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1.
Int J Mol Sci ; 25(12)2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38928049

RESUMEN

The current hypothesis on the pathophysiology of multiple sclerosis (MS) suggests the involvement of both inflammatory and neurodegenerative mechanisms. Disease Modifying Therapies (DMTs) effectively decrease relapse rates, thus reducing relapse-associated disability in people with MS. In some patients, disability progression, however, is not solely linked to new lesions and clinical relapses but can manifest independently. Progression Independent of Relapse Activity (PIRA) significantly contributes to long-term disability, stressing the urge to unveil biomarkers to forecast disease progression. Twenty-five adult patients with relapsing-remitting multiple sclerosis (RRMS) were enrolled in a cohort study, according to the latest McDonald criteria, and tested before and after high-efficacy Disease Modifying Therapies (DMTs) (6-24 months). Through Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells. Multivariate logistic and linear models with interactions were generated. Robustness was assessed by randomization tests in R. A subset of miRNAs, correlated with PIRA, and the Expanded Disability Status Scale (EDSS), was selected. To refine the patient stratification connected to the disease trajectory, we computed a robust logistic classification model derived from baseline miRNA expression to predict PIRA status (AUC = 0.971). We built an optimal multilinear model by selecting four other miRNA predictors to describe EDSS changes compared to baseline. Multivariate modeling offers a promising avenue to uncover potential biomarkers essential for accurate prediction of disability progression in early MS stages. These models can provide valuable insights into developing personalized and effective treatment strategies.


Asunto(s)
Progresión de la Enfermedad , MicroARNs , Esclerosis Múltiple Recurrente-Remitente , Humanos , MicroARNs/genética , Masculino , Femenino , Adulto , Esclerosis Múltiple Recurrente-Remitente/genética , Persona de Mediana Edad , Biomarcadores , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Leucocitos Mononucleares/metabolismo , Estudios de Cohortes , Recurrencia , Perfilación de la Expresión Génica/métodos
2.
Front Immunol ; 14: 1234869, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38152407

RESUMEN

Background and objectives: Multiple sclerosis (MS) is a chronic, progressive neurological disease characterized by early-stage neuroinflammation, neurodegeneration, and demyelination that involves a spectrum of heterogeneous clinical manifestations in terms of disease course and response to therapy. Even though several disease-modifying therapies (DMTs) are available to prevent MS-related brain damage-acting on the peripheral immune system with an indirect effect on MS lesions-individualizing therapy according to disease characteristics and prognostic factors is still an unmet need. Given that deregulated miRNAs have been proposed as diagnostic tools in neurodegenerative/neuroinflammatory diseases such as MS, we aimed to explore miRNA profiles as potential classifiers of the relapsing-remitting MS (RRMS) patients' prospects to gain a more effective DMT choice and achieve a preferential drug response. Methods: A total of 25 adult patients with RRMS were enrolled in a cohort study, according to the latest McDonald criteria before (pre-cladribine, pre-CLA; pre-ocrelizumab, pre-OCRE, time T0) and after high-efficacy DMTs, time T1, 6 months post-CLA (n = 10, 7 F and 3 M, age 39.0 ± 7.5) or post-OCRE (n = 15, 10 F and 5 M, age 40.5 ± 10.4) treatment. A total of 15 age- and sex-matched healthy control subjects (9 F and 6 M, age 36.3 ± 3.0) were also selected. By using Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells (PBMC). miRNA-target networks were obtained by miRTargetLink, and Pearson's correlation served to estimate the association between miRNAs and outcome clinical features. Results: First, the miRNA profiles of pre-CLA or pre-OCRE RRMS patients compared to healthy controls identified modulated miRNA patterns (40 and seven miRNAs, respectively). A direct comparison of the two pre-treatment groups at T0 and T1 revealed more pro-inflammatory patterns in the pre-CLA miRNA profiles. Moreover, both DMTs emerged as being capable of reverting some dysregulated miRNAs toward a protective phenotype. Both drug-dependent miRNA profiles and specific miRNAs, such as miR-199a-3p, miR-29b-3p, and miR-151a-3p, emerged as potentially involved in these drug-induced mechanisms. This enabled the selection of miRNAs correlated to clinical features and the related miRNA-mRNA network. Discussion: These data support the hypothesis of specific deregulated miRNAs as putative biomarkers in RRMS patients' stratification and DMT drug response.


