Turku Bioscience Centre, University of Turku and Åbo Akademi University, FIN-20520, Turku, Finland.
Turku Doctoral Programme of Molecular Medicine, University of Turku, FI-20014, Turku, Finland.
Clin Epigenetics. 2019 Sep 2;11(1):130. doi: 10.1186/s13148-019-0729-7.
Alzheimer's disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs.
Comparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value ≤ 0.05. Several of the affected genes are primarily associated with neuronal functions and pathologies and do not display disease-associated differences in gene expression in blood. The DNA methylation mark in ADARB2 gene was found to be differentially methylated also in the anterior hippocampus, including entorhinal cortex, of non-twin cases and controls. Targeted bisulfite pyrosequencing of the DNA methylation mark in ADARB2 gene in 62 Finnish and Swedish twin pairs revealed that, in addition to the disease status, DNA methylation of this region is influenced by gender, age, zygosity, APOE genotype, and smoking. Further analysis of 120 Swedish twin pairs indicated that this specific DNA methylation mark is not predictive for Alzheimer's disease and becomes differentially methylated after disease onset.
DNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer's disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels.
阿尔茨海默病是由神经退行性过程引起的，该过程早在可以做出诊断之前就已经开始。能够早期干预疾病进程的新预后或诊断标志物将具有非常高的价值。环境和生活方式因素在很大程度上调节疾病风险，并可能通过表观遗传机制（如 DNA 甲基化）影响发病机制。由于环境和生活方式因素可能影响身体的多个组织，我们假设疾病相关的 DNA 甲基化特征可在不一致的双胞胎对的外周血中检测到。
对 23 对具有代表性的芬兰双胞胎进行比较，采用双亚硫酸盐测序法发现，11 个基因组区域的外周血 DNA 甲基化差异至少为 15.0%中位数甲基化差异，且 FDR 调整的 p 值≤0.05。受影响的几个基因主要与神经元功能和病理有关，在血液中未显示与疾病相关的基因表达差异。在非双胞胎病例和对照组的前海马体（包括内嗅皮层）中也发现了 ADARB2 基因的 DNA 甲基化标记存在差异。在 62 对芬兰和瑞典双胞胎中对 ADARB2 基因的 DNA 甲基化标记进行靶向双亚硫酸盐焦磷酸测序，结果表明，除了疾病状态外，该区域的 DNA 甲基化还受性别、年龄、同卵性、APOE 基因型和吸烟的影响。对 120 对瑞典双胞胎的进一步分析表明，这种特定的 DNA 甲基化标记不能预测阿尔茨海默病，并且在疾病发病后会发生差异甲基化。
在阿尔茨海默病不一致的双胞胎的外周血中可以检测到 DNA 甲基化差异。这些 DNA 甲基化特征可以作为疾病标志物具有价值，并为发病机制的分子机制提供见解。我们没有发现 DNA 甲基化标记与血液中的基因表达相关的证据。需要进一步的研究来阐明相关基因在神经元功能中的潜在重要性，并验证单个标记或标记组的预后或诊断价值。
