Methylation analysis of multiple genes in blood DNA of Alzheimer’s disease and healthy individuals

Tannorella, Pierpaola; Stoccoro, Andrea; Tognoni, Gloria; Petrozzi, Lucia; Salluzzo, Maria Grazia; Ragalmuto, Alda; Siciliano, Gabriele; Haslberger, Alexander G.; Bosco, Paolo; Bonuccelli, Ubaldo; Migliore, Lucia; Coppedè, Fabio

doi:10.1016/j.neulet.2015.06.009

Cited by 68 publications

(63 citation statements)

References 21 publications

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“…Alternatively, two studies [50, 51] showed no difference in DNA methylation of APP in brain tissue between AD and healthy controls. Fourteen studies found no difference or clear pattern in methylation of the following genes: 12-LOX [34], debrin-like protein gene [34], p450 epoxygenase gene [34], MAPT , PSEN1 , UCHL1 , SST [52], SSTR4 [52], F2RL2 [45], SOD-1 [48] and GRN [53] in brain tissue; PS1 [49], PS2 [49] and tau1 [49], SMARCA 5 [54], CHD1 [54], BDNF [55], SIRT1 [55], PSEN1 [55{Tannorella, 2015 #2823], genes involved in DNA repair [56], genes involved in homocysteine pathway [57], CTSB [58], CTSD [58], DDT [58], TSC1 [58], NRD1 [58] and NDUFA6 [58] in blood cells; HSPA8 [59], HSPA9 [59], ApoE4 [47, 49], SNAP25 [60], SORL 1 , SIRT1 and SIRT3 [49, 54, 60] in both blood cells and brain tissue (Table 2). However, 7 studies showed differences in methylation patterns of CpG sites (within same gene some CpG sites were hypomethylated and some others were hypermethylated, in AD cases) examined at the following genes: SORL1 [61], ABCA7 [61], SLC2A4 [61], BIN1 [61], HSPA8 [59], HSPA9 [59], DR4 gene [62], BDNF4 [43, 44], SIRT1 [49], APP [47], MAPT [47] and GSK3B [47].…”

Section: Resultsmentioning

confidence: 99%

The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review

et al. 2016

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ImportanceEpigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in neurodegenerative diseases (ND) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).ObjectiveTo systematically review studies investigating epigenetic marks in AD or PD.MethodsEleven bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, Scopus, PubMed, Cinahl (EBSCOhost), Cochrane Central, ProQuest, Lilacs, Scielo and Google Scholar) were searched until July 11th 2016 to identify relevant articles. We included all randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined associations between epigenetic marks and ND. Two independent reviewers, with a third reviewer available for disagreements, performed the abstract and full text selection. Data was extracted using a pre-designed data collection form.ResultsOf 6,927 searched references, 73 unique case-control studies met our inclusion criteria. Overall, 11,453 individuals were included in this systematic review (2,640 AD and 2,368 PD outcomes). There was no consistent association between global DNA methylation pattern and any ND. Studies reported epigenetic regulation of 31 genes (including cell communication, apoptosis, and neurogenesis genes in blood and brain tissue) in relation to AD and PD. Methylation at the BDNF, SORBS3 and APP genes in AD were the most consistently reported associations. Methylation of α-synuclein gene (SNCA) was also found to be associated with PD. Seven studies reported histone protein alterations in AD and PD.ConclusionMany studies have investigated epigenetics and ND. Further research should include larger cohort or longitudinal studies, in order to identify clinically significant epigenetic changes. Identifying relevant epigenetic changes could lead to interventional strategies in ND.

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Section: Resultsmentioning

confidence: 99%

The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review

et al. 2016

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“…In this regard, it was suggested that MTHFR hypermethylation might confer a growth advantage to cancer cells and contribute to the cancer phenotype in tumors of the upper aero-digestive tract [25]. Moreover, MTHFR promoter methylation levels have been correlated with cancer risk factors and with markers of impaired folate metabolism, including tobacco smoking, low circulating folates and vitamin B12, high homocysteine levels, and increased chromosome instability [15,18,26,27]. …”

