Huang Jian V, Cardenas Andres, Colicino Elena, Schooling C Mary, Rifas-Shiman Sheryl L, Agha Golareh, Zheng Yinan, Hou Lifang, Just Allan C, Litonjua Augusto A, DeMeo Dawn L, Lin Xihong, Oken Emily, Hivert Marie-France, Baccarelli Andrea A
a Department of Environmental Health Sciences , Columbia Mailman School of Public Health , NY , NY , USA.
b School of Public Health, Li Ka Shing Faculty of Medicine , The University of Hong Kong , Hong Kong SAR , People's Republic of China.
Epigenetics. 2018;13(10-11):1072-1087. doi: 10.1080/15592294.2018.1543503. Epub 2018 Nov 13.
Obesity is associated with higher cardio-metabolic risk even in childhood and adolescence; whether this association is mediated by epigenetic mechanisms remains unclear. We examined the extent to which mid-childhood body mass index (BMI) z-score (median age 7.7 years) was associated with cardio-metabolic risk score in early adolescence (median age 12.9 years) via mid-childhood DNA methylation among 265 children in the Project Viva. We measured DNA methylation in leukocytes using the Infinium Human Methylation450K BeadChip. We assessed mediation CpG-by-CpG using epigenome-wide association analyses, high-dimensional mediation analysis, and natural effect models. We observed mediation by mid-childhood DNA methylation at 6 CpGs for the association between mid-childhood BMI z-score and cardio-metabolic risk score in early adolescence in the high-dimensional mediation analysis (accounting for 10% of the total effect) and in the natural effect model (β = 0.04, = 3.2e-2, accounting for 13% of the total effect). The natural direct effect of BMI z-score on cardio-metabolic risk score was still evident (β = 0.27, = 1.1e-25). We also observed mediation by mid-childhood DNA methylation at 5 CpGs that was in the opposite direction from the total effect (natural effect model: β = -0.04, = 2.0e-2). Mediation in different directions implies a complex role of DNA methylation in the association between BMI and cardio-metabolic risk and needs further investigation. Future studies with larger sample size and greater variability in cardio-metabolic risk will further help elucidate the role of DNA methylation for cardio-metabolic risk.
肥胖即使在儿童期和青少年期也与较高的心血管代谢风险相关；这种关联是否由表观遗传机制介导仍不清楚。在“活力计划”的265名儿童中，我们研究了儿童中期体重指数（BMI）z评分（中位年龄7.7岁）通过儿童中期DNA甲基化与青春期早期（中位年龄12.9岁）心血管代谢风险评分之间的关联程度。我们使用Infinium Human Methylation450K BeadChip测量白细胞中的DNA甲基化。我们通过全表观基因组关联分析、高维中介分析和自然效应模型评估逐个CpG的中介作用。在高维中介分析中（占总效应的10%）以及在自然效应模型中（β = 0.04，P = 3.2e - 2，占总效应的13%），我们观察到儿童中期DNA甲基化在6个CpG位点介导了儿童中期BMI z评分与青春期早期心血管代谢风险评分之间的关联。BMI z评分对心血管代谢风险评分的自然直接效应仍然显著（β = 0.27，P = 1.1e - 25）。我们还观察到儿童中期DNA甲基化在5个CpG位点的中介作用与总效应方向相反（自然效应模型：β = -0.04，P = 2.0e - 2）。不同方向的中介作用意味着DNA甲基化在BMI与心血管代谢风险关联中起复杂作用，需要进一步研究。未来样本量更大且心血管代谢风险变异性更高的研究将进一步有助于阐明DNA甲基化对心血管代谢风险的作用。
