Alcohol misuse represents worldwide an important risk factor for death and disability. Excessive alcohol consumption is widely diffused in different ethnicities and alcohol use is part of the ...lifestyle of both young and old people. The genetic basis of alcohol dependence concerning ethanol metabolism and the pathways of reward circuits are well known. The role of genetic variants in the neurobiology of addiction as well as in response to medication in alcoholism therapy still represents an intriguing argument that needs to be deeply analyzed and explained. The molecular approach to the study of these aspects could be difficult because of the large number of genes and variations involved. Our work is intended to offer an overview of genes and variants involved in alcohol addiction and pharmacogenetics. Our aim is to delineate a molecular approach strategy to look at alcohol dependence from a genetic and applicative point of view. The indications provided in this work should be of help for those who wish to undertake a molecular study of this multifactorial disease.
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.
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.
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.
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.
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.
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.
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;
= 9) and two "controls'' with low BIS scores and 10/10 vs. 9/x genotype (
= 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.
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.
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.
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).
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 C
GG C
GG C
GG and C
G C
G 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.
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.
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.
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.
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.
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.
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 (
= 10, 7 F and 3 M, age 39.0 ± 7.5) or post-OCRE (
= 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.
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.
These data support the hypothesis of specific deregulated miRNAs as putative biomarkers in RRMS patients' stratification and DMT drug response.
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