1,720,976 research outputs found
Increased MTHFR promoter methylation in mothers of Down syndrome individuals
Full text linkDespite that advanced maternal age at conception represents the major risk factor for the birth of a child with Down syndrome (DS), most of DS babies are born from women aging less than 35 years. Studies performed in peripheral lymphocytes of those women revealed several markers of global genome instability, including an increased frequency of micronuclei, shorter telomeres and impaired global DNA methylation. Furthermore, young mothers of DS individuals (MDS) are at increased risk to develop dementia later in life, suggesting that they might be "biologically older" than mothers of euploid babies of similar age.Mutations in folate pathway genes, and particularly in the methylenetetrahydrofolate reductase (MTHFR) one, have been often associated with maternal risk for a DS birth as well as with risk of dementia in the elderly. Recent studies pointed out that also changes in MTHFR methylation levels can contribute to human disease, but nothing is known about MTHFR methylation in MDS tissues.We investigated MTHFR promoter methylation in DNA extracted from perypheral lymphocytes of 40 MDS and 44 matched control women that coinceived their children before 35 years of age, observing a significantly increased MTHFR promoter methylation in the first group (33.3 ± 8.1% vs. 28.3 ± 5.8%; p = 0.001). In addition, the frequency of micronucleated lymphocytes was available from the women included in the study, was higher in MDS than control mothers (16.1 ± 8.6‰ vs. 10.5 ± 4.3‰ p = 0.0004), and correlated with MTHFR promoter methylation levels (r = 0.33; p = 0.006).Present data suggest that MTHFR epimutations are likely to contribute to the increased genomic instability observed in cells from MDS, and could play a role in the risk of birth of a child with DS as well as in the onset of age related diseases in those women
Artificial Neural Networks Link One-Carbon Metabolism to Gene-Promoter Methylation in Alzheimer's Disease
Full text linkBackground: There is increasing interest in DNA methylation studies in Alzheimer's disease (AD), but little is still known concerning the relationship between gene-promoter methylation and circulating biomarkers of one-carbon metabolism in patients. Objective: To detect the connections among circulating folate, homocysteine (hcy) and vitamin B12 levels and promoter methylation levels of PSEN1, BACE1, DNMT1, DNMT3A, DNMT3B, and MTHFR genes in blood DNA. Methods: We applied a data mining system called Auto Contractive Map to an existing database of 100 AD and 100 control individuals. Results: Low vitamin B12 was linked to the AD condition, to low folates, and to high hcy. Low PSEN1 methylation was linked to low folate levels as well as to low promoter methylation of BACE1 and DNMTs genes. Low hcy was linked to controls, to high folates and vitamin B12, as well as to high methylation levels of most of the studied genes. Conclusions: The present pilot study suggests that promoter methylation levels of the studied genes are linked to circulating levels of folates, hcy, and vitamin B12
Methylation analysis of DNA repair genes in Alzheimer's disease
No full textThere is substantial evidence of impaired DNA repair activities in Alzheimer's disease (AD) neurons and peripheral tissues, inducing some investigators to speculate that this could partially result from promoter hypermethylation of DNA repair genes, resulting in gene silencing in those tissues. In the present study a screening cohort composed by late-onset AD (LOAD) patients and healthy matched controls was evaluated with a commercially available DNA methylation array for the assessment of the methylation levels of a panel of 22 genes involved in major DNA repair pathways in blood DNA. We then applied a cost-effective PCR based methylation-sensitive high-resolution melting (MS-HRM) technique, in order to evaluate the promoter methylation levels of the following DNA repair genes: OGG1, PARP1, MRE11A, BRCA1, MLH1, and MGMT. The analysis was performed in blood DNA from 56 LOAD patients and 55 matched controls, including the samples previously assessed with the DNA methylation array as validating samples. Both approaches revealed that all the investigated genes were largely hypomethylated in LOAD and control blood DNA, and no difference between groups was observed. Collectively, present data do not support an increased promoter methylation of some of the major DNA repair genes in blood DNA of AD patients
DNMT3B promoter polymorphisms and maternal risk of birth of a child with Down syndrome.
No full textSTUDY QUESTION:
Are DNMT3B promoter polymorphisms among maternal risk factors for the birth of a child with Down syndrome (DS)?
SUMMARY ANSWER:
Present results suggest that combinations of functional DNMT3B promoter polymorphisms might modulate maternal risk of birth of a child with DS.
