Genetic association of FKBP5 with trait resilience in Korean male patients with alcohol use disorder

AbstractThe FKBP5 gene is known to have an important role in alcohol use disorder (AUD) in response to stress and has been reported to affect stress responses by interacting with childhood trauma. This study investigated the effects of the FKBP5 polymorphism rs1360780 and childhood trauma on trait resilience in male patients with AUD. In addition, allele-specific associations between FKBP5 DNA methylation and resilience were examined. In total, 297 men with AUD were assessed for alcohol use severity, childhood trauma, resilience, and impulsivity. Genotyping for FKBP5 rs1360780 and DNA methylation were analyzed. The effects of the rs1360780 single nucleotide polymorphism (SNP) and clinical variables on resilience were tested using linear regression analysis. Possible associations between FKBP5 DNA methylation and resilience were tested with partial correlation analysis. The rs1360780 risk allele, a low education level, and high impulsivity were associated with diminished resilience, whereas no significant main or interaction effect of childhood trauma with the SNP rs1360780 genotype on resilience was shown. No significant association between FKBP5 DNA methylation and resilience was found. The present study demonstrated the involvement of the rs1360780 risk allele in trait resilience in men with AUD, suggesting that the genetic vulnerability of FKBP5 may influence resilience related to AUD.

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Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration

Drug Metabolism and Personalized Therapy ◽

10.1515/dmpt-2017-0021 ◽

2017 ◽

Vol 32 (3) ◽

Cited By ~ 6

Author(s):

Dmitry A. Sychev ◽

Mikhail S. Zastrozhin ◽

Igor I. Miroshnichenko ◽

Natalia V. Baymeeva ◽

Valery V. Smirnov ◽

...

Keyword(s):

Alcohol Use ◽

Alcohol Use Disorder ◽

Equilibrium Concentration ◽

Primary Objective ◽

Plasma Drug ◽

Metabolism Rate ◽

Genes Encoding ◽

Allele Specific ◽

Male Patients ◽

Contradictory Data

AbstractBackground:Haloperidol is used for the treatment of alcohol use disorders in patients with signs of alcohol-related psychosis. Haloperidol therapy poses a high risk of adverse drug reactions (ADR). Contradictory data, which include the effects of genetic polymorphisms in genes encoding the elements of haloperidol biotransformation system on haloperidol metabolism rate and plasma drug concentration ratio, are described in patients with different genotypes. The primary objective of this study was to investigate the effects ofMethods:The study included 69 male patients with alcohol use disorder. Genotyping was performