A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk
A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk
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DOI：
10.1007/s11357-017-0001-z
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发表时间：
2017-12-01
期刊：
影响因子：
5.6
通讯作者：
Conneely, Karen N.
中科院分区：
文献类型：
--
作者：
Grant, Crystal D.;Jafari, Nadereh;Conneely, Karen N.
DNA甲基化（DNAm）已被发现在整个基因组中显示出稳健和广泛的年龄相关变化。来自全血的DNAm谱可以非常准确地用于预测人类衰老速率。我们试图测试基于DNAm的年龄预测是否与2型糖尿病（T2D）相关的表型有关，目的是确定潜在由DNAm介导的风险因素。我们的参与者是43名参加妇女健康倡议的妇女。我们通过Illumina 450K甲基化阵列在三个时间点从参与者的全血样本中获得甲基化数据，平均覆盖每个参与者16年。我们采用了Horvath的方法和软件，该软件使用353个CpG上的DNAm来形成基于DNAm的实际年龄估计。然后，我们计算了每个时间点的表观遗传年龄加速度，或Delta（年龄）。我们拟合线性混合模型来表征Delta（年龄）如何对衰老和糖尿病相关表型和风险因素的纵向模型做出贡献。对于大多数参与者来说，Delta（年龄）保持不变，表明年龄加速通常随时间而稳定。我们发现Delta（年龄）与体重指数（p = 0.0012），腰围（p = 0.033）和空腹血糖（p = 0.0073）相关，与BMI的关系在多重检验校正后保持显著性。在一个由157名WHI参与者组成的更大的队列中进行了为期3年的复制，但没有成功，这可能是由于所涵盖的时间范围较短。我们的研究结果表明，DNAm有可能作为衰老和糖尿病相关表型之间的中介，或者，可以作为这些表型的生物标志物。
DNA methylation (DNAm) has been found to show robust and widespread age-related changes across the genome. DNAm profiles from whole blood can be used to predict human aging rates with great accuracy. We sought to test whether DNAm-based predictions of age are related to phenotypes associated with type 2 diabetes (T2D), with the goal of identifying risk factors potentially mediated by DNAm. Our participants were 43 women enrolled in the Women's Health Initiative. We obtained methylation data via the Illumina 450K Methylation array on whole blood samples from participants at three timepoints, covering on average 16 years per participant. We employed the method and software of Horvath, which uses DNAm at 353 CpGs to form a DNAm-based estimate of chronological age. We then calculated the epigenetic age acceleration, or Delta(age), at each timepoint. We fit linear mixed models to characterize how Delta(age) contributed to a longitudinal model of aging and diabetes-related phenotypes and risk factors. For most participants, Delta(age) remained constant, indicating that age acceleration is generally stable over time. We found that Delta(age) associated with body mass index (p = 0.0012), waist circumference (p = 0.033), and fasting glucose (p = 0.0073), with the relationship with BMI maintaining significance after correction for multiple testing. Replication in a larger cohort of 157 WHI participants spanning 3 years was unsuccessful, possibly due to the shorter time frame covered. Our results suggest that DNAm has the potential to act as a mediator between aging and diabetes-related phenotypes, or alternatively, may serve as a biomarker of these phenotypes.