Huang R C, Garratt E S, Pan H, Wu Y, Davis E A, Barton S J, Burdge G C, Godfrey K M, Holbrook J D, Lillycrop K A
a Telethon Institute for Child Health Research; University of Western Australia ; Perth, Australia.
b Academic Unit of Human Development and Health; Faculty of Medicine; University of Southampton ; Southampton , UK.
Epigenetics. 2015;10(11):995-1005. doi: 10.1080/15592294.2015.1080411.
Childhood obesity is a major public health issue. Here we investigated whether differential DNA methylation was associated with childhood obesity. We studied DNA methylation profiles in whole blood from 78 obese children (mean BMI Z-score: 2.6) and 71 age- and sex-matched controls (mean BMI Z-score: 0.1). DNA samples from obese and control groups were pooled and analyzed using the Infinium HumanMethylation450 BeadChip array. Comparison of the methylation profiles between obese and control subjects revealed 129 differentially methylated CpG (DMCpG) loci associated with 80 unique genes that had a greater than 10% difference in methylation (P-value < 0.05). The top pathways enriched among the DMCpGs included developmental processes, immune system regulation, regulation of cell signaling, and small GTPase-mediated signal transduction. The associations between the methylation of selected DMCpGs with childhood obesity were validated using sodium bisulfite pyrosequencing across loci within the FYN, PIWIL4, and TAOK3 genes in individual subjects. Three CpG loci within FYN were hypermethylated in obese individuals (all P < 0.01), while obesity was associated with lower methylation of CpG loci within PIWIL4 (P = 0.003) and TAOK3 (P = 0.001). After building logistic regression models, we determined that a 1% increase in methylation in TAOK3, multiplicatively decreased the odds of being obese by 0.91 (95% CI: 0.86 - 0.97), and an increase of 1% methylation in FYN CpG3, multiplicatively increased the odds of being obese by 1.03 (95% CI: 0.99 - 1.07). In conclusion, these findings provide evidence that childhood obesity is associated with specific DNA methylation changes in whole blood, which may have utility as biomarkers of obesity risk.
儿童肥胖是一个主要的公共卫生问题。在此，我们研究了DNA甲基化差异是否与儿童肥胖相关。我们研究了78名肥胖儿童（平均BMI Z评分：2.6）和71名年龄及性别匹配的对照儿童（平均BMI Z评分：0.1）全血中的DNA甲基化谱。将肥胖组和对照组的DNA样本混合，使用Infinium HumanMethylation450 BeadChip芯片进行分析。肥胖组和对照组受试者甲基化谱的比较显示，有129个差异甲基化的CpG（DMCpG）位点与80个独特基因相关，这些基因的甲基化差异大于10%（P值<0.05）。DMCpG中富集的主要通路包括发育过程、免疫系统调节、细胞信号调节以及小GTP酶介导的信号转导。通过对个体受试者FYN、PIWIL4和TAOK3基因内位点进行亚硫酸氢盐焦磷酸测序，验证了所选DMCpG甲基化与儿童肥胖之间的关联。肥胖个体中FYN内的三个CpG位点甲基化程度较高（所有P<0.01），而肥胖与PIWIL4（P = 0.003）和TAOK3（P = 0.001）内CpG位点的低甲基化相关。构建逻辑回归模型后，我们确定TAOK3甲基化增加1%，肥胖几率成倍降低0.91（95%CI：0.86 - 0.97），FYN CpG3甲基化增加1%，肥胖几率成倍增加1.03（95%CI：0.99 - 1.07）。总之，这些发现提供了证据，表明儿童肥胖与全血中特定的DNA甲基化变化相关，这些变化可能作为肥胖风险的生物标志物。
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