Georgia Prevention Institute, Department of Pediatrics, Georgia Regents University, Augusta, GA, USA.
Epigenetics. 2013 May;8(5):522-33. doi: 10.4161/epi.24506. Epub 2013 Apr 17.
Besides differential methylation, DNA methylation variation has recently been proposed and demonstrated to be a potential contributing factor to cancer risk. Here we aim to examine whether differential variability in methylation is also an important feature of obesity, a typical non-malignant common complex disease. We analyzed genome-wide methylation profiles of over 470,000 CpGs in peripheral blood samples from 48 obese and 48 lean African-American youth aged 14-20 y old. A substantial number of differentially variable CpG sites (DVCs), using statistics based on variances, as well as a substantial number of differentially methylated CpG sites (DMCs), using statistics based on means, were identified. Similar to the findings in cancers, DVCs generally exhibited an outlier structure and were more variable in cases than in controls. By randomly splitting the current sample into a discovery and validation set, we observed that both the DVCs and DMCs identified from the first set could independently predict obesity status in the second set. Furthermore, both the genes harboring DMCs and the genes harboring DVCs showed significant enrichment of genes identified by genome-wide association studies on obesity and related diseases, such as hypertension, dyslipidemia, type 2 diabetes and certain types of cancers, supporting their roles in the etiology and pathogenesis of obesity. We generalized the recent finding on methylation variability in cancer research to obesity and demonstrated that differential variability is also an important feature of obesity-related methylation changes. Future studies on the epigenetics of obesity will benefit from both statistics based on means and statistics based on variances.
除了差异甲基化，最近还提出并证明 DNA 甲基化变异是癌症风险的一个潜在促成因素。在这里，我们旨在研究甲基化的差异可变性是否也是肥胖的一个重要特征，肥胖是一种典型的非恶性常见复杂疾病。我们分析了 48 名肥胖和 48 名瘦的非洲裔美国青少年（年龄在 14-20 岁）外周血样本中超过 470,000 个 CpG 的全基因组甲基化谱。使用基于方差的统计数据确定了大量差异可变 CpG 位点（DVC），以及使用基于均值的统计数据确定了大量差异甲基化 CpG 位点（DMC）。与癌症中的发现相似，DVC 通常表现出异常结构，并且在病例中比在对照中更具可变性。通过将当前样本随机分为发现和验证集，我们观察到从第一组中识别出的 DVC 和 DMC 都可以独立地预测第二组中的肥胖状态。此外，DMC 所包含的基因和 DVC 所包含的基因都表现出肥胖症和相关疾病（如高血压、血脂异常、2 型糖尿病和某些类型的癌症）的全基因组关联研究中确定的基因的显著富集，支持它们在肥胖症的病因和发病机制中的作用。我们将癌症研究中关于甲基化可变性的最新发现推广到肥胖症，并证明差异可变性也是肥胖相关甲基化变化的一个重要特征。未来关于肥胖症的表观遗传学研究将受益于基于均值和基于方差的统计数据。
