Objective: To evaluate the possible mediation effect of DNA methylation in the associations between birth weight and adulthood obesity in women in China. Methods: A cross-sectional survey was conducted in 1 602 women with genetic relationship in urban area of Shanghai during March-December 2016. Information about their birth weight, birth length, current lifestyle and disease history were collected and body measurement was conducted at the interview. DNA methylation at specific sites of GNASAS, IGF2, IGF2-R, IL10 and LEP were measured using bisulphite pyrosequencing. Generalized estimating equations models with restricted cubic spline functions were used to estimate the associations of birth weight with BMI, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-hip ratio (WHtR) in adulthood, and their associations with DNA methylation were evaluated using multilevel linear models. Multilevel structural equation models were used to evaluate the mediation effect of DNA methylation. Results: A significant non-linear association was observed between birth weight and WC as well as WHtR (P<0.05). Lower birth weight was associated with higher level of methylation at IGF2-DMR (CpG1, 2), IGF2-R (CpG8, 10, 13, 16 and 17), with β coefficients and 95%CI being -4.35 (-7.30- -1.39), -4.50 (-7.59- -1.41), -2.33 (-4.60- -0.05), -1.78 (-3.88- -0.33), -2.58 (-4.82- -0.34), -2.03 (-4.00- -0.06) and -1.87 (-3.73- -0.01), respectively, but related with a lower level of methylation at LEP CpG16 (β=4.19, 95%CI: 0.37- 8.00). Lower level of methylation at IGF2-DMR (CpG7), IGF2-R (CpG3, 5, 8, 9, 10, 14, 17, 19) and LEP (CpG3, 8, 10) was associated with larger WC, with β coefficients ranging from -0.016 to -0.040 (all P<0.05). Methylation at IGF2-R CpG8 was observed to mediate the association of birth weight and WC, and could explain 3.3% of the association. Conclusion: Our results suggested that DNA methylation might mediate the effect of nutrition in uteri on adulthood central obesity in women in China.
目的： 了解DNA甲基化在女性出生体重与成年期肥胖风险关联中可能的中介效应。 方法： 2016年3－12月对1 602名上海市闵行区有亲缘关系的2~4代女性进行调查，收集出生体重和身长、当前生活方式和疾病史等信息，并测量身高、体重、腰围（WC）、臀围。利用所采集的外周血，采用焦磷酸法检测鸟苷酸结合蛋白活性刺激肽反义RNA1（GNASAS）、胰岛素样生长因子2（IGF2）、胰岛素样生长因子2受体（IGF2-R）、白介素10（IL10）和瘦素（LEP）5个基因上特异性位点的甲基化水平。采用结合限制性立方样条函数的广义估计方程模型评估出生体重与成年期BMI、WC、腰臀比（WHR）、腰围身高比（WHtR）的关联，使用多水平回归模型分别评估出生体重及上述体型指标与各特异位点甲基化水平的关联。中介效应基于多水平结构方程模型进行评估。 结果： 出生体重与WC及WHtR均呈现显著的非线性关联（P<0.05），与IGF2差异甲基化区（IGF2-DMR）CpG1、2，IGF2-R CpG8、10、13、16和17的甲基化水平呈显著的负向关联，回归系数β值（95%CI）分别为-4.35（-7.30~-1.39）、-4.50（-7.59~-1.41）、-2.33（-4.60~-0.05）、-1.78（-3.88~-0.33）、-2.58（-4.82~-0.34）、-2.03（-4.00~-0.06）和-1.87（-3.73~-0.01），与LEP CpG16的甲基化水平呈正向关联（β=4.19，95%CI：0.37~8.00）。IGF2-DMR CpG7，IGF2-R CpG3、5、8、9、10、14、17和19，以及LEP CpG3、8和10的甲基化水平均与WC呈显著的负向关联，相应的β值在-0.016~-0.040之间（P<0.05）。IGF2-R CpG8的甲基化水平可能在出生体重与成年期WC关联中起中介作用（P<0.001），可以解释两者关联的3.3%。 结论： DNA甲基化水平可能介导生命早期营养状况对女性成年期腹部肥胖的影响。.
Keywords: Birth weight; DNA methylation; Mediation effect; Obesity.