肥胖治疗的主要挑战之一是解释个体对特定饮食和身体活动干预的反应的高度变异性。通过这项研究,我们检验了以下假设:特定的DNA甲基化变化反映了个体对生活方式干预的反应性,并且可能作为成功减重的表观遗传学预测因子.
我们对120名受试者(90%为男性,平均±SD年龄=49±9岁,身体质量指数(BMI)=30.2±3.3kg/m2),来自18个月CENTRAL随机对照试验,接受地中海/低碳水化合物或低脂饮食,有或没有体育锻炼。
分析比较体重下降最突出的男性受试者(反应者,平均体重变化-16%)与无反应者(2.4%)(每个N=10)显示,包括LRRC27,CRISP2和SLFN12在内的几个基因的DNA甲基化存在显着变化(所有调整。P<1×10-5)。基因本体论分析表明,细胞粘附等生物学过程和钙离子结合等分子功能可能对肥胖介入治疗的成功具有重要作用。相对体重减轻(%)的全基因组关联鉴定出15个CpG与干预后的体重变化呈负相关(所有组合P<1×10-4),包括新的和已知的肥胖候选者,例如NUDT3和NCOR2。与年龄和BMI(AUCROC=0.56)等预测因子相比,基线DNA甲基化评分更好地预测成功的体重减轻[曲线下面积(AUC)接受者操作特征(ROC)=0.95-1.0]。
18个月生活方式干预后的体重减轻与特定的甲基化特征相关。此外,所鉴定基因中的甲基化差异可以作为预测减肥治疗成功的预后生物标志物,从而有助于患者定制肥胖治疗的进展。
One of the major challenges in obesity treatment is to explain the high variability in the individual\'s response to specific dietary and physical activity interventions. With this
study, we tested the hypothesis that specific DNA methylation changes reflect individual responsiveness to lifestyle intervention and may serve as epigenetic predictors for a successful weight-loss.
We conducted an explorative genome-wide DNA methylation analysis in blood samples from 120 subjects (90% men, mean ± SD age = 49 ± 9 years, body mass-index (BMI) = 30.2 ± 3.3 kg/m2) from the 18-month CENTRAL randomized controlled
trial who underwent either Mediterranean/low-carbohydrate or low-fat diet with or without physical activity.
Analyses comparing male subjects with the most prominent body weight-loss (responders, mean weight change - 16%) vs. non-responders (+ 2.4%) (N = 10 each) revealed significant variation in DNA methylation of several genes including LRRC27, CRISP2, and SLFN12 (all adj. P < 1 × 10-5). Gene ontology analysis indicated that biological processes such as cell adhesion and molecular functions such as calcium ion binding could have an important role in determining the success of interventional therapies in obesity. Epigenome-wide association for relative weight-loss (%) identified 15 CpGs being negatively correlated with weight change after intervention (all combined P < 1 × 10- 4) including new and also known obesity candidates such as NUDT3 and NCOR2. A baseline DNA methylation score better predicted successful weight-loss [area under the curve (AUC) receiver operating characteristic (ROC) = 0.95-1.0] than predictors such as age and BMI (AUC ROC = 0.56).
Body weight-loss following 18-month lifestyle intervention is associated with specific methylation signatures. Moreover, methylation differences in the identified genes could serve as prognostic biomarkers to predict a successful weight-loss therapy and thus contribute to advances in patient-tailored obesity treatment.