Asunto(s)
MicroARNs , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Adulto , Humanos , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/genética , Cladribina , Esclerosis Múltiple/tratamiento farmacológico , Leucocitos Mononucleares , Estudios de Cohortes
3.
Biomedicines ; 11(9)2023 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-37760987

RESUMEN

Epigenetic modifications, such as changes in DNA methylation, have been linked to several diseases in recent years. The purpose of our study was to search for biomarkers that (using non-invasive techniques) could assist the clinician in the prognosis of infant/adolescent psychopathology. We previously showed that changes in methylation of the 5'-UTR in the DAT1/SLC6A3 gene can be used as a biomarker for the prognosis of initial severe ADHD: treatment-resistant severe ADHD children were characterized by methylated CpG 1 in particular, while methylated CpGs 2 and 6 were then found in children who improved after the therapy. Further, we confirmed these outcomes and provided the hypothesis that symptomatology might be influenced by the children's genotype and family environment. In particular, levels of CpG 3 methylation in the heterozygous ADHD children were associated with high paternal own risk or stress. Eventually, we found that the same biomarkers are more broadly useful in the field of internalizing or externalizing symptoms (when a certain vulnerability is already present in the child). In particular, it was seen how inheriting specific 9-repeat or 10-repeat VNTR alleles from the mother or from the father could modify the pattern of methylation at the 5'-UTR of the DAT1 gene. A specific pattern of methylations (with CpG 2 following either CpGs 1 + 3 or CpG 6 at the DAT1 5'-UTR) has been associated, therefore, with the likelihood of an internalizing or externalizing developmental trajectory entailing ADHD-like psycho-pathological characteristics. Since each individual responds differently to a specific treatment, we suggest that these methylation patterns may be used as biomarkers to monitor the outcome and/or predict the success of a given therapy (personalized medicine).

4.
Children (Basel) ; 10(3)2023 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-36980142

RESUMEN

Attention-deficit/hyperactivity disorder (ADHD), a neuropsychiatric condition characterized by inattention, hyperactivity, and impulsivity, afflicts 5% of children worldwide. Each ADHD patient presents with individual cognitive and motivational peculiarities. Furthermore, choice of appropriate therapy is still up to clinicians, who express somewhat qualitative advice on whether a child is being successfully cured or not: it would be more appropriate to use an objective biomarker to indicate whether a treatment led to benefits or not. The aim of our work is to search for such clinical biomarkers. We recruited 60 ADHD kids; psychopathological scales were administered at recruitment and after six weeks of therapy. Out of such a cohort of ADHD children, we rigorously extracted two specific subgroups; regardless of the initial severity of their disease, we compared those who obtained the largest improvement (ΔCGAS > 5) vs. those who were still characterized by a severe condition (CGAS < 40). After such a therapy, methylation levels of DNA extracted from buccal swabs were measured in the 5'-UTR of the DAT1 gene. CpGs 3 and 5 displayed, in relation to the other CpGs, a particular symmetrical pattern; for "improving" ADHD children, they were methylated together with CpG 2 and CpG 6; instead, for "severe" ADHD children, they accompanied a methylated CpG 1. These specific patterns of methylation could be used as objective molecular biomarkers of successful cures, establishing if a certain therapy is akin to a given patient (personalized medicine). Present data support the use of post-therapy molecular data obtained with non-invasive techniques.

