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OBJECTIVE: In addition to teaching theoretical and clinical-practical skills, the development of individual moral competence should be another core concern in medical school. However, research suggests that moral competence in students of human medicine stagnates or even declines during the course of medical school. Therefore, the present cross-sectional study investigated the moral competence of medical students at the beginning of their studies and during their practical year, as well as the effects of testosterone as a neurohormone on moral judgment. METHODS: By means of a cross-sectional study, the moral judgment ability of 24 first-year and 16 practical year students of Hannover Medical School was recorded and evaluated with the Moral Competence Test (MCT) according to Lind. The testosterone serum level of the study participants was statistically related to the MCT results. RESULTS: No significant differences between first-year (mean±standard deviation (SD): 13.16±8.21) and practical year students (mean±SD: 11.24±8.07) with regard to moral competence as per the MCT were identified (p=0.36). Higher serum testosterone levels did not show a statistically significant correlation with moral competence (r=-0.09, p=0.58). CONCLUSION: Our results do not show a clear trend whether moral competence is lower in medical students in advanced semesters compared to the beginning of medical school and whether moral competence is influenced by the neurohormone testosterone. Nevertheless, it seems reasonable to implement moral competence training for medical students early, continuously, and as individually designed as possible during medical school (and to evaluate it in further studies) in order to preventively counteract stagnation or regression of moral judgment.
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Estudiantes de Medicina , Humanos , Estudios Transversales , Principios Morales , Juicio , Evaluación EducacionalRESUMEN
Background: The model of neuroinflammation has been proposed as a possible explanation of depression. Investigations of serum levels of tumor necrosis factor-α (TNF-α) in depressed patients have previously shown contradictory results of increased and decreased levels of TNF-α during the treatment of depression. Methods: We compared the serum levels of TNF-α in two cohorts of patients suffering from depression (ICD-10 criteria): one cohort from a psychotherapeutic unit (n = 18), where patients were treated with Cognitive Behavioral Analysis System of Psychotherapy (CBASP), and the other cohort from a psychiatric day care unit (n = 16). Both cohorts were investigated at the beginning and at the end of treatment. The intensity of depression was measured by means of the Beck Depression Inventory, 2nd edition (BDI-II) at both time points. Results: We observed a statistically significant increase of TNF-α in the psychotherapeutic unit at time point 2 compared to time point 1 (T = -14.71, p < 0.001), but not in the psychiatric day care unit. In both cohorts, BDI-II scores at time point 2 were significantly decreased compared to time point 1 (psychiatric day care unit: T = 3.32, p = 0.005; psychotherapeutic unit: T = 6.22, p < 0.001). There was a significant correlation in the psychotherapeutic unit at time point 2 (r = -0.682, p = 0.02). Conclusion: As TNF-α was increased at time point 2 in the psychotherapeutic unit but not in patients of the psychiatric day care unit, we propose the different durations of pretreatments in both cohorts and the associated processes of neuroinflammation as a possible explanation for our results. The lack of information about the time course of TNF-α in depression could in general explain the huge variety of TNF-α levels in different cohorts of depressed patients reported in the literature.
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Depresión/sangre , Depresión/terapia , Enfermedades Neuroinflamatorias/sangre , Enfermedades Neuroinflamatorias/terapia , Psicoterapia/métodos , Factor de Necrosis Tumoral alfa/sangre , Adulto , Biomarcadores/sangre , Estudios de Cohortes , Depresión/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neuroinflamatorias/diagnóstico , Escalas de Valoración Psiquiátrica , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: Opioid dependence is a severe disease which is associated with a high risk of relapse, even in cases of successful withdrawal therapy. Studies have shown alterations of the hypothalamic-pituitary-gonadal axis in opioid-dependent patients, such as decreased testosterone serum levels in affected males. Sex hormones and the steroid 5-alpha-reductase 2 (SRD5A2) V89L polymorphism are associated with craving during alcohol withdrawal, but little is known about their impact on symptomatology of opioid dependence. METHODS: In this study, we analyzed 2 independent male cohorts of opioid-dependent patients for possible alterations in testosterone serum levels compared to non-opioid-dependent controls. In one of the cohorts, we additionally investigated associations of testosterone serum levels and 3 SRD5A2 polymorphisms with symptoms of opioid dependence, measured by the Heroin Craving Questionnaire (HCQ). RESULTS: In the patient groups, we found significantly decreased testosterone serum levels compared to the control groups. Furthermore, we found significant associations of both the testosterone serum levels and the SRD5A2 V89L polymorphism with opioid craving assessed by the HCQ. CONCLUSION: Our data show a possible role of testosterone metabolism in opioid dependence, which may be relevant for the establishment of future treatment strategies.