WHAT IS KNOWN ALREADY:
The DNMT3B gene codes for DNA methyltransferase 3b (DNMT3b), a protein required for genome-wide de novo methylation, for the establishment of DNA methylation patterns during development and for regulating the histone code and DNA methylation at centromeric regions. Two common functional DNMT3B promoter polymorphisms, namely -149 C > T (rs2424913) and -579 G > T (rs1569686), have been extensively investigated in cancer genetic association studies but less is known about their role in non-cancer diseases. Early in 1999, it was supposed that impaired DNA methylation of pericentromeric regions might represent a maternal risk factor for having a baby with DS.
STUDY DESIGN, SIZE AND DURATION:
We aimed to investigate DNMT3B -149 C > T and -579 G > T polymorphisms as maternal risk factors for the birth of a child with DS. The study was performed on DNA samples from 172 mothers of DS individuals (135 aged <35 years when they conceived) and 157 age-matched mothers of unaffected individuals.
PARTICIPANTS/MATERIALS, SETTING AND METHODS:
Genotyping was performed by means of the PCR-RFLP technique.
MAIN RESULTS AND THE ROLE OF CHANCE:
The DNMT3B -579T allele [odds ratio (OR) = 0.68; 95% confidence interval (CI) = 0.48-0.94, P = 0.02], the DNMT3B -579 GT genotype (OR = 0.55; 95% CI = 0.35-0.87 , P = 0.01) and the combined DNMT3B -579 GT + TT genotype (OR = 0.55; 95% CI = 0.36-0.86 , P = 0.008) were associated with reduced risk of birth of a child with DS. A joint effect of the two polymorphisms was observed and the combined -579 GT/-149 CC genotype resulted in decreased DS risk (OR = 0.22; 95% CI = 0.08-0.64, P = 0.003). The effect remained statistically significant after Bonferroni's correction for multiple comparisons. Similar results were obtained when the analysis was restricted to women who conceived a DS child before 35 years of age.
LIMITATIONS AND REASONS FOR CAUTION:
To the best of our knowledge, this is the first genetic association study aimed at evaluating DNMT3B polymorphisms as maternal risk factors for DS. Replication of the findings in other populations is required.
WIDER IMPLICATIONS OF THE FINDINGS:
If confirmed in subsequent studies, DNMT3B promoter polymorphisms might be additional markers to be taken into account when evaluating the contribution of one-carbon (folate) metabolism to the maternal risk of birth of a child with D
Association study between the DNMT3A -448A>G polymorphism and risk of Alzheimer's disease in Caucasians of Italian origin
Full text linkIncreasing evidence points to an epigenetic contribution in Alzheimer's disease (AD) pathogenesis. In this regard, variants and polymorphisms of DNA methyltransferase genes (DNMTs) are being investigated for their contribution to cognitive decline and dementia, but results are still scarce or controversial. In the present study we genotyped 710 Caucasian subjects of Italian descent, including 320 late-onset AD (LOAD) patients, 70 individuals with amnestic Mild Cognitive Impairment (MCI), and 320 matched healthy controls, for the presence of a functional DNMT3A -448A>G (rs1550117) polymorphism, searching for association with disease risk. In addition, we searched for correlation between the studied polymorphism and circulating levels of folate, homocysteine (hcy) and vitamin B12, all involved in DNA methylation reactions and available from 189 LOAD patients and 186 matched controls. Both allele and genotype frequencies of rs1550117 were closely similar between MCI, LOAD and control subjects, and no association with dementia or pre-dementia conditions was observed. Plasma hcy levels were significantly higher (p = 0.04) and serum folate levels significantly lower (p = 0.01) in LOAD than in controls, but no difference in circulating folate, hcy or vitamin B12 levels was seen between carriers and non-carriers of the minor DNMT3A -448A allele. Collectively, present results confirmed previous associations of increased hcy and decreased folate with LOAD risk, but do not support an association between the DNMT3A -448A>G polymorphism and AD in our population
A Pilot Study Evaluating the Contribution of SLC19A1 (RFC-1) 80G>A Polymorphism to Alzheimer's Disease in Italian Caucasians
Full text linkAlzheimer's disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. Polymorphisms of genes involved in folate metabolism have been frequently suggested as risk factors for sporadic AD. A common c.80G>A polymorphism (rs1051266) in the gene coding for the reduced folate carrier (SLC19A1 gene, commonly known as RFC-1 gene) was investigated as AD risk factor in Asian populations, yielding conflicting results. We screened a Caucasian population of Italian origin composed of 192 sporadic AD patients and 186 healthy matched controls, for the presence of the RFC-1 c.80G>A polymorphism, and searched for correlation with circulating levels of folate, homocysteine, and vitamin B12. No difference in the distribution of allele and genotype frequencies was observed between AD patients and controls. No correlation was observed among the genotypes generated by the RFC-1 c.80G>A polymorphism and circulating levels of folate, homocysteine, and vitamin B12 either in the whole cohort of subjects or after stratification into clinical subtypes. Present results do not support a role for the RFC-1 c.80G>A polymorphism as independent risk factor for sporadic AD in Italian Caucasians
Folate metabolism, Alzheimer's Disease and Epigenetics
No full textThe possible contribution of folate metabolism in modulating the methylation profile and the expression of disease-related genes has attracted substantial research in the field of complex diseases, such as Alzheimer’s disease (AD), likely resulting from still not well understood gene-environment interactions. Several hypotheses have been formulated linking impaired folate metabolism to AD risk, among them one of the most arguing suggests that it could result in altered DNA methylation and expression of genes involved in disease pathogenesis.
