Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging

Troina, Italy

Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging

Troina, Italy
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Stoccoro A.,University of Pisa | Stoccoro A.,University of Siena | Tannorella P.,University of Pisa | Salluzzo M.G.,Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging | And 6 more authors.
Journal of Alzheimer's Disease | Year: 2017

Background: A functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, namely C677T (rs1801133), results in increased Hcy levels and has been associated with risk of late-onset Alzheimer's disease (LOAD). Many investigators reported association between rs1801133 and LOAD risk in Asian populations and in carriers of the apolipoprotein E (APOE) ϵ4 allele, but recent meta-analyses suggest a contribution also in other populations, including Caucasians and/or northern Africans. Objective: To further address this issue, we performed a relatively large case-control study, including 581 LOAD patients and 468 matched controls of Italian origin. APOE data were available for a subgroup of almost 600 subjects. Methods: Genotyping for rs1801133 was performed with PCR-RFLP techniques. Results: In the total population, the MTHFR 677T allele (OR=1.20; 95 CI=1.01-1.43) and carriers of the MTHFR 677T allele (CTTT versus CC: OR=1.34; 95 CI=1.03-1.73) resulted in increased LOAD risk. Similarly, in APOE ϵ4 carriers, we observed an increased frequency of MTHFR 677CT carriers (CT versus CC: OR=2.82; 95 CI=1.25-6.32). Very interestingly, also in non-APOE ϵ4 carriers, both MTHFR 677T allele (OR=1.38; 95 CI=1.03-1.85) and MTHFR 677TT genotype (OR=2.08; 95 CI=1.11-3.90) were associated with LOAD. All these associations survived after corrections for age, gender, and multiple testing. Conclusions: The present results suggest that the MTHFR C677T polymorphism is likely a LOAD risk factor in our cohort, either in APOE ϵ4 or in non-APOE ϵ4 carriers.


Coppede F.,University of Pisa | Bosco P.,Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging | Lorenzoni V.,Sant'Anna School of Advanced Studies | Migheli F.,University of Pisa | And 5 more authors.
Molecular Biology Reports | Year: 2013

Methionine synthase (MTR) is required for the conversion of homocysteine (hcy) to methionine in the one-carbon metabolic pathway. Previous studies investigating a common MTR 2756A>G polymorphism as a maternal risk factor for the birth of a child with Down syndrome (DS) are conflicting and limited by small case-control cohorts, and its contribution to circulating hcy levels is still debated. We performed a large case-control study and a meta-analysis of the literature to further address the role of MTR 2756A>G as a maternal risk factor for the birth of a child with DS. 286 mothers of a DS child (MDS) and 305 control mothers of Italian origin were included in the case-control study. Genotyping was performed by means of PCR/RFLP technique. Data on circulating levels of hcy, folates, and vitamin B12 were available for 189 MDS and 194 control mothers. The meta analysis of previous and present data involved a total of 8 studies (1,171 MDS and 1,402 control mothers). Both the case-control study and the meta-analysis showed no association of MTR 2756A>G with the maternal risk of birth of a child with DS (OR = 1.15; 95 % CI 0.85-1.55, and OR = 1.08; 95 % CI 0.93-1.25, respectively), even after stratification of the overall data available for the meta-analysis into ethnic groups. No association of the studied polymorphism with circulating levels of hcy, folates, and vitamin B12 was observed. Present data do not support a role for MTR 2756A>G as independent maternal risk factor for a DS birth. © 2013 Springer Science+Business Media Dordrecht.


Coppede F.,University of Pisa | Bosco P.,Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging | Lorenzoni V.,Sant'Anna School of Advanced Studies | Denaro M.,University of Pisa | And 6 more authors.
Molecular Biology Reports | Year: 2014

We performed a large case-control study and a meta-analysis of the literature to address the role of the methionine synthase reductase (MTRR) c.66A>G polymorphism as a maternal risk factor for the birth of a child with Down Syndrome (DS) among Caucasian women. A total of 253 mothers of a DS child (MDS) and 298 control mothers of Italian origin were included in the case-control study. The meta-analysis of previous and present data involved a total of seven studies performed in Caucasian populations (971 MDS and 1,387 control mothers). Results from the meta-analysis indicated overall a positive significant association between MTRR c.66A>G genotype [OR 1.36 (95 % CI 1.10-1.68), dominant model] and allele frequencies [OR 1.26 (95 % CI 1.04-1.51), allele contrast model] and maternal risk of birth of a child with DS. A sensitivity analysis revealed some interesting differences between Europeans, Caucasians of European descent, and inhabitants of Mediterranean regions, suggesting the possibility of population-specific modifying factors. The case-control study revealed association of the polymorphism with increased folate levels, and a possible interaction with the methionine synthase (MTR) c.2756A>G one, that resulted in a borderline significant maternal risk of birth of a child with DS for the double heterozygous MTR 2756AG/MTRR 66AG genotype [OR 1.79 (95 % CI 1.00-3.18)]. Overall, present data suggest that the MTRR c.66A>G polymorphism represents a risk factor for the birth of a child with DS among white Caucasian women. However, the combined presence of other genetic factors and interactions with geographic and environmental ones, can modify the effect of the single polymorphism alone, leading to population specific effect sizes. © 2014 Springer Science+Business Media.


Coppede F.,University of Pisa | Bosco P.,Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging | Tannorella P.,University of Pisa | Romano C.,Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging | And 3 more authors.
Human Reproduction | Year: 2013

Study Question Are DNMT3B promoter polymorphisms among maternal risk factors for the birth of a child with Down syndrome (DS)?SUMMARY ANSWERPresent results suggest that combinations of functional DNMT3B promoter polymorphisms might modulate maternal risk of birth of a child with DS.WHAT IS KNOWN ALREADYThe 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 DURATIONWe 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 Method SGenotyping 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 CautionTo 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 FindingsIf 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 DS. Study Funding/Competing Interest (S)None of the authors has any competing interest. This work was partially supported by the Italian Ministry of Health and '5 per mille' funding. © 2012 The Author.


Tannorella P.,University of Pisa | Stoccoro A.,University of Pisa | Tognoni G.,University of Pisa | Petrozzi L.,University of Pisa | And 8 more authors.
Neuroscience Letters | Year: 2015

We 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. © 2015 Elsevier Ireland Ltd.


PubMed | University of Vienna, University of Pisa and Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging
Type: | Journal: Neuroscience letters | Year: 2015

We collected blood DNA from 120 late-onset Alzheimers 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 4 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.


Malaguarnera G.,University of Catania | Gagliano C.,University of Catania | Giordano M.,University of Catania | Salomone S.,University of Catania | And 8 more authors.
BioMed Research International | Year: 2014

Homocysteine has been associated with extracellular matrix changes. The diabetic retinopathy is a neurovascular complication of diabetes mellitus and it is the leading cause of vision loss among working adults worldwide. In this study, we evaluate the role of homocysteine in diabetic retinopathy analyzing the plasma levels of homocysteine in 63 diabetic type 2 patients with nonproliferative retinopathy (NPDR), 62 patients with proliferative diabetic retinopathy (PDR), 50 healthy subjects used as control group, and 75 randomly selected patients. © 2014 Giulia Malaguarnera et al.

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