Section: Discussionmentioning

confidence: 99%

“…However, as far as MTHFR promoter methylation in the blood is concerned, it should be noted that rather than being a specific marker of a given disease, it could represent a more general biomarker of increased genomic instability. For example, some studies suggest a correlation between hyperhomocysteinemia and MTHFR promoter methylation [26]; others have linked MTHFR promoter methylation in blood cells with markers of chromosome damage, such as an increased frequency of micronuclei [27] or alterations of LINE-1 methylation and stability [15], and there is also indication that MTHFR promoter methylation in blood DNA might reflect dietary B-group vitamin deficiency [18,30] or environmental exposure to cancerous agents, such as those deriving from tobacco smoking [15]. Collectively, those studies suggest that increased MTHFR promoter methylation in blood cells might be a more general marker of impaired one-carbon metabolism and genome instability, rather than a specific disease biomarker.…”

Section: Discussionmentioning

confidence: 99%

“…Standard curves with known methylation ratios were included in each assay and were used to deduce the methylation ratio of each blood, adjacent healthy tissue, and tumor tissue. Validation of the MS-HRM assays was performed by means of pyrosequencing, as detailed elsewhere [26]. In order to obtain single methylation percentage values from MS-HRM assays, we applied an interpolation method developed and described by us, which allowed us to obtain precise HRM methylation values comparable to those obtained by pyrosequencing [37].…”

Section: Methodsmentioning

confidence: 99%

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Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Lopomo

Ricciardi

Maestri

et al. 2016

IJMS

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Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is known, however, concerning epigenetic changes occurring in thymomas from MG individuals. To further address this issue, we analyzed DNA methylation levels of genes involved in one-carbon metabolism (MTHFR) and DNA methylation (DNMT1, DNMT3A, and DNMT3B) in blood, tumor tissue, and healthy thymic epithelial cells from MG patients that underwent a surgical resection of a thymic neoplasm. For the analyses we applied the methylation-sensitive high-resolution melting technique. Both MTHFR and DNMT3A promoters showed significantly higher methylation in tumor tissue with respect to blood, and MTHFR also showed significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells. Both DNMT1 and DNMT3B promoter regions were mostly hypomethylated in all the investigated tissues. The present study suggests that MTHFR methylation is increased in thymomas obtained from MG patients; furthermore, some degrees of methylation of the DNMT3A gene were observed in thymic tissue with respect to blood.

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“…Recent epigenetics studies have shown blood DNA methylation changes in a number of neurological and psychiatric diseases, including Alzheimer’s disease, Parkinson’s disease, Down’s syndrome, infantile spasm, depressive disorders and schizophrenia4344454647484950515253545556. Investigations into peripheral DNA methylation changes are considered important to help develop novel biomarkers for early diagnosis of some brain diseases.…”

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confidence: 99%

Blood DNA methylation pattern is altered in mesial temporal lobe epilepsy

Long

Feng

Kang

et al. 2017

Sci Rep

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Mesial temporal lobe epilepsy (MTLE) is a common epileptic disorder; little is known whether it is associated with peripheral epigenetic changes. Here we compared blood whole genomic DNA methylation pattern in MTLE patients (n = 30) relative to controls (n = 30) with the Human Methylation 450 K BeadChip assay, and explored genes and pathways that were differentially methylated using bioinformatics profiling. The MTLE and control groups showed significantly different (P < 1.03e-07) DNA methylation at 216 sites, with 164 sites involved hyper- and 52 sites hypo- methylation. Two hyper- and 32 hypo-methylated sites were associated with promoters, while 87 hyper- and 43 hypo-methylated sites corresponded to coding regions. The differentially methylated genes were largely related to pathways predicted to participate in anion binding, oxidoreductant activity, growth regulation, skeletal development and drug metabolism, with the most distinct ones included SLC34A2, CLCN6, CLCA4, CYP3A43, CYP3A4 and CYP2C9. Among the MTLE patients, panels of genes also appeared to be differentially methylated relative to disease duration, resistance to anti-epileptics and MRI alterations of hippocampal sclerosis. The peripheral epigenetic changes observed in MTLE could be involved in certain disease-related modulations and warrant further translational investigations.

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Methylation analysis of multiple genes in blood DNA of Alzheimer’s disease and healthy individuals

Cited by 68 publications

References 21 publications

The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review

The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Blood DNA methylation pattern is altered in mesial temporal lobe epilepsy

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