Aim of this project is to understand the correlation between folate metabolism and epigenetic modifications of genes related to AD. For this purpose, we screened 205 late onset Alzheimer’s disease (LOAD) patients, 74 subjects with Mild Cognitive Impairment (MCI) and 175 healthy controls for the presence of the common polymorphisms in folate metabolism gene, searching for association with disease risk. Moreover, we searched for correlation between each of the studied polymorphisms and available data on plasma homocysteine (Hcy), serum folate and vitamin B12 values. Finally, we analyzed analyzed the methylation levels of genes involved in amyloid-beta peptide production (PSEN1 and BACE1), in DNA methylation (DNMT1, DNMT3A and DNMT3B), and in one-carbon metabolism (MTHFR), searching for correlation with age and gender, with biomarkers of one-carbon metabolism.
We observed a significant increase frequency of MTRR 66G allele and MTRR 66GG genotype in AD patients with respect to controls and a significant increase frequency of MTR 2756G allele in MCI subjects. Several interactions between the studied polymorphisms and biochemical biomarkers were observed.
Methylation analysis revealed no difference in mean methylation levels between AD and control groups, but MCI patients showed higher methylation levels with respect the other groups in almost all the studied genes. MTHFR methylation showed an inverse correlation with age. Inverse correlation between plasma homocysteine and MTHFR, DNMT1 and PSEN1 methylation was observed. Positive correlation was observed between serum folate levels and MTHFR methylation
Polimorfismi dei geni della via metabolica dei folati e livelli ematici di folati, omocisteina e vitamina B12 in pazienti affetti da Malattia di Alzheimer
No full textLa Malattia di Alzheimer (MA) è un disordine neurodegenerativo ad esordio tardivo e rappresenta la più comune forma di demenza (circa l’80% dei casi). La MA è caratterizzata clinicamente da una progressiva riduzione di volume a livello dei lobi frontale e temporale, dell’ippocampo e dell’amigdala, come conseguenza della degenerazione delle sinapsi e della morte dei neuroni, la quale porta alla perdita di memoria associata a cambiamenti nel comportamento e nella personalità. Tali regioni sono inoltre caratterizzate dalla presenza di placche amiloidi extracellulari (placche senili) e di grovigli neurofibrillari composti da aggregati intracellulari della proteina tau iperfosforilata. Sebbene le manifestazioni cliniche e le caratteristiche neuropatologiche sono state ben illustrate, l’eziologia della malattia è ancora sconosciuta. Negli anni passati è stato dimostrato che sia fattori genetici che fattori ambientali possono portare allo sviluppo di questa malattia; i dati epidemiologici identificano infatti due tipi di MA: una forma autosomica dominante, che comprende circa il 5-15% dei casi e della quale si conoscono 3 geni deterministici (APP, PSEN1 e PSEN2), e una forma sporadica, la quale mostra una patogenesi complessa e risulta da un’interazione tra fattori genetici, epigenetici, ambientali e stocastici.
Recentemente, vari studi clinici ed epidemiologici hanno posto l’attenzione su una possibile associazione tra la MA e la via metabolica dei folati. È stato infatti dimostrato che individui affetti dalla MA mostrano un decremento dei livelli plasmatici dei folati e un aumento dei livelli di omocisteina sia nel plasma che nel liquor.