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3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , Ansia/fisiología , Proteínas de la Membrana/genética , Trastornos Relacionados con Opioides/sangre , Trastornos Relacionados con Opioides/genética , Trastornos Relacionados con Opioides/fisiopatología , Testosterona/sangre , Adulto , Estudios de Cohortes , Humanos , Masculino , Polimorfismo GenéticoRESUMEN
AIMS: Childhood trauma is of importance for the manifestation of substance-related disorders and maintenance of hypothalamic-pituitary-adrenal (HPA)-axis disorders. Since stress plays a crucial role in opioid compliance and craving, we investigated the immediate effects of diacetylmorphine application on the HPA axis. In particular, adrenocorticotropic hormone (ACTH) and cortisol secretion, as well as satiety regulating proopiomelanocortin peptides α-melanocyte-stimulating hormone (MSH) and ß-endorphin (END) in a cohort of opioid-dependent patients in diamorphine maintenance treatment concerning the clinical severity of their childhood trauma. METHODS: We compared the serum levels of ACTH, cortisol, MSH, and END in 15 opioid-dependent patients. All participants received treatment with diamorphine and were observed at 5 timepoints before and after injection. We split the cohort into 2 subgroups concerning childhood trauma measured by the Childhood Trauma Questionnaire. RESULTS: Splitting in 2 subgroups for mild (5) and severe trauma (10), we found that while both groups show a significant reduction of ACTH and cortisol levels over time, slopes display different progressions over time for cortisol (F[1.6] = 9.38, p = 0.02), while remaining identical for ACTH (F[1.6] = 1.69, p = 0.24). Also, levels of both MSH and END were significantly lower in severely traumatized patients. CONCLUSIONS: For the first time, we present a detailed representation of stress- and addiction-related proteins for the first 5 h after diamorphine application, demonstrating the interrelationship between stress hormones and childhood trauma as well as its potential effects on the progression of addictions such as opioid dependence.
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Experiencias Adversas de la Infancia , Dependencia de Heroína , Heroína , Estrés Psicológico/psicología , Heridas y Lesiones/psicología , Hormona Adrenocorticotrópica/sangre , Adulto , Niño , Estudios de Cohortes , Femenino , Heroína/farmacología , Heroína/uso terapéutico , Dependencia de Heroína/tratamiento farmacológico , Dependencia de Heroína/metabolismo , Humanos , Hidrocortisona/sangre , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Persona de Mediana Edad , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Encuestas y Cuestionarios/estadística & datos numéricos , betaendorfina/sangreRESUMEN
NGF and VEGF are known to be involved in different psychiatric diseases. In order to verify hints from basic research that both neurotrophines interact with each other, serum levels of NGF and VEGF were measured in a cohort of 33 healthy individuals and correlated. NGF level was 126.30 pg/mL (±155.43), and VEGF level was 57.28 pg/mL (±44.48). Both factors were significantly correlated, confirming their interaction and legitimising the usage of their respective ratio (0.8 (±0.42)) as a less varying additional marker in prospective studies.
