Dissertation
Dissertation > Medicine, health > Neurology and psychiatry > Psychiatry > Mental disorders of toxic > Alcohol disorder

The Changes of GABRA1Gene Histone H3K9Acetylation and Gene Expression in Alcohol-dependent Patients

Author LeiJinPing
Tutor ZhangRuiLing
School Xinxiang Medical
Course Psychiatry and Mental Health
Keywords alcohol dependence GABRA1 histone acetylation gene expression
CLC R749.62
Type Master's thesis
Year 2013
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BackgroundAlcohol dependence is a complex disease which is caused by interactions of multiple genetic and environmental factors. Current studies show that epigenetic modifications are involved in the pathological process of alcohol dependence, and the GABAA receptors are involved in neurobiology process of alcohol dependence. GABRA1gene is associated with some behavioral phenotypes in alcohol-dependent patients, but the exact mechanism remains unclear. This article explores the relationship between GABRA1gene expression and clinical characters from the aspect of epigenetic modifications in alcohol-dependent patients.Objective1. To explore the role of GABRA1gene epigenetic modifications in the pathogenesis of alcohol dependence by analysing the relative levels of GABRA1gene histone H3K.9acetylation and gene expression in alcohol dependence case group and the relationship between them.2. To explore the relationship between epigenetic modifications and clinical characters by analyzing respectively the relationships between severity or craving from alcohold-ependent patients and the levels of GABRA1gene histone H3K9acetylation and gene expression.Methods1. According to DSM-IV diagnosis criteria, alcohol dependence case group was recruited. Control group was recruited matched with case group on age, degree of education and region. The severity of alcohol-dependent symptoms was measured using the Alcohol Use Disorders Identification Test (AUDIT) in two groups. Alcohol carving was assessed at admission using the Obessive Compulsive Drinking Scale (OCDS) in case group.2. DNA fragments were extracted through the Chromatin Immunoprecipitation(Chip) assay. The levels of histone H3K9modifications in GABRA1and GAPDH gene promoter were measured by Real-time PCR. The relative levels of GABRA1gene was calculated between case group and control group using the2-ΔΔCT method. Different levels of histone H3K9acetylation were measured using two independent sample t-test between the two groups.3. The levels of GABRA1gene expression were measured by Real-time PCR between case group and control group. The relative levels of GABRA1mRNA were standardized by compared with GAPDH using the2-ΔΔCT method. Different expression levels were compared by using two independent sample t-test between the two groups.4. In addition to analyse the relationship beween histone H3K9acetylation level in GABRA1gene promoter region and GABRA1mRNA expression level, the relationships between severity or craving from alcohol-dependent patients and the levels of GABRA1gene histone H3K9acetylation and gene expression were measured respectively through Pearson correlation analysis method in case group.Results1. This research collected50cases,36healthy controls, all were male. The age of cases and controls were (41.18±1.34) years and (41.40±1.70) years. Cases and controls had no significant differences on age (t=0.363, P=0.718). The mean of the OCDS total score and OCDS-os score and OCDS-cs score were22.36±0.77,9.30±0.37,13.10±0.44respectively in case group. The average number of AUDIT was19.06±0.81(values greater than or equal to8as a positive).2. Compared with control group (1.00±0.00, n=36), histone H3K9acetylation level of GABRA1gene promoter region (2.39±0.15,n=50) was significantly increased (t=9.036, P=0.000) in the peripheral blood of case group, histone H3K9acetylation level of GAPDH gene promoter region (1.06±0.03, n=50) promoter region was no significant difference (t=1.748, P=0.084) in the peripheral blood of case group.3. Compared with the control group (1.00±0.00, n=36), GABRA1mRNA level (2.13±0.14, n=50) was significantly higher (t=7.582,P=0.000) in peripheral blood of case group.4. The expression level of GABRA1gene was positively correlated (r=0.338, P=0.016) with histone H3K9acetylation level of GABRA1gene promoter region in case group.5. There were no correlation among OCDS total score, OCDS-os score, OCDS-cs score and the level of GABRA1gene histone H3K9acetylation (r=-0.093, P=0.521; r=-0.152, P=0.292; r=-0.056, P=0.700). OCDS total score was positively correlated with the level of GABRA1gene expression (r=0.323, P=0.022), OCDS-os score was positively correlated with the level of GABRA1gene expression (r=0.296, P=0.037), OCDS-cs score was positively correlated with the level of GABRA1gene expression (r=0.308, P=0.020).6. Alcohol severity scale AUDIT was no correlated with the level of GABRA1gene histone H3K9acetylation (r=0.144, P=0.318). Alcohol severity scale AUDIT was positively correlated with the level of GABRA1gene expression (r=0.340, P=0.016).Conclusion1. Increasing histone H3K.9acetylation in GABRA1promotor region promoted GABRA1mRNA expression may be one of the biological mechanisms of alcohol dependence.2. Increasing expression level of GABRA1gene was associated with carving and severity extents in alcohol-dependent patients.

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