I folati derivano interamente dalla dieta e sono nutrienti essenziali per l’organismo in quanto vengono utilizzati come cofattori e come donatori di unità carboniose attivate in vari processi biosintetici, come la sintesi dei nucleotidi e degli amminoacidi. I folati entrano nel nostro organismo sotto forma di una miscela complessa di composti di poliglutammato. Tali composti vengono convertiti nell’intestino ad acido folico, che può essere assorbito dalle cellule con meccanismo di trasporto attivo che coinvolge il carrier dei folati ridotto (RFC); tuttavia tale composto non è biologicamente attivo, per cui esso viene trasformato da una serie di enzimi citoplasmatici in tetraidrofolato (THF), il quale entra a far parte di vari pathway biosintetici.
Lo scopo di questa tesi è quello di valutare una possibile associazione tra polimorfismi dei geni della via metabolica dei folati, quali MTHFR C677T, TYMS ripetizione di 28 bp, MTR A2756G e MTRR A66G, e il rischio di sviluppare la malattia di Alzheimer. In questo studio è stata valutata la frequenza di tali polimorfismi in una popolazione di 378 pazienti e 308 controlli sani mediante la tecnica della PCR-RFLP. Inoltre, in un sottogruppo della popolazione, è stata valutata la correlazione tra ognuno dei polimorfismi oggetto dello studio ed i valori ematici di acido folico, omocisteina e vitamina B12.
Lo studio ha evidenziato un incremento significativo nella frequenza dell’allele MTHFR 677T (0.48 vs. 0.42; p=0.019) e dei genotipi MTHFR 677CT (OR=1,46; 95%CI=1,03-2,06) e MTHFR 677TT (OR=1,62; 95%CI=1,05-2,49), nei soggetti AD rispetto ai controlli. È stato inoltre osservato un aumento significativo della frequenza dell’allele MTRR 66G (0.49 vs. 0.43; p=0.044) e del genotipo MTRR 66GG (OR=1,57; 95%CI=1,01-2,46) nel gruppo dei pazienti.
I soggetti AD presentano, rispetto ai controlli, un aumento dei livelli plamastici di omocisteina (22.7+15.3 vs 14.5+5.7 μmol/L; p=0.037) e una diminuzione dei livelli di folati (5.7+4.9 vs. 7.8+7.2 ng/mL; p=0.005). È inoltre emerso che esistono varie interazioni tra questi marker biochimici e i polimorfismi presi in esame
Germline variants in genes of the subcortical maternal complex and Multilocus Imprinting Disturbance are associated with miscarriage/infertility or Beckwith-Wiedemann progeny
No full textBeckwith-Wiedemann syndrome (BWS, OMIM # 130650) is an imprinting disorder, associated with overgrowth and increased risk of embryonal tumors. Patients carrying hypomethylation in the KCNQ1OT1:TSS DMR (11p15.5) show MLID (Multilocus Imprinting Disturbance) upon epimutations at other imprinted regions. Few cases of BWS MLID's mothers with biallelic pathogenetic variants in maternal effect genes, mainly components of the subcortical maternal complex, are reported. We describe two families, one with a history of conception difficulties with a novel homozygous nonsense NLRP2 variant and another experiencing 8 miscarriages with a compound heterozygous PADI6 variant
Methylation analysis of multiple genes in blood DNA of Alzheimer's disease and healthy individuals
No full textWe collected blood DNA from 120 late-onset Alzheimer's disease (AD) patients and 115 healthy matched controls and analysed the methylation levels of genes involved in amyloid-beta peptide production (PSEN1 and BACE1), in DNA methylation (DNMT1, DNMT3A and DNMT3B), and in one-carbon metabolism (MTHFR), searching for correlation with age and gender, with biomarkers of one-carbon metabolism (plasma homocysteine, and serum folate and vitamin B12 levels), and with disease status (being healthy or having AD). We also evaluated the contribution of the APOE ε4 allele, the major late-onset AD genetic risk factor, to the studied gene methylation levels. All the genes showed low mean methylation levels (<5%) in both AD and control DNA, no difference between groups, and no correlation with the studied biomarkers, except for MTHFR that showed methylation levels ranging from 5% to 75%, and correlation with circulating biomarkers of one-carbon metabolism. However, mean MTHFR methylation levels were similar between groups (31.1% in AD and 30.7% in controls, P=0.58). Overall, present data suggest that none of the studied regions is differently methylated in blood DNA between AD and control subjects
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