5.
Genes (Basel) ; 14(1)2023 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-36672931

RESUMEN

A working hypothesis issues from patterns of methylation in the 5'-UTR of the DAT1 gene. We considered relationships between pairs of CpGs, of which one on the main-gene strand and another on the complementary opposite strand (COS). We elaborated on data from ADHD children: we calculated all possible combinations of probabilities (estimated by multiplying two raw values of methylation) in pairs of CpGs from either strand. We analyzed all correlations between any given pair and all other pairs. For pairs correlating with M6-M6COS, some pairs had cytosines positioning to the reciprocal right (e.g., M3-M2COS and M6-M5COS), other pairs had cytosines positioning to the reciprocal left (e.g., M2-M3COS; M5-M6COS). Significant pair-to-pair correlations emerged between main-strand and COS CpG pairs. Through graphic representations, we hypothesized that DNA folded to looping conformations: the C1GG C2GG C3GG and C5G C6G motifs would become close enough to allow cytosines 1-2-3 to interact with cytosines 5-6 (on both strands). Data further suggest a sliding, with left- and right-ward oscillations of DNA strands. While thorough empirical verification is needed, we hypothesize simultaneous methylation of main-strand and COS DNA ("methylation dynamics") to serve as a promising biomarker.


Asunto(s)
Metilación de ADN , ADN , Niño , Humanos , ADN/metabolismo
6.
Neurosci Lett ; 791: 136916, 2022 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-36252849

RESUMEN

Psychopathological symptoms such as depression/anxiety vs attention or aggression problems, in children, have been associated to altered expression of the DAT1/SLC6A3 gene. Inheriting specific 9- or 10-repeat VNTR alleles could modify the pattern of methylation in the CpGs islands at the 5'-UTR of the DAT1 gene. Through accurate recruitment at primary schools, we ended up with four subgroups of children: 9/9 and 10/10 homozygous; 9/10 heterozygous born from 9/10 mothers and 10/10 fathers (called heM); 9/10 heterozygous born from 10/10 mothers and 9/10 fathers (called heF). (Epi)genetical changes were found to be in relation to internalizing and externalizing symptoms: compared to other genotypes, our 9/9 children exhibited mainly internalizing symptoms, while 10/10 genotype was previously associated with ADHD severity. We found that 10/10 children bear 5'-UTR motifs showing a CpGs 1-2-3-5 unity with anticorrelated CpG 6, while 9/9 children showed rather a demethylated CpG 1 linked to demethylated CpG 6. We found two different patterns between heMs and heFs: a feature of heM children is in CpGs 1-3 methylated pattern with CpGs 2, 5 and 6 demethylated together, supporting a "split" unitary destiny. Within the heF children, the status for CpGs 3 + 6 remained opposite, yet pattern of (de)methylation was not well defined. The prevailing one between inherited parental alleles may somewhat influence the motif destiny of heterozigous children. Present work aimed to identify novel epigenetic biomarkers, to be exploited as fairly indicators of children's psychopathological vulnerability.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Trastornos Mentales , Masculino , Humanos , Alelos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Regiones no Traducidas 5'/genética , Padre , Genotipo , Fenotipo , Trastornos Mentales/genética , Trastorno por Déficit de Atención con Hiperactividad/genética
7.
Eat Weight Disord ; 27(7): 2605-2616, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35508584

RESUMEN

PURPOSE: Eating disturbances are complex heritable conditions that can be influenced by both genetic and environmental factors but are poorly studied in early development. The aim of this research was to investigate the association of genetic polymorphisms within dopaminergic pathways with early feeding problems. METHODS: We analyzed the presence of VNTR polymorphisms of DRD4 (rs1805186) and DAT1 (rs28363170) in overeating (N = 45), undereating (N = 48) and control (N = 44) young children. We also assessed presence of externalizing, internalizing and dysregulation symptoms by the Child Behavior Checklist and quality of mother-child interactions during feeding by the Italian adaptation of the Scale for the Assessment of Feeding Interaction, respectively. RESULTS: Both polymorphisms were associated with children's eating behavior, psychological symptoms and quality of interaction with their mothers, suggesting that: (a) the DRD4 4-repeat allele behaves as a protective factor, the 2-repeats and 7-repeats alleles as risk factors, for undereating behavior, the general quality of mother-child interaction and internalizing, externalizing and dysregulated symptoms; and (b) the DAT1 9-repeats allele behaves as a protective factor, the 10-repeats allele as a risk factor, for overeating behavior, the general quality of mother-child interaction, internalizing, externalizing and dysregulated symptoms. Finally, a gene x gene interaction is suggested between the DAT1 9-repeat or 10-repeat allele and the DRD4 4-repeat allele. CONCLUSIONS: Our results suggest a role for DRD4 and DAT1 in an early susceptibility to eating disturbances. LEVEL OF EVIDENCE III: Evidence obtained from well-designed case-control analytic study.


Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Trastornos de Alimentación y de la Ingestión de Alimentos , Receptores de Dopamina D4 , Alelos , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Hiperfagia , Relaciones Madre-Hijo , Polimorfismo Genético , Receptores de Dopamina D4/genética
8.
Behav Brain Res ; 406: 113246, 2021 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-33745985

RESUMEN

Accumulating research addressed epigenetic modifications and their role on behavioral phenotypes. We recently proposed to study methylation dynamics of two CpG motifs within the 5'-UTR of dopamine transporter (DAT) gene. Starting from a normative population sample of young adults, we selected three sub-groups based on their prevalent symptoms: subjects were assigned to Internalizing, Externalizing and Low-risk sub-groups according to elevated scores in specific phenotypic scales. Using a new approach, we calculated three independent matrixes of cross-correlation between CpG methylation levels, one within each phenotypic sub-group, to determine in which dynamics did the sub-groups differ. We found specific cross-correlation patterns in Externalizing (CpG1, 2 and 3, opposite to the methylation at CpG6) and Internalizing individuals (CpG1 methylation opposite to CpG2, 3 and 6), while Low-risk individuals could follow both trends. The aim of our study was to look for a specific DAT methylation pattern, providing a biomarker that allows early identification of the risk for psycho-pathological deviance.


Asunto(s)
Síntomas Conductuales/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Epigénesis Genética/genética , Adulto , Islas de CpG , Metilación de ADN/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Regiones Promotoras Genéticas/genética , Riesgo , Adulto Joven
9.
JMIR Ment Health ; 7(12): e17341, 2020 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-33361057

RESUMEN

BACKGROUND: International research has emphasized that youths are at higher risk for the onset of internet addiction (IA), but studies investigating biological, psychological, and social factors associated with this condition are limited. OBJECTIVE: This study aims to investigate the possible association between IA and genetic polymorphisms in monoamine oxidase A (MAO-A), serotonin-transporter (5-HTTPR), dopamine receptor (DRD4), and dopamine transporter (DAT1) genes by considering the role played by the perception of young adults in their family functioning and their depression, anxiety, and avoidant personality problems. METHODS: In a sample of 104 male and female young adults aged between 19 and 23 years (mean age 21.87, SD 2.29 years) recruited from universities in the central southern part of Italy, we addressed the presence of IA using the Young criteria of the IA test. Moreover, the perception of young adults of their family functioning and their psychopathological symptoms were assessed through the Family Assessment Device (FAD) and the Adult Self-Report, respectively. RESULTS: We found no significant association between IA and any genetic polymorphisms, neither among males or females. Young adults with IA reported significantly higher scores in the subscale of FAD affective responsiveness (AR; P=.01) and in depressive problems (P=.02), anxiety problems (P=.009), and avoidant personality problems (P=.003) than those in the control group. Results of mediation analyses showed a mediation role played by depressive symptoms (B=0.99; 95% CI 0.22 to 1.97) and avoidant personality problems (B=1.09; 95% CI 0.32 to 2.05) of young adults on the relationship between the FAD, AR, and IA. Finally, this relationship was moderated by the genotype of the 5-HTTLPR (P<.001), DAT1 (P<.001), and MAO-A (P<.001) genes in young adults. CONCLUSIONS: This exploratory study supports the recent evidence on the mutual relationship among biological, individual, and social risk factors associated with IA in young adulthood. Our findings may have important clinical implications for the development of prevention and treatment programs.

