DNA methylation (DNAm) patterns across the genome changes during aging and development of complex diseases including type 2 diabetes (T2D). Our study aimed to estimate DNAm trajectories of CpG sites associated with T2D, epigenetic age (DNAmAge), and age acceleration based on four epigenetic clocks (GrimAge, Hannum, Horvath, phenoAge) in the period 10 years prior to and up to T2D onset. In this nested case–control study within Doetinchem Cohort Study, we included 132 incident T2D cases and 132 age- and sex-matched controls. DNAm was measured in blood using the Illumina Infinium Methylation EPIC array. From 107 CpG sites associated with T2D, 10 CpG sites (9%) showed different slopes of DNAm trajectories over time (p < 0.05) and an additional 8 CpG sites (8%) showed significant differences in DNAm levels (at least 1%, p-value per time point < 0.05) at all three time points with nearly parallel trajectories between incident T2D cases and controls. In controls, age acceleration levels were negative (slower epigenetic aging), while in incident T2D cases, levels were positive, suggesting accelerated aging in the case group. We showed that DNAm levels at specific CpG sites, up to 10 years before T2D onset, are different between incident T2D cases and healthy controls and distinct patterns of clinical traits over time may have an impact on those DNAm profiles. Up to 10 years before T2D diagnosis, cases manifested accelerated epigenetic aging. Markers of biological aging including age acceleration estimates based on Horvath need further investigation to assess their utility for predicting age-related diseases including T2D.

在衰老和包括 2 型糖尿病 (T2D) 在内的复杂疾病的发展过程中，整个基因组的 DNA 甲基化 (DNAm) 模式会发生变化。我们的研究旨在根据 4 个表观遗传时钟（GrimAge、Hannum、Horvath、phenoAge）估计 T2D 发病前 10 年期间与 T2D 相关的 CpG 位点的 DNAm 轨迹、表观遗传年龄 (DNAmAge) 和年龄加速。在 Doetinchem 队列研究中的这项巢式病例对照研究中，我们纳入了 132 例 T2D 病例和 132 例年龄和性别匹配的对照。使用 Illumina Infinium 甲基化 EPIC 阵列测量血液中的 DNAm。在与 T2D 相关的 107 个 CpG 位点中，10 个 CpG 位点 (9%) 随着时间的推移显示出不同的 DNAm 轨迹斜率 ( p  < 0.05)，另外 8 个 CpG 位点 (8%) 显示出 DNAm 水平的显着差异（至少 1%，每个时间点的p值 < 0.05) 在所有三个时间点，T2D 病例和对照之间的轨迹几乎平行。在对照组中，年龄加速水平为负值（表观遗传衰老较慢），而在 T2D 病例中，年龄加速水平为正值，表明病例组衰老加速。我们发现，在 T2D 发病前 10 年，特定 CpG 位点的 DNAm 水平在 T2D 发病病例和健康对照之间存在差异，并且随着时间的推移，临床特征的不同模式可能会对这些 DNAm 谱产生影响。在 T2D 诊断前 10 年，病例就表现出表观遗传加速老化。生物衰老标志物（包括基于 Horvath 的年龄加速估计）需要进一步研究，以评估其在预测包括 T2D 在内的年龄相关疾病方面的效用。