DNA methyltransferase haplotype is associated with Alzheimer's disease

Pezzi, Júlio Carlos; Ens, Cíntia; Borba, Ericksen; Schumacher-Schuh, Artur; Andrade, Fabiana Michelsen de; Chaves, Márcia Lorena Fagundes; Fiegenbaum, Marilu; Camozzato, Ana Luiza

doi:10.1016/j.neulet.2014.07.013

Cited by 18 publications

(11 citation statements)

References 31 publications

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“…For example, increasing evidence suggests that the DNMT3B -149C>T polymorphism, either alone or in haplotype combination with other non-coding DNMT3B polymorphisms, contributes to the maternal risk for having a child with Down syndrome [47,48,49], and has been associated with an increased risk of prematurity [30], with childhood immune thrombocytopenia [50,51] and autoimmune thyroid disease [52]. The association of the DNMT3B -149C>T polymorphism with neurological and neurodegenerative diseases, either alone or in haplotype combination, is still controversial [53,54,55,56].…”

Section: Discussionmentioning

confidence: 99%

Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

Coppedè

Stoccoro

Tannorella

et al. 2019

IJMS

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Methylenetetrahydrofolate reductase (MTHFR) is a pivotal enzyme in the one-carbon metabolism, a metabolic pathway required for DNA synthesis and methylation reactions. MTHFR hypermethylation, resulting in reduced gene expression, can contribute to several human disorders, but little is still known about the factors that regulate MTHFR methylation levels. We performed the present study to investigate if common polymorphisms in one-carbon metabolism genes contribute to MTHFR methylation levels. MTHFR methylation was assessed in peripheral blood DNA samples from 206 healthy subjects with methylation-sensitive high-resolution melting (MS-HRM); genotyping was performed for MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), MTRR 66A>G (rs1801394), MTR 2756A>G (rs1805087), SLC19A1 (RFC1) 80G>A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp ins/del (rs34489327), DNMT3A -448A>G (rs1550117), and DNMT3B -149C>T (rs2424913) polymorphisms. We observed a statistically significant effect of the DNMT3B -149C>T polymorphism on mean MTHFR methylation levels, and particularly CT and TT carriers showed increased methylation levels than CC carriers. The present study revealed an association between a functional polymorphism of DNMT3B and MTHFR methylation levels that could be of relevance in those disorders, such as inborn defects, metabolic disorders and cancer, that have been linked to impaired DNA methylation.

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Section: Discussionmentioning

confidence: 99%

Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

Coppedè

Stoccoro

Tannorella

et al. 2019

IJMS

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“…Genetic association studies have identified SNPs in DNMT3A associated with mild cognitive impairment ( Chouliaras et al, 2015 ), and aged mice show a reduction in the density of DNMT3 positive cells within the hippocampus as assessed by immunohistochemistry ( Chouliaras et al, 2011 ). Where other DNMT family members have been interrogated for their association with Alzheimer’s, DNMT1 did not show any association, while DNMT3B was found to be associated with Alzheimer’s in one study ( Pezzi et al, 2014 ) though not in another ( Coppede et al, 2012 ).…”

Section: Dna Methylation Changes Associated With Alzheimer’s Diseasementioning

confidence: 84%

The Contribution and Therapeutic Potential of Epigenetic Modifications in Alzheimer’s Disease

Wood

2018

Front. Neurosci.

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Alzheimer’s disease is a progressive neurodegenerative disorder, affecting 50 million people worldwide, for which there is no cure, or effective treatment. Individuals suffering from Alzheimer’s show a decline in cognition over time beginning with memory loss and ultimately leading to severe dementia, and inability to care for themselves. The cause of Alzheimer’s is not known but likely involves a combination of genetic, biochemical, and environmental factors. Some genes have been identified as risk factors but monozygotic twins discordant for Alzheimer’s disease suggest other factors must contribute to development of the disease. Investigation on epigenetic marks including DNA methylation and post-translational modifications of histones have shown that the patterns of these modifications change with age in the human population. Though individuals show specific differences in epigenetic marks at the individual gene level, there is a consistent pattern of epigenetic changes at the genome scale across the population. Similar changes have been identified in patients with Alzheimer’s disease, though these occur at an earlier age compared to healthy individuals. The early cognitive impairment in Alzheimer’s disease can be mistaken for premature ageing correlating with the timing of epigenetic changes occurring at a younger age in individuals with Alzheimer’s. Such observations suggest that the epigenetic changes may contribute to disease pathology. Exactly how epigenetic modifications contribute to specific aspects of Alzheimer’s disease is the focus of many researcher groups across the world. A number of drugs are available that inhibit the enzymes that modify chromatin and change the epigenetic landscape of the genome. Therefore, an understanding of the role of chromatin modifications in Alzheimer’s could offer an opportunity for novel therapeutic strategies. Research using animal models of Alzheimer’s suggests that the epigenetic changes in Alzheimer’s disease may have a profound impact on cognition and underlie cognitive impairment while there is no clear evidence that they might contribute directly to neuronal loss.

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“…Interestingly, a recently published case-control study focusing on the association between variants of DNMT1 (rs2162560, rs759920) and DNMT3B (rs998382,rs2424913, rs242932) and AD identified a significant association between a DNMT3B haplotype and AD [8]. Meanwhile, another case-control study did not detect any associations between two DNMT3B polymorphisms and AD [7].…”

Section: Discussionmentioning

confidence: 97%

“…Alterations in DNA methylation have previously been associated with agerelated cognitive decline in rodents and with AD in human postmortem brains [2][3][4], while DNA methylation changes are closely associated with aging [5]. Apart from case-control studies on genetic associations between AD and genetic variants in MTHFR [6], DNMT1, DNMT3B [7,8] and TET1 [9], no studies to date have investigated associations between genetic variation in DNA methylation regulating genes and longitudinal measures of cognitive decline. Given the clinical relevance of early diagnosis, prediction and possibilities for preventive strategies, biomarker discovery studies increasingly focus on longitudinal analyses of high-risk individuals, such as subjects with mild cognitive impairment (MCI) [10].…”

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confidence: 99%

DNMT3A Moderates Cognitive Decline in Subjects with Mild Cognitive Impairment: Replicated Evidence from Two Mild Cognitive Impairment Cohorts

et al. 2015

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Epigenetic dysregulation has been associated with cognitive decline and Alzheimer's disease. The present study investigated associations between common SNPs in genes regulating DNA methylation and age-related changes in cognitive decline in two independent prospective cohorts of patients suffering from mild cognitive impairment. An association between the rs1187120 SNP in DNMT3A and annual decline in cognitive functioning was discovered and replicated, suggesting that DNMT3A moderates cognitive decline in subjects with mild cognitive impairment.

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DNA methyltransferase haplotype is associated with Alzheimer's disease

Cited by 18 publications

References 31 publications

Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

The Contribution and Therapeutic Potential of Epigenetic Modifications in Alzheimer’s Disease

DNMT3A Moderates Cognitive Decline in Subjects with Mild Cognitive Impairment: Replicated Evidence from Two Mild Cognitive Impairment Cohorts

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