10.
Artículo en Inglés | MEDLINE | ID: mdl-33138218

RESUMEN

Internet influences our communication, social and work interactions, entertainment, and many other aspects of life. Even if the original purpose was to simplify our lives, an excessive and/or maladaptive use of it may have negative consequences. The dopamine transporter (DAT1) gene was studied in relation to addictions, including excessive use of the Internet. The crucial role of DAT1 was previously underlined in modulating emotional aspects, such as affiliative behaviors. The present research follows a new approach based on cross-correlation between (de)methylation levels in couples of CpG loci, as previously shown. We investigated the possible relationships between Internet addiction, impulsivity, quality of attachment, DAT1 genotypes (from the 3'-untranslated region (UTR) variable number of tandem repeats (VNTR) poly-morphism), and the dynamics of methylation within the 5'-UTR of the DAT1 gene. From a normative sample of 79 youths, we extrapolated three subgroups a posteriori, i.e., one "vulnerable" with high Internet Addiction Test (IAT) scores (and high Barrat Impulsivity Scale (BIS) scores; n = 9) and two "controls'' with low BIS scores and 10/10 vs. 9/x genotype (n = 12 each). Controls also had a "secure" attachment pattern, while genotypes and attachment styles were undistinguished in the vulnerable subgroup (none showed overt Internet addiction). We found a strongly positive correlation in all groups between CpG2 and CpG3. An unsuspected relationship between the 3'-UTR genotype and a 5'-UTR intra-motif link was revealed by CpG5-CpG6 comparison. The negative correlation between the CpG3-CpG5 positions was quite significant in the control groups (both with genotype 10/10 and with genotype 9/x), whereas a tendency toward positive correlation emerged within the high IAT group. In conclusion, future attention shall be focused on the intra- and inter-motif interactions of methylation on the CpG island at the 5'-UTR of DAT1.


Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Trastorno de Adicción a Internet , Regiones no Traducidas 3' , Regiones no Traducidas 5' , Adolescente , Metilación de ADN , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Genotipo , Humanos , Conducta Impulsiva , Trastorno de Adicción a Internet/genética , Metilación , Repeticiones de Minisatélite
11.
Adv Biol Regul ; 78: 100753, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33022465

RESUMEN

Parkinson's disease (PD) is a neuro-degenerative disorder affecting the striatal motor system, caused by the loss of neuronal cells in the mid-brain, where reduced amounts of dopamine do cause involuntary movements and others symptoms. Alterations of methylome have been reported in PD epigenomic studies, and also human dopamine transporter gene (DAT1, SLC6A3) is considered as a candidate risk factor for PD. Since the DNA methylation on DAT promoter may well have a role in the development of this disease, we aimed to further assess the epigenetic control, by focusing on specific CpG sites located in the 5'-untranslated region (5'-UTR) of the DAT1 gene. Significant changes in DAT 5'-UTR methylation were already found in peripheral blood mononuclear cells (PBMCs) of PD subjects (Rubino et al., 2020). Of note, methylation values at the CpG 5 were increased. We run on same data a novel statistical approach: cross-correlation between pairs of loci. CpG 5 was the only always-differing variable but, alternatively, CpGs 2 and 6 or CpGs 1 and 3 were also significantly correlated with CpG 5. Interestingly, this picture emerged for those patients whose M2xM6 index was above-median; loci were rather independent for below-median patients. Present data may shed light into dynamics occurring at 5'-UTR of DAT1, a gene involved in PD but also in many psycho-physiological pathologies.


Asunto(s)
Regiones no Traducidas 5' , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Enfermedad de Parkinson/genética , Islas de CpG , Epigénesis Genética , Regulación de la Expresión Génica , Humanos
13.
Psychiatry Res ; 291: 113154, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32554184

RESUMEN

Attention Deficit/Hyperactivity Disorder (ADHD) is the most common neuro-developmental alteration in childhood. To date, its diagnosis is exclusively clinical, however recent studies focused on searching for objective biomarkers. We recently reported a selective alteration of DNA methylation in the 5'-UTR of dopamine transporter (DAT1) gene, in a 1CGG2CGG3CGG and a 5CG6CG motif, for ADHD patients (compared to controls). Presently, we looked for DNA methylation of the corresponding CpG sites but complementary on the opposite strand ("COS"). Exploiting a novel cross-correlation approach, we found a core M5 - M5 COS and M2 - M2 COS relationship with relatively free M1 and M6 COS extremes. Our data might be relevant, to find a new biomarker to diagnose ADHD in affected subjects.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/genética , Metilación de ADN/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Epigénesis Genética/genética , Niño , Estudios de Cohortes , Femenino , Marcadores Genéticos/genética , Humanos , Masculino
14.
Acta Neurol Scand ; 142(3): 275-280, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32415851

