DNMT3B Promoter Polymorphisms and Risk of Late Onset Alzheimer’s Disease

Abstract

The vast majority of Alzheimer's disease (AD) are late-onset forms (LOAD) likely due to the contribution of genetic, environmental, and stochastic factors, superimposed on a physiologically age-related decline of neuronal functions. Increasing evidence indicates epigenetic modifications in LOAD brains, and many of the environmental factors associated with AD risk, such as heavy metals and dietary factors, are able to modify the epigenome. There is also indication that environmentally-induced early life modifications of the genome during embryogenesis and brain development could contribute to the development of the disease later in life. DNA methyltransferase 3b (DNMT3b) is an enzyme involved in de novo methylation of the genome during embryogenesis, expressed in progenitor cells during neurogenesis. In the present study we evaluated two functional DNMT3B promoter polymorphisms, namely -149 C > T (rs2424913) and - 579 G > T (rs1569686), as candidate LOAD risk factors. Our analysis of 376 Italian LOAD patients and 308 matched controls revealed no difference in allele frequencies between the case an the control group (OR = 1.10 (0.88-1.39) for rs2424913, and OR = 1.02 (0.81-1.28) for rs1569686). Also the genotype distributions of both polymorphisms were closely similar between groups, and no significant effect on disease age at onset was observed. Overall, present results do not support a major role for rs2424913 or rs1569686 in LOAD pathogenesis.

Editorial (Epigenetics: A Paradigm Shift in Understanding Alzheimer’s Disease)

“…Therefore, in considering epigenetics as a potential mechanism that could contribute to AD pathogenesis late in life, the most conservative view would be to look only early in life to identify the perturbations to the gene expression program that may have occurred during brain development. This hypothesis could be supported by the findings reported in this special issue by Coppedè regarding DNMT3B promoter polymorphisms as a risk factor for AD [1]. Fundamental differences in DNA methylation could be due to such variations in DNA methylase gene regulation.…”

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

“…91 Two DNMT3B promoter polymorphisms (rs2424913 and rs1569686) were also studied as candidate risk factors for late-onset AD, though no significant effect on disease age of onset was found for either one. 92 Not all cases of abnormal methylation in disease are hypermethylation, however. For example, promoter-specific demethylation has been found in patients with PD.…”

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

“…Meanwhile, another case-control study did not detect any associations between two DNMT3B polymorphisms and AD [7]. Our study included two of the polymorphisms tested in the aforementioned studies (namely DNMT3B rs2424913 and rs242932) and did not find any replicated associations between DNMT3B variants and cognitive decline in the MCI cohorts.…”

“…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].…”