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Factor de Crecimiento Nervioso/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto , Estudios de Cohortes , Femenino , Voluntarios Sanos , Humanos , Masculino , Dominios y Motivos de Interacción de ProteínasRESUMEN
The dopaminergic neurotransmission is known to be of crucial importance in addictive behavior. Epigenetic regulation like methylation of DNA influences the function of dopaminergic transmission. The present study investigated alterations of DNA methylation in the dopamine D2 receptor (DRD2)-gene in patients suffering from alcohol dependence. The study sample consists of 99 alcohol dependent males admitted for alcohol withdrawal treatment and a control group of 33 healthy participants. Blood samples underwent bisulfite sequencing to determine levels of DNA-methylation of the promoter region of the DRD2 gene. Mixed linear modeling was used to test differences between patients and controls, course of methylation during detoxification. While DRD2-gene methylation did not differ significantly between patients and controls, we found a significant increase of DRD2-gene methylation during alcohol withdrawal/early abstinence. Craving, measured with the Obsessive Compulsive Drinking Scale (OCDS), was significantly associated with DRD2-gene methylation. Furthermore, smoking significantly influenced DRD2-gene methylation in both, patients and controls. As in other types of addictive disorders, DRD2-gene methylation is altered during alcohol withdrawal/early abstinence. The findings regarding an association with alcohol craving and tobacco consumption point towards a crucial role of DRD2-gene methylation in the neurobiology of addictive behavior.
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Metilación de ADN/efectos de los fármacos , Receptores de Dopamina D2/genética , Síndrome de Abstinencia a Sustancias/metabolismo , Adulto , Alcoholismo/metabolismo , Estudios de Casos y Controles , Ansia , Epigénesis Genética/efectos de los fármacos , Humanos , Masculino , Regiones Promotoras Genéticas/efectos de los fármacos , Receptores de Dopamina D2/sangre , Receptores de Dopamina D2/metabolismoRESUMEN
AIMS: The nerve growth factor (NGF) and the vascular endothelial growth factor-A (VEGF-A) may be of importance for psychiatric diseases including substance use disorders. The aim of the study was to identify differences in the regulation of both neuropeptides via the DNA-methylation status of the promotor regions of NGF and VEGF-A in different forms of maintenance therapy for opioid dependence and the related stress regulation via the hypothalamic-pituitary-adrenal axis. METHODS: We compared methylation levels of opioid-dependent patients receiving treatment with diamorphine (n = 28) or levomethadone (n = 54) and similar levels in a healthy control group (n = 72). RESULTS: There was a significantly higher methylation of VEGF-A in opioid-maintained patients with levomethadone compared to that in the control group (estimated marginal means [EMM] [SE]): 0.036 [0.003] vs. 0.020 [0.003]; p < 0.001). We performed a cluster analysis for NGF, splitting up the results in 4 clusters. We found significant changes in methylation rates of the opioid-maintained patients compared to the controls in cluster I ([EMM] [SE]: 0.064 [0.005] vs. 0.084 [0.006]; p = 0.03), cluster II ([EMM] [SE]: 0.133 [0.013] vs. 0.187 [0.014]; p < 0.001) and cluster III ([EMM] [SE]: 0.190 [0.014] vs. 0.128 [0.016]; p < 0.001). CONCLUSIONS: The results are of importance, as they indicate that long-term changes in stress regulation regulated by neurotrophines are a crucial part of the symptomatology of opioid dependence, thus influencing drug consumption and the different forms of opioid-maintenance therapies.