RESUMEN

OBJECTIVES: The involvement of epigenetics mechanisms in the transcriptional regulation of key genes has been investigated in the initiation and progression of neurodegenerative disorders, including Parkinson's disease (PD). Among others, we, here, focused the attention on the dopamine transporter (DAT) gene playing a critical role in maintaining the integrity of dopaminergic neurons. MATERIALS AND METHODS: We performed bisulfite pyrosequencing to examine DNA methylation levels of six CpG sites in the 5'-UTR of DAT1 gene in human peripheral blood mononuclear cells (PBMCs) obtained from 101 sporadic PD patients and 59 healthy controls. RESULTS: We selectively report for CpG5 an increase in DNA methylation levels in PD subjects respect to controls, that almost reaches statistical significance (30.06 ± 12.4 vs 26.58 ± 7.6, P = .052). Of interest, a significantly higher methylation at specific CpG sites (ANOVA: P = .029) was observed in PD subjects with advanced stage of illness. Namely, a multivariate regression analysis showed that a higher methylation level at specific CpG sites in the group of PD patients was associated with increased methylation at CpG2, CpG3, and with H&Y stage but not with age and gender. This regression model explains the 38% of the variance of methylation at CpG5. CONCLUSION: Our results do seem to suggest that the methylation level of CpG5 is different between PD patients and controls. Moreover, this methylation level for CpG5 may be associated also with the stage of disease.


Asunto(s)
Regiones no Traducidas 5'/genética , Metilación de ADN , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Enfermedad de Parkinson/genética , Factores de Edad , Anciano , Islas de CpG/genética , Neuronas Dopaminérgicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monocitos/química , Enfermedad de Parkinson/patología , Factores Sexuales
15.
Front Neurol ; 11: 599517, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33551959

RESUMEN

Background: The Wolframin His611Arg polymorphism can influence drug consumption in psychiatric patients with impulsive addictive behavior. This cross-sectional study aims to assess the prevalence of the Wolframin His611Arg polymorphism in MOH, a secondary headache belonging to the spectrum of addictive disorders, episodic migraine (EM), and healthy subjects (HS), and its influence on drug consumption. Methods: One-hundred and seventy-two EM, 107 MOH, and 83 HS were enrolled and genotyped for the Wolframin His611Arg polymorphism. Subjects were classified as homozygous for allele His (H/H subjects), homozygous for allele Arg (R/R subjects), and heterozygous (H/R subjects), regrouped as R/R and carriers of allele H (non-R/R), and matched for clinical data. Results: There were no differences in allelic distributions between the three groups (p = 0.19). Drug consumption and other clinical characteristics were not influenced by the Wolframin His611Arg polymorphism (p = 0.42; ß = 0.04) in the EM group. Among the MOH population, R/R subjects consumed more analgesics (p < 0.0001; ß = -0.38), particularly combination drugs (p = 0.0001; d = 2.32). Discussion: The Wolframin His611Arg polymorphism has a similar prevalence between the MOH, EM, and HS groups. The presence of the R/R genotype does not influence symptomatic drug consumption in EM, whereas it determines an increased use of symptomatic drugs in the MOH group, in particular combination drugs (i.e., drugs containing psychoactive compounds). Conclusions: Our findings are consistent with the hypothesis that the Wolframin His611Arg polymorphism plays its effect only in the MOH population, influencing the impulsivity control underlying addictive behavior.

