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Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer's disease.
Clinical Epigenetics ( IF 4.8 ) Pub Date : 2019-09-02 , DOI: 10.1186/s13148-019-0729-7
Mikko Konki 1, 2 , Maia Malonzo 3 , Ida K Karlsson 4, 5 , Noora Lindgren 6, 7 , Bishwa Ghimire 1, 8 , Johannes Smolander 1 , Noora M Scheinin 7, 9, 10 , Miina Ollikainen 8 , Asta Laiho 1 , Laura L Elo 1 , Tapio Lönnberg 1 , Matias Röyttä 11 , Nancy L Pedersen 5, 12 , Jaakko Kaprio 8, 13 , Harri Lähdesmäki 3 , Juha O Rinne 7, 14 , Riikka J Lund 1
Affiliation  

BACKGROUND 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. RESULTS 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. CONCLUSIONS 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.

中文翻译:

阿尔茨海默氏病不一致的双胞胎中外周血DNA甲基化差异。

背景技术阿尔茨海默氏病是由神经变性过程导致的,该过程在做出诊断之前就已经开始。能够及早介入疾病过程的新的预后或诊断标志物将具有很高的价值。环境和生活方式因素在很大程度上调节了疾病的风险,并可能通过表观遗传机制(例如DNA甲基化)影响发病机理。由于环境和生活方式因素可能会影响身体的多个组织,因此我们假设与疾病相关的DNA甲基化特征可在不一致双胞胎对的外周血中检测到。结果比较了23个疾病不一致的芬兰双胞胎对和减少的亚硫酸氢盐测序,发现11个基因组区域的外周血DNA甲基化差异至少为15。0%甲基化中值差异和FDR调整后的p值≤0.05。几个受影响的基因主要与神经元功能和病理相关,在血液中的基因表达中未显示与疾病相关的差异。发现非双胞胎病例和对照的ADARB2基因中的DNA甲基化标记在前海马(包括内嗅皮层)中也被甲基化。有针对性的亚硫酸氢盐焦磷酸测序对62对芬兰和瑞典双胞胎中ADARB2基因的DNA甲基化标记显示,除疾病状况外,该区域的DNA甲基化还受到性别,年龄,接合性,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老年痴呆症。病并在疾病发作后甲基化。结论在阿尔茨海默氏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甲基化标记可能具有作为疾病标记物的价值,并提供了发病机理的分子机制的见解。我们没有发现任何证据表明DNA甲基化标记将与血液中的基因表达相关。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物组的预后或诊断价值。这些DNA甲基化标记可能具有作为疾病标记物的价值,并提供了发病机理的分子机制的见解。我们没有发现任何证据表明DNA甲基化标记将与血液中的基因表达相关。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物组的预后或诊断价值。这些DNA甲基化标记可能具有作为疾病标记物的价值,并提供了发病机理的分子机制的见解。我们没有发现任何证据表明DNA甲基化标记将与血液中的基因表达相关。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物组的预后或诊断价值。
更新日期:2019-09-02
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