Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study
Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study
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DOI：
10.1111/acel.12293
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发表时间：
2015-02-01
期刊：
影响因子：
7.8
通讯作者：
Arnett, Donna K.
中科院分区：
文献类型：
--
作者：
Ma, Yiyi;Smith, Caren E.;Arnett, Donna K.
虽然载脂蛋白E（APOE）变异与年龄相关性疾病有关，但其潜在机制尚不清楚，DNA甲基化可能是一个潜在的机制。使用Infinium Human Methylation 450阵列测量的993名参与者的甲基化数据，（年龄范围从18岁到87岁）在降脂药物和饮食网络（GOLDN）研究的遗传学中，和来自DNA元件百科全书（ENCODE）联盟，结合已发表的甲基化数据集，我们描述了APOE基因座内13个CpG位点的甲基化模式，它们与跨细胞类型的基因表达的相关性，以及它们与年龄、血浆脂质和序列变异的关系。基于甲基化水平和基因区域，我们将13个APOE CpG位点分为三组：第1组显示高甲基化（>50%），位于启动子区域，第2组显示低甲基化（50%），位于外显子4。APOE甲基化与基因表达呈负相关（最小r=-0.66，P =0.004）。APOE甲基化与年龄（最小P=2.06E-08）和血浆总胆固醇（最小P=3.53E-03）显著相关。最后，APOE甲基化模式在APOE β变体（最小P=3.51E-05）和启动子变体rs 405509（最小P=0.01）之间存在差异，这进一步显示了与年龄的显著相互作用（P=0.03）。这些结果表明，甲基化可能是一个潜在的机制解释APOE功能与衰老有关，并呼吁进一步的分子机制的研究。
Although apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (>50%) and were located in the promoter region, Group 2 exhibited hypomethylation (50%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r=-0.66, P=0.004). APOE methylation was significantly associated with age (minimum P=2.06E-08) and plasma total cholesterol (minimum P=3.53E-03). Finally, APOE methylation patterns differed across APOE epsilon variants (minimum P=3.51E-05) and the promoter variant rs405509 (minimum P=0.01), which further showed a significant interaction with age (P=0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies.