Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Lancet. 2015 Feb 26;385 Suppl 1:S81. doi: 10.1016/S0140-6736(15)60396-8.
Preterm infants are at increased risk of cardiometabolic disease in later life. Extrauterine growth restriction, catch-up growth, altered adiposity, and abnormal hypothalamic-pituitary-adrenal axis activity could be predisposing factors. Altered DNA methylation (5-methylcytosine, 5mC) might be one underlying mechanism. We hypothesised that preterm infants have altered 5mC at the linked differentially methylated region 2 (DMR2) of IGF2 and the H19 imprinting control region (H19 ICR) compared with term infants over the first year of life.
We recruited 46 preterm (range 25 weeks + 2 days' gestation to 31 + 5, mean 28 + 6) and 40 term infants (38 + 3 to 42 + 2 weeks' gestation, mean 40 + 2). Anthropometric variables including body composition were measured at term age and 3 months corrected age with air displacement plethysmography and at 1-year-corrected age with skin-fold thickness. Salivary cortisol was measured at 3 months corrected age after the physical examination. Percentage methylation (%5mC) was analysed with pyrosequencing on buccal DNA. Statistical analysis used Student's t test and multivariate linear regression.
Preterm infants demonstrated growth deficit early in postnatal life but had greater percentage body fat at term age (β=5·73, p<0·001), but not at 3 months (β=-0·28, p=0·82). Compared with term infants, preterm infants had a blunted cortisol response to physical examination (mean difference 0·38 μg/dL, p=0·024). At birth, preterm infants had a significant decrease in %5mC at DMR2 compared with term infants at birth (β=-11·48, p<0·001) and compared with preterm infants at term-corrected age (t=3·13, p=0·01). By term-corrected age, preterm infants had decreased %5mC at both DMR2 (β=-2·84, p=0·013) and the H19 ICR (β=-2·31, p=0·048) compared with term infants at birth, although this difference disappeared at 1 year. Social deprivation was independently associated with decreased %5mC at DMR2 at birth (β=-1·73, p=0·006) and term-corrected age (β=-0·86, p=0·016) but not at 1 year (β=-0·89, p=0·07).
Our results show that decreased %5mC accompanies the early growth deficit in preterm infants. The marked reduction in %5mC at IGF2 DMR2 in preterm infants at birth compared with term-age supports existing evidence that imprinting at secondary regions is established after fertilisation, whereas imprinting is established during gametogenesis at primary regions (H19 ICR). Both regions might be susceptible to early life stressors such as preterm birth and social deprivation.
Chief Scientist Office of the Scottish Government.
早产儿在生命后期患心脏代谢疾病的风险增加。宫外生长受限、追赶生长、体脂改变和下丘脑-垂体-肾上腺轴活性改变可能是易感因素。DNA 甲基化（5-甲基胞嘧啶，5mC）改变可能是潜在的机制之一。我们假设与足月婴儿相比，早产儿在生命的第一年 IGF2 连接的差异甲基化区域 2（DMR2）和 H19 印迹控制区（H19 ICR）的 5mC 存在改变。
我们招募了 46 名早产儿（胎龄 25 周+2 天至 31+5，平均 28+6）和 40 名足月婴儿（胎龄 38+3 至 42+2 周，平均 40+2）。在足月年龄和 3 个月矫正年龄时使用空气置换体描记法测量人体成分等体格参数，在 1 岁矫正年龄时使用皮褶厚度测量人体成分。在 3 个月矫正年龄时，在体格检查后测量唾液皮质醇。使用焦磷酸测序法在口腔 DNA 上分析 5mC 的百分比（%5mC）。统计分析采用 Student's t 检验和多元线性回归。
早产儿在出生后早期表现出生长不足，但在足月年龄时体脂百分比更高（β=5·73，p<0·001），但在 3 个月时没有差异（β=-0·28，p=0·82）。与足月婴儿相比，早产儿在体格检查时皮质醇反应减弱（平均差异 0·38 μg/dL，p=0·024）。在出生时，与足月婴儿相比，早产儿的 DMR2 处的%5mC 明显减少（β=-11·48，p<0·001），与早产儿的足月校正年龄相比也减少（t=3·13，p=0·01）。在足月校正年龄时，与出生时的足月婴儿相比，早产儿的 DMR2（β=-2·84，p=0·013）和 H19 ICR（β=-2·31，p=0·048）的%5mC 减少，尽管这种差异在 1 岁时消失。社会剥夺与 DMR2 出生时的%5mC 减少独立相关（β=-1·73，p=0·006）和足月校正年龄时的%5mC 减少（β=-0·86，p=0·016），但与 1 岁时无关（β=-0·89，p=0·07）。
我们的结果表明，%5mC 的减少伴随着早产儿的早期生长不足。与足月婴儿相比，早产儿 IGF2 DMR2 处的%5mC 在出生时明显减少，这支持了现有证据，即次级区域的印迹在受精后建立，而主要区域（H19 ICR）的印迹在配子发生过程中建立。这两个区域可能容易受到早产和社会剥夺等早期生活应激源的影响。
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