16.
Artículo en Inglés | MEDLINE | ID: mdl-31323798

RESUMEN

Parental psychopathological risk is considered as one of the most crucial features associated with epigenetic modifications in offspring, which in turn are thought to be related to their emotional/behavioral profiles. The dopamine active transporter (DAT) gene is suggested to play a significant role in affective/behavioral regulation. On the basis of the previous literature, we aimed at verifying whether children's DAT1 polymorphisms moderated the relationship between parents' psychological profiles, children's emotional/behavioral functioning, and DAT1 methylation in a normative sample of 79 families with school-age children (Ntot = 237). Children's biological samples were collected through buccal swabs, while Symptom Check-List-90 item Revised, Adult Self Report, and Child Behavior Check-List/6-18 was administered to assess parental and children's psychological functioning. We found that higher maternal externalizing problems predicted the following: higher levels of children's DAT1 methylation at M1, but only among children with 10/10 genotype; higher levels of methylation at M2 among children with 10/10 genotype; while lower levels for children with a 9-repeat allele. There was also a positive relationship between fathers' externalizing problems and children's externalizing problems, only for children with a 9-repeat allele. Our findings support emerging evidence of the complex interplay between genetic and environmental factors in shaping children' emotional/behavioral functioning, contributing to the knowledge of risk variables for a child's development and psychological well-being.


Asunto(s)
Conducta Infantil , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Emociones , Padre/psicología , Madres/psicología , Adulto , Niño , Metilación de ADN , Depresión , Femenino , Humanos , Masculino , Metilación , Padres , Estrés Psicológico
17.
Front Neurosci ; 13: 683, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31354407

RESUMEN

Adenosine A2A receptors (A2ARs) have attracted considerable attention as an important molecular target for the design of Parkinson's disease (PD) therapeutic compounds. Here, we studied the transcriptional regulation of the A2AR gene in human peripheral blood mononuclear cells (PBMCs) obtained from PD patients and in the striatum of the well-validated, 6-hydroxydopamine (6-OHDA)-induced PD mouse model. We report an increase in A2AR mRNA expression and protein levels in both human cells and mice striata, and in the latter we could also observe a consistent reduction in DNA methylation at gene promoter and an increase in histone H3 acetylation at lysine 9. Of particular relevance in clinical samples, we also observed higher levels in the receptor gene expression in younger subjects, as well as in those with less years from disease onset, and less severe disease according to clinical scores. In conclusion, the present findings provide further evidence of the relevant role of A2AR in PD and, based on the clinical data, highlight its potential role as disease biomarker for PD especially at the initial stages of disease development. Furthermore, our preclinical results also suggest selective epigenetic mechanisms targeting gene promoter as tool for the development of new treatments.

18.
Neurosci Lett ; 690: 83-88, 2019 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-30316985

RESUMEN

L-dopa-induced dyskinesias (LID) is a common motor side effect of levodopa therapy of Parkinson's disease (PD). The identified predictors may only partially account for the risk of developing LID and genetic factors may contribute to this variability. The present study is aimed to investigate whether polymorphisms in the dopamine transporter gene (DAT) are associated with the risk of developing LID. Genotyping of the 40-bp VNTR (rs28363170) and rs393795 (A/C) polymorphisms of the DAT gene was performed in a well-characterized cohort of 181 Italian PD patients in treatment with L-DOPA for 3 years or more. The results of our study show that there is no difference in dyskinesias prevalence among carriers of the two DAT gene polymorphisms. However, the combination of the two genotypes 10R/10R (rs28363170) and A carrier (rs393795) of the DAT gene reduces the risk of LID occurrence during long-term therapy with l-DOPA with respect to the PD subjects who did not carry these alleles (OR = 0.31; 95% CI, 0.09-0.88). Also based on a logistic regression analysis, the 10R/10R and the A carrier allele of the rs393795 polymorphisms of the DAT gene, could reduce the susceptibility to develop LID during levodopa therapy adjusted by demographical and clinical variables (OR = 0.19; 95% CI, 0.05-0.69). Additional studies further investigating the rs28363170 and rs393795 polymorphisms with LID in PD are needed to clarify their role in different ethnicities.


Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Discinesia Inducida por Medicamentos/genética , Predisposición Genética a la Enfermedad/genética , Levodopa/efectos adversos , Enfermedad de Parkinson/genética , Polimorfismo Genético , Anciano , Alelos , Discinesia Inducida por Medicamentos/epidemiología , Femenino , Genotipo , Haplotipos , Humanos , Italia/epidemiología , Masculino , Repeticiones de Minisatélite/genética , Prevalencia
19.
Eur Child Adolesc Psychiatry ; 27(2): 241-252, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28822049

RESUMEN

In view of the need for easily accessible biomarkers, we evaluated in ADHD children the epigenetic status of the 5'-untranslated region (UTR) in the SLC6A3 gene, coding for human dopamine transporter (DAT). We analysed buccal swabs and sera from 30 children who met DSM-IV-TR criteria for ADHD, assigned to treatment according to severity. Methylation levels at six-selected CpG sites (among which, a CGGCGGCGG and a CGCG motif), alone or in combination with serum titers in auto-antibodies against dopamine transporter (DAT aAbs), were analysed for correlation with CGAS scores (by clinicians) and Conners' scales (by parents), collected at recruitment and after 6 weeks. In addition, we characterized the DAT genotype, i.e., the variable number tandem repeat (VNTR) polymorphisms at the 3'-UTR of the gene. DAT methylation levels were greatly reduced in ADHD patients compared to control, healthy children. Within patients carrying at least one DAT 9 allele (DAT 9/x), methylation at positions CpG2 and/or CpG6 correlated with recovery, as evident from delta-CGAS scores as well as delta Conners' scales ('inattentive' and 'hyperactive' subscales). Moreover, hypermethylation at CpG1 position denoted severity, specifically for those patients carrying a DAT 10/10 genotype. Intriguingly, high serum DAT-aAbs titers appeared to corroborate indications from high CpG1 versus high CpG2/CpG6 levels, likewise denoting severity versus recovery in DAT 10/10 versus 9/x patients, respectively. These profiles suggest that DAT 5'UTR epigenetics plus serum aAbs can serve as suitable biomarkers, to confirm ADHD diagnosis and/or to predict the efficacy of treatment.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/genética , Polimorfismo Genético/genética , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Niño , Femenino , Genotipo , Humanos , Masculino
20.
Front Psychiatry ; 8: 303, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29375406

RESUMEN

BACKGROUND: The effect of gene polymorphisms and promoter methylation, associated with maladaptive developmental outcomes, vary depending on environmental factors (e.g., parental psychopathology). Most studies have focused on 0- to 5-year-old children, adolescents, or adults, whereas there is dearth of research on school-age youths and pre-adolescents. METHODS: In a sample of 21 families recruited at schools, we addressed parents' psychopathological symptoms (through SCL-90-R); offspring emotional-behavioral functioning (through CBCL-6-18); dopamine transporter gene (DAT1) for epigenetic status of the 5'-untranslated region (UTR) and for genotype, i.e., variable number of tandem repeats polymorphism at the 3'-UTR. Possible associations were explored between bio-genetic and psychological characteristics within the same individual and between triplets of children, mothers, and fathers. RESULTS: DAT methylation of CpG at positions M1, M6, and M7 in mothers was correlated with maternal (phobic) anxiety, whereas in fathers' position M6 was related to paternal depression, anxiety, hostility, psychoticism, and higher Global Severity Index (GSI). No significant correlations were found between maternal and offspring DAT methylation. Significant correlations were found between fathers' methylation at CpG M1 and children's methylation at CpG M6. Linear regressions showed that mothers and fathers' GSI predicted children's methylation at CpG sites M2, M3, and M6, whereas fathers' GSI predicted children's methylation at CpG sites, particularly M1, M2, and M6. Moreover, offspring methylation of DAT at CpG M2 predicted somatic complaint, internalizing and attention problems; methylation of DAT at CpG M6 predicted withdraw. CONCLUSION: This study may have important clinical implication for the prevention and treatment of emotional-behavioral difficulties in children, as it adds to previous knowledge about the role of genetic and environmental factors in predicting psychopathological symptoms within non-clinical populations.

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