DNMT3A rs1550117 Polymorphism is Associated With Late-Onset Alzheimer’s Disease in a Chinese Population

Chen, Ling; Dai, Fangyu; Hu, Wanhua; Chen, Kelong; Wu, Zhimin; Zhang, Yuting; Zhou, Rong

doi:10.1177/1533317515603688

Cited by 7 publications

(3 citation statements)

References 37 publications

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“…Treatment modalities using various HDAC inhibitors, which can enhance synaptic plasticity, learning and memory, have emerged as potential new strategies for therapeutic intervention in neurodegenerative diseases, including AD, Huntington’s disease, and Parkinson’s disease (Konsoula and Barile, 2012). Analysis of polymorphisms of DNMT3A and DNMT3B support a major role for these loci in the pathogenesis of late-onset AD and these polymorphisms can be used as stratification markers to predict an individual’s susceptibility to late-onset AD (Coppedè et al, 2012; Ling et al, 2016). The immunohistochemistry results reported here demonstrate that the Histone H3 DNA methyltransferases, DNMT3A and DNMT3B, were up-regulated in response to treatment with alcohol extracts from G. lucidum (Figure 7), indicating that G. lucidum can influence these DNA methyltransferases to regulate the DNA methylation, and that this may be an important signaling pathway influenced by G. lucidum in delaying the progress of AD and/or aging.…”

Section: Discussionmentioning

confidence: 99%

Alcohol Extracts From Ganoderma lucidum Delay the Progress of Alzheimer’s Disease by Regulating DNA Methylation in Rodents

Lai

Guo²,

Chen³

et al. 2019

Front. Pharmacol.

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Age-related changes in methylation are involved in the occurrence and development of tumors, autoimmune disease, and nervous system disorders, including Alzheimer’s disease (AD), in elderly individuals; hence, modulation of these methylation changes may be an effective strategy to delay the progression of AD pathology. In this study, the AD model rats were used to screen the main active extracts from the mushroom, Ganoderma lucidum , for anti-aging properties, and their effects on DNA methylation were evaluated. The results of evaluation of rats treated with 100 mg/kg/day of D -galactose to induce accelerated aging showed that alcohol extracts of G. lucidum contained the main active anti-aging extract. The effects on DNA methylation of these G. lucidum extracts were then evaluated using SAMP8 and APP/PS1 AD model mice by whole genome bisulfite sequencing, and some methylation regulators including Histone H3, DNMT3A, and DNMT3B in brain tissues were up-regulated after treatment with alcohol extracts from G. lucidum . Molecular docking analysis was carried out to screen for molecules regulated by specific components, including ganoderic acid Mk, ganoderic acid C6, and lucidone A, which may be active ingredients of G. lucidum , including the methylation regulators of Histone H3, MYT, DNMT3A, and DNMT3B. Auxiliary tests also demonstrated that G. lucidum alcohol extracts could improve learning and memory function, ameliorate neuronal apoptosis and brain atrophy, and down-regulate the expression of the AD intracellular marker, Aβ 1-42 . We concluded that alcohol extracts from G. lucidum , including ganoderic acid and lucidone A, are the main extracts involved in delaying AD progression.

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Section: Discussionmentioning

confidence: 99%

Alcohol Extracts From Ganoderma lucidum Delay the Progress of Alzheimer’s Disease by Regulating DNA Methylation in Rodents

Lai

Guo²,

Chen³

et al. 2019

Front. Pharmacol.

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“…Polymorphism rs1550117 of DNMT3A has been shown in association with the late-onset Alzheimer's disease. Specifically, patients with an AA genotype showed a 2.08-fold risk when compared to patients with a GG genotype (Ling et al, 2016). When investigating the imprinting disorder Beckwith-Wiedemann syndrome, Dagar and colleagues screened variants within the DNMT1 coding region and identified three patients (out of 53 examined) who contained three rare missense variants: rs138841970: C>T, rs150331990: A>G, and rs757460628: G>A; encoding NP_001124295 p.Arg136Cys, p.His1118Arg, and p.Arg1223His, respectively (Dagar et al, 2018).…”

Section: Interactions Of Genetic Variants and Epigenetic Patterns Formentioning

confidence: 99%

Crosstalk of Genetic Variants, Allele-Specific DNA Methylation, and Environmental Factors for Complex Disease Risk