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Epigénesis Genética/efectos de los fármacos , Factor de Crecimiento Nervioso/efectos de los fármacos , Trastornos Relacionados con Opioides , Regiones Promotoras Genéticas/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacos , Adulto , Analgésicos Opioides/uso terapéutico , Metilación de ADN/efectos de los fármacos , Femenino , Heroína/farmacología , Heroína/uso terapéutico , Humanos , Masculino , Metadona/farmacología , Metadona/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológicoRESUMEN
AIMS: Aldehyde dehydrogenase 2 (ALDH2) protects cells from ethanol toxicity by metabolizing acetaldehyde. We studied the single nucleotide polymorphism (SNP) rs886205s located between a negative and a positive regulating promoter element in the ALDH2 gene. The negative regulatory region was already associated with differential DNA methylation in the two allele variations of rs886205 SNP. Another CpG island, in the positive regulatory region of the ALDH2 promoter, extends through the SNP rs886205 and a nuclear receptor response element. METHODS: We assessed rs886305 genotype and DNA methylation using bisulfite sequencing in a cohort of 83 male alcohol-dependent patients undergoing detoxification treatment (Days 1, 7 and 14) and in 33 male age-matched controls. Luciferase reporter assays were performed to address the functional significance of genotype and methylation. RESULTS: We observed a higher methylation in alcohol-dependent patients compared to controls. Patients with AA (n = 52) or GG/GA (n = 31) genotype differed significantly in baseline methylation levels as well as in methylation kinetics during withdrawal. AA carriers display an increase in methylation from low baseline levels while GG/GA showed the inverse pattern. The reporter gene assays corroborate these data by showing a significant effect of genotype on ALDH2 expression as well as an interaction between genotype and methylation. CONCLUSION: Our results describe a new regulatory role of rs886205 in the methylation of ALDH2 promoter region and provide additional insight into the complex regulation of ALDH2 under the condition of alcohol dependence. SHORT SUMMARY: Genetic variations have been described to influence DNA promoter methylation of various genes. We investigated the association between the polymorphism rs886205, located on ALDH2 promoter and methylation kinetics of the neighboring CpG island in alcohol-dependent patients. Luciferase reporter assays showed functional significance of genotype, methylation and a genotype-epigenotype interaction in vitro.
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Alcoholismo/genética , Aldehído Deshidrogenasa Mitocondrial/genética , Metilación de ADN , Polimorfismo Genético/genética , Adulto , Secuencia de Bases , Depresores del Sistema Nervioso Central/farmacología , Estudios de Cohortes , Inducción Enzimática/efectos de los fármacos , Etanol/farmacología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Caracteres Sexuales , Testosterona/sangreRESUMEN
AIMS: Neurotrophins have been linked to the symptomatology of alcohol dependence. We aimed to investigate a possible association between the methylation of the promoters of both neurotrophins, the serum levels of the cytokines and core symptoms of alcohol dependence as withdrawal severity and anxiety. METHODS: In this study we investigated a possible association between alterations in the methylation of the BDNF IV/NGF I gene promoter and the cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) in 55 male alcohol-dependent patients. RESULTS: Mean methylation of the promoter of the BDNF gene was significantly associated with the TNF-α serum levels and the CIWA-score during withdrawal (P < 0.001). Moreover, mean methylation of the NGF I promoter was significantly associated with the IL-6 serum levels and STAI-I score during withdrawal (P < 0.001). CONCLUSION: Our results suggest an association between the epigenetic regulation of both neurotrophins, BDNF and NGF, cytokine release and the symptomatology of alcohol dependence. They imply that changes in the methylation of neurotrophins may contribute to the symptomatology of alcohol dependence by affecting relevant downstream signaling cascades.
