the amount of protein produced from them) during development of the fetus, resulting in an increased susceptibility to metabolic disease in later life. As little is known of the epigenetic changes induced by maternal GDM within mothers with obesity, a high-risk population for GDM, we examined relationships between DNA methylation in infants born to mothers with obesity who developed GDM and those who did not and the mother’s blood glucose concentration. We then examined whether a dietary and physical activity intervention during pregnancy, designed to improve maternal glycaemia, modified the DNA methylation changes in the infant associated with maternal GDM exposure. Using samples from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT) of lifestyle intervention (low glycaemic index (GI) diet plus physical activity) versus standard care in pregnant women with obesity, we investigated cord blood DNA methylation levels from 557 newborn infants. Maternal GDM status and high circulating maternal glucose levels were associated with modest changes in DNA methylation in the infants. The methylation changes observed in the infant associated with maternal GDM exposure appeared to be reduced by the pregnancy lifestyle intervention. These findings suggest that the impact of high maternal circulating glucose levels on DNA methylation in the infant can be modified by a lifestyle intervention in pregnancy. Follow-up studies are needed to establish whether the reduction in DNA methylation changes observed in infants from mothers with GDM undertaking the lifestyle intervention is accompanied by improved health outcomes of the children in later life.
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影响因子：
16.2
作者：
Black MH;Sacks DA;Xiang AH;Lawrence JM
通讯作者：
Lawrence JM
影响因子：
16.2
作者：
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通讯作者：
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影响因子：
15.8
作者：
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通讯作者：
Ensenauer R
影响因子：
7.7
作者：
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通讯作者：
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影响因子：
5.8
作者：
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通讯作者：
Irizarry, Rafael A.