2019

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Over the past decades, genome-wide association studies (GWAS) have identified thousands of phenotype-associated DNA sequence variants for potential explanations of inter-individual phenotypic differences and disease susceptibility. However, it remains a challenge for translating the associations into causative mechanisms for complex diseases, partially due to the involved variants in the noncoding regions and the inconvenience of functional studies in human population samples. So far, accumulating evidence has suggested a complex crosstalk among genetic variants, allele-specific binding of transcription factors (ABTF), and allele-specific DNA methylation patterns (ASM), as well as environmental factors for disease risk. This review aims to summarize the current studies regarding the interactions of the aforementioned factors with a focus on epigenetic insights. We present two scenarios of single nucleotide polymorphisms (SNPs) in coding regions and non-coding regions for disease risk, via potentially impacting epigenetic patterns. While a SNP in a coding region may confer disease risk via altering protein functions, a SNP in non-coding region may cause diseases, via SNP-altering ABTF, ASM, and allele-specific gene expression (ASE). The allelic increases or decreases of gene expression are key for disease risk during development. Such ASE can be achieved via either a “SNP-introduced ABTF to ASM” or a “SNP-introduced ASM to ABTF.” Together with our additional in-depth review on insulator CTCF, we are convinced to propose a working model that the small effect of a SNP acts through altered ABTF and/or ASM, for ASE and eventual disease outcome (named as a “SNP intensifier” model). In summary, the significance of complex crosstalk among genetic factors, epigenetic patterns, and environmental factors requires further investigations for disease susceptibility.

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“…DNA methyltransferase 3 alpha is thought to function in de novo methylation and has been shown to be necessary and sufficient to mediate IR in mouse and human adipocytes [ 71 ]. Associations of DNMT3A genetic mutations with cognitive decline and late-onset AD risk have also been reported [ 72 , 73 ].…”

Section: Discussionmentioning

confidence: 99%

Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus

Sarnowski,

Huan,

et al. 2023

Clin Epigenet

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Background Insulin resistance (IR) is a major risk factor for Alzheimer’s disease (AD) dementia. The mechanisms by which IR predisposes to AD are not well-understood. Epigenetic studies may help identify molecular signatures of IR associated with AD, thus improving our understanding of the biological and regulatory mechanisms linking IR and AD. Methods We conducted an epigenome-wide association study of IR, quantified using the homeostatic model assessment of IR (HOMA-IR) and adjusted for body mass index, in 3,167 participants from the Framingham Heart Study (FHS) without type 2 diabetes at the time of blood draw used for methylation measurement. We identified DNA methylation markers associated with IR at the genome-wide level accounting for multiple testing (P < 1.1 × 10−7) and evaluated their association with neurological traits in participants from the FHS (N = 3040) and the Religious Orders Study/Memory and Aging Project (ROSMAP, N = 707). DNA methylation profiles were measured in blood (FHS) or dorsolateral prefrontal cortex (ROSMAP) using the Illumina HumanMethylation450 BeadChip. Linear regressions (ROSMAP) or mixed-effects models accounting for familial relatedness (FHS) adjusted for age, sex, cohort, self-reported race, batch, and cell type proportions were used to assess associations between DNA methylation and neurological traits accounting for multiple testing. Results We confirmed the strong association of blood DNA methylation with IR at three loci (cg17901584–DHCR24, cg17058475–CPT1A, cg00574958–CPT1A, and cg06500161–ABCG1). In FHS, higher levels of blood DNA methylation at cg00574958 and cg17058475 were both associated with lower IR (P = 2.4 × 10−11 and P = 9.0 × 10–8), larger total brain volumes (P = 0.03 and P = 9.7 × 10−4), and smaller log lateral ventricular volumes (P = 0.07 and P = 0.03). In ROSMAP, higher levels of brain DNA methylation at the same two CPT1A markers were associated with greater risk of cognitive impairment (P = 0.005 and P = 0.02) and higher AD-related indices (CERAD score: P = 5 × 10−4 and 0.001; Braak stage: P = 0.004 and P = 0.01). Conclusions Our results suggest potentially distinct epigenetic regulatory mechanisms between peripheral blood and dorsolateral prefrontal cortex tissues underlying IR and AD at CPT1A locus.

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DNMT3A rs1550117 Polymorphism is Associated With Late-Onset Alzheimer’s Disease in a Chinese Population

Cited by 7 publications

References 37 publications

Alcohol Extracts From Ganoderma lucidum Delay the Progress of Alzheimer’s Disease by Regulating DNA Methylation in Rodents

Alcohol Extracts From Ganoderma lucidum Delay the Progress of Alzheimer’s Disease by Regulating DNA Methylation in Rodents

Crosstalk of Genetic Variants, Allele-Specific DNA Methylation, and Environmental Factors for Complex Disease Risk

Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus

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