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Síntomas Afectivos/genética , Síntomas Afectivos/psicología , Alcoholismo/genética , Alcoholismo/psicología , Citocinas/fisiología , Epigénesis Genética/genética , Factores de Crecimiento Nervioso/fisiología , Transducción de Señal/genética , Adulto , Síntomas Afectivos/etiología , Factor Neurotrófico Derivado del Encéfalo/genética , Depresores del Sistema Nervioso Central/metabolismo , Metilación de ADN , Etanol/metabolismo , Femenino , Humanos , Interleucina-6/genética , Masculino , Modelos Psicológicos , Factor de Crecimiento Nervioso/genética , Pruebas Neuropsicológicas , Síndrome de Abstinencia a Sustancias/genética , Síndrome de Abstinencia a Sustancias/psicología , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Clinical studies report that substance addictions are associated with sociocognitive impairments. Regarding opiate-addicted patients, the few existing studies point to deficits in empathic abilities. Previous research suggests that testosterone might be a relevant biomarker of these impairments. The authors aimed to investigate whether opiate-addicted patients show specific impairments in emotional (empathic concern, personal distress) and cognitive empathy compared to healthy controls. Furthermore, the authors aimed to assess possible associations of testosterone levels with impaired empathic abilities in the patients' group. In this cross-sectional study, 27 opiate-addicted, diacetylmorphine-maintained patients (21 males, age mean 41.67 years, standard deviation 8.814) and 31 healthy controls (23 males, age mean 40.77 years, standard deviation 8.401) matched in age, sex, and educational level were examined. Cognitive and emotional empathy were measured via the German version of the Interpersonal Reactivity Index and salivary testosterone levels were assessed. The authors found higher personal distress scores (p < 0.01, d = 0.817) and higher testosterone (p < 0.001, d = 1.093) in the patients' group compared to controls. Moreover, a positive correlation was found between testosterone and personal distress among the patients' group (r = 0.399, p < 0.05). Opiate-addicted patients show specific impairments in emotional empathy, namely higher personal distress, which has clinical implications regarding social cognition rehabilitation and relapse prevention. The current data point toward testosterone as a possible biomarker for these sociocognitive impairments and suggest that high personal distress and high testosterone during withdrawal are possible markers for severe opiate addiction.
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Empatía , Trastornos Relacionados con Opioides/fisiopatología , Trastornos Relacionados con Opioides/psicología , Estrés Fisiológico , Estrés Psicológico/psicología , Testosterona/análisis , Adulto , Biomarcadores/análisis , Cognición , Estudios Transversales , Análisis Factorial , Alemania , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Saliva , Facultades de MedicinaRESUMEN
The administration of diacetylmorphine (DAM) reduces the activation of the hypothalamic-pituitary-adrenal (HPA) axis in opioid-maintained patients. However, the epigenetic effects of DAM on addiction-related genes have not been investigated yet. In a randomized controlled study, we examined the immediate effects of intravenous DAM versus placebo on the promoter methylation of the POMC (pro- opiomelanocortin) and NR3C1 (glucocorticoid receptor 1) genes. Twenty-eight heroin-dependent patients on DAM-assisted treatment received either DAM or saline in a randomized crossover design and 17 healthy participants received saline only. EDTA blood samples were taken 25 min before and 10 min after the injection of DAM or saline. We found reciprocal regulation effects for DAM versus saline application regarding the methylation of POMC; while DAM injection significantly increased methylation, saline injection led to a significant decrease in methylation for patients as well as controls. NR3C1 data did not show significant changes in methylation. Injection of DAM blunted stress hormone levels and the POMC promoter methylation of heroin-dependent patients. These findings provide first preliminary insights into the epigenetic mechanisms underlying the emotional regulation effects of DAM-assisted treatment in severe heroin-dependent patients.
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Metilación de ADN/efectos de los fármacos , Dependencia de Heroína/tratamiento farmacológico , Heroína/administración & dosificación , Narcóticos/administración & dosificación , Proopiomelanocortina/genética , Receptores de Glucocorticoides/genética , Administración Intravenosa , Adulto , Estudios Cruzados , Emociones/efectos de los fármacos , Emociones/fisiología , Epigénesis Genética/efectos de los fármacos , Femenino , Dependencia de Heroína/genética , Dependencia de Heroína/metabolismo , Dependencia de Heroína/psicología , Humanos , Masculino , Proopiomelanocortina/metabolismo , Regiones Promotoras Genéticas , Receptores de Glucocorticoides/metabolismo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Brain-derived neurotrophic factor (BDNF) appears to play a crucial role in the reward response to drugs such as heroin. The primary objective of the present study was to examine epigenetic changes and serum levels of BDNF in patients undergoing different opiate-based maintenance treatments. We compared patients receiving treatment with either levomethadone (n = 55) or diamorphine (n = 28) with a healthy control group (n = 51). When comparing all subjects (patients and controls), BDNF serum levels showed a negative correlation with the BDNF IV promoter methylation rate (r = -0.177, p = 0.048). Furthermore, BDNF serum levels negatively correlated with Beck's Depression Inventory measurements (r = -0.177, p < 0.001). Patients receiving diamorphine maintenance treatment showed slightly decreased BDNF serum levels compared to healthy controls, whereas patients on levomethadone maintenance treatment with or without heroine co-use showed a pronounced decrease (analysis of covariance: control vs. levomethadone with and without heroine co-use: p < 0.0001, diamorphine vs. levomethadone with heroine co-use: p = 0.043, diamorphine vs. levomethadone without heroine co-use: p < 0.0001). According to these findings, methylation of the BDNF IV promoter showed the highest level in patients receiving levomethadone without heroine co-use (linear mixed model: control vs. levomethadone group without heroine co-use: p = 0.008, with heroin co-use: p = 0.050, diamorphine vs. levomethadone group with heroine co-use: p = 0.077 and without heroine co-use: p = 0.015.). For the first time, we show an epigenetic mechanism that may provide an explanation for mood destabilization in levomethadone maintenance treatment.
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Analgésicos Opioides/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo/sangre , Heroína/uso terapéutico , Metadona/uso terapéutico , Trastornos Relacionados con Opioides/sangre , Trastornos Relacionados con Opioides/tratamiento farmacológico , Adulto , Analgésicos Opioides/farmacología , Factor Neurotrófico Derivado del Encéfalo/genética , Estudios de Casos y Controles , Depresión/etiología , Epigénesis Genética/efectos de los fármacos , Femenino , Heroína/farmacología , Humanos , Masculino , Metadona/farmacología , Metilación/efectos de los fármacos , Persona de Mediana Edad , Trastornos Relacionados con Opioides/psicología , Regiones Promotoras Genéticas/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Estadísticas no Paramétricas , Encuestas y Cuestionarios , Escala Visual AnalógicaRESUMEN
Preclinical and clinical studies show associations between testosterone and brain-derived neurotrophic growth factor (BDNF) serum levels. BDNF and testosterone have been independently reported to influence alcohol consumption. Therefore, we aimed to investigate a possible interplay of testosterone and BDNF contributing to alcohol dependence. Regarding possible interplay of testosterone and BDNF and the activity of the hypothalamic pituitary axis (HPA), we included cortisol serum levels in our research. We investigated testosterone and BDNF serum levels in a sample of 99 male alcohol-dependent patients during alcohol withdrawal (day 1, 7, and 14) and compared them to a healthy male control group (n = 17). The testosterone serum levels were significantly (p < 0.001) higher in the patients' group than in the control group and decreased significantly during alcohol withdrawal (p < 0.001). The decrease of testosterone serum levels during alcohol withdrawal (days 1-7) was significantly associated with the BDNF serum levels (day 1: p = 0.008). In a subgroup of patients showing high cortisol serum levels (putatively mirroring high HPA activity), we found a significant association of BDNF and testosterone as well as with alcohol craving measured by the Obsessive and Compulsive Drinking Scale (OCDS). Our data suggest a possible association of BDNF and testosterone serum levels, which may be relevant for the symptomatology of alcohol dependence. Further studies are needed to clarify our results.
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Trastornos Inducidos por Alcohol/sangre , Factor Neurotrófico Derivado del Encéfalo/sangre , Ansia , Síndrome de Abstinencia a Sustancias/sangre , Testosterona/sangre , Adulto , Trastornos Inducidos por Alcohol/complicaciones , Estudios de Casos y Controles , Humanos , Hidrocortisona/sangre , Masculino , Síndrome de Abstinencia a Sustancias/complicaciones , Adulto JovenRESUMEN
OBJECTIVE: Natriuretic peptides participate in the collection of metabolic effects during alcohol withdrawal. Having witnessed modulation of other natriuretic peptides in alcohol-dependent patients during alcohol withdrawal, we were interested in the relation of brain natriuretic peptide (BNP) methylation with protein expression and craving in this longitudinal study. METHODS: Ninety-nine male patients were compared to 101 healthy controls concerning epigenetic regulation and protein expression during detoxification treatment. RESULTS: With BNP expression being GATA4 dependent, we observed a correlation of GATA4 binding site methylation and protein expression. BNP serum levels and Obsessive Compulsive Drinking Scale scores are significantly decreased during withdrawal. Focusing on the two CpGs that are between GATA transcription factor binding sites, statistical analysis revealed a reversely proportional methylation pattern, significantly increasing with ongoing detoxification and thereby supporting the observed serum level changes. CONCLUSION: Without the functional knowledge about regulation of BNP expression via the GATA transcription factor, it would have been easy to take the mean results of the global CpG data and propose a direct relationship between methylation and expression. Thus, these findings are a voice for functionally and mechanistically approved results. There was no causal relationship between protein expression levels and epigenetic changes. Further research is needed which includes protein expression and other approaches.
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Trastornos Relacionados con Alcohol/metabolismo , Trastornos Relacionados con Alcohol/patología , Factor de Transcripción GATA4/genética , Péptido Natriurético Encefálico/metabolismo , Adolescente , Adulto , Trastornos Relacionados con Alcohol/genética , Sitios de Unión/genética , Ansia/fisiología , Citosina/análogos & derivados , Citosina/metabolismo , Metilación de ADN , Epigénesis Genética , Femenino , Factor de Transcripción GATA4/metabolismo , Regulación de la Expresión Génica , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenRESUMEN
Acetaldehyde, the carcinogenic metabolite of ethanol known to provoke aversive symptoms of alcohol consumption, is predominantly eliminated by aldehyde dehydrogenase 2 (ALDH2). Reduced ALDH2 activity correlates with low alcohol tolerance and low risk for alcohol dependence. The ALDH2 promoter polymorphism rs886205 (A>G) is associated with decreased promoter activity, but a molecular mechanism and allele-dependent ALDH2 protein expression has not been described yet. On the basis of allele-dependent epigenetic effects, we analyzed the rs886205 genotype, methylation rates of cytosine-phosphatidyl-guanine (CpG)-sites within a regulatory promoter region and ALDH2 protein levels in 82 alcohol-dependent patients during a 2-week withdrawal and compared them to 34 matched controls. Patients without the G-allele of rs886205 showed higher methylation of the promoter region than controls and readily adapted epigenetically as well as on protein level during withdrawal, while patients with the G-allele displayed retarded methylation readjustment and no change in ALDH2 protein levels. Our data provide novel insights into an unknown genetic-epigenetic interaction, revealing impaired ALDH2 protein expression in patients with the G-allele of rs886205. Additionally, we checked for an association between rs886205 and protection against alcohol dependence and found a trend association between the G-allele and protection against alcohol dependence that needs replication in a larger Caucasian cohort.
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Alcoholismo/genética , Aldehído Deshidrogenasa/genética , Metilación de ADN , Epigénesis Genética/genética , Regulación de la Expresión Génica/genética , Regiones Promotoras Genéticas/genética , Adulto , Aldehído Deshidrogenasa/metabolismo , Aldehído Deshidrogenasa Mitocondrial , Alelos , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Polimorfismo Genético , Factores ProtectoresRESUMEN
The neurotrophic growth factor brain derived neurotrophic factor (BDNF) was linked to the risk of alcohol relapse in clinical studies. In this study we investigated alterations in the methylation of the BDNF gene during alcohol withdrawal (day 1, 7 and 14) in 99 male alcohol-dependent patients compared to age matched healthy males (n=33). In particular, we aimed to investigate a possible association between the BDNF promoter methylation and the self-reported duration of alcohol abstinence before relapse. Mean methylation of the BDNF promoter was significantly increased in alcohol-dependent patients compared to the healthy controls (F=10.014, p<0.001) and decreased significantly during alcohol-withdrawal (F=10.014, p<0.001). Moreover, mean methylation was associated with depressive (F=2.014, p<0.001) and anxious symptoms in the alcohol-dependent patients (F=2.228, p<0.001). On day 14 of alcohol-withdrawal we found significantly higher methylation rates in those patients who abstained longer before relapse compared to those patients who abstained shorter (F=9.938, p<0.001). Our results suggest an association between BDNF expression and the symptomatology of alcohol withdrawal and imply that changes in the methylation of the BDNF IV gene may contribute to alcohol consumption.
Asunto(s)
Alcoholismo/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Metilación de ADN , Predisposición Genética a la Enfermedad , Regiones Promotoras Genéticas , Adulto , Alcoholismo/diagnóstico , Alcoholismo/metabolismo , Alcoholismo/psicología , Ansiedad/genética , Ansiedad/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Islas de CpG , Depresión/genética , Depresión/metabolismo , Humanos , Masculino , Pronóstico , Estudios Prospectivos , Psicometría , Recurrencia , Riesgo , Síndrome de Abstinencia a Sustancias/genética , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/psicología , Factores de TiempoRESUMEN
Recent studies have shown that smoking and alcoholism may be associated with altered DNA methylation and that alcohol consumption might induce changes in DNA methylation by altering homocysteine metabolism. In this monocenter study, we included 363 consecutive patients referred for hospitalization for alcohol detoxification treatment. Blood samples were obtained on treatment days 1, 3, and 7 for measurement of global DNA methylation in leukocytes by liquid chromatography tandem mass spectrometry. Genomic DNA was used for genotyping the following seven genetic variants of homocysteine metabolism: cystathionine beta-synthase (CBS) c.844_855ins68, dihydrofolate-reductase (DHFR) c.594 + 59del19bp, methylenetetrahydrofolate-reductase (MTHFR) c.677C > T and c.1298A > C, methyltetrahydrofolate-transferase (MTR) c.2756A > G, reduced folate carrier 1 (RFC1) c.80G > A, and transcobalamin 2 c.776C > G. Multivariate linear regression showed a positive correlation of global DNA methylation with alcohol consumption and smoking on day 1 of hospitalization. DNA methylation was not correlated with homocysteine or vitamin plasma levels, nor with the tested genetic variants of homocysteine metabolism. This suggests a direct effect of alcohol consumption and smoking on DNA methylation, which is not mediated by effects of alcohol on homocysteine metabolism.
Asunto(s)
Alcoholismo/sangre , Alcoholismo/epidemiología , Metilación de ADN/fisiología , Fumar/sangre , Fumar/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Alcoholismo/genética , Estudios de Cohortes , Femenino , Variación Genética/fisiología , Alemania/epidemiología , Homocisteína/sangre , Humanos , Masculino , Persona de Mediana Edad , Fumar/genéticaRESUMEN
We examined potential changes in brain-derived neurotrophic factor (BDNF) serum levels and promoter methylation of the BDNF gene in 11 patients with treatment-resistant major depressive disorder during a series of electroconvulsive therapy (ECT). Blood samples were taken before, 1 and 24 h after ECT treatment sessions 1, 4, 7 and 10. Patients remitting under ECT had significantly lower mean promoter methylation rates, especially concerning the exon I promoter, compared to non-remitters (both p < 0.002). These findings may point to a depression subtype in which ECT is particularly beneficial.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/genética , Metilación de ADN , Trastorno Depresivo Mayor/terapia , Trastorno Depresivo Resistente al Tratamiento/terapia , Terapia Electroconvulsiva , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Resistente al Tratamiento/sangre , Trastorno Depresivo Resistente al Tratamiento/genética , Exones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Different studies have described evidence for an association between leptin serum levels and craving in alcohol dependent patients. As leptin expression is regulated by DNA methylation we investigated changes of DNA methylation of the LEP gene promoter region in alcohol dependent patients undergoing withdrawal. Results show that low methylation status is associated with increasing serum leptin levels and elevation of craving for alcohol in the referring patients group. These findings point towards a pathophysiological relevance of changes in DNA methylation of the LEP gene promoter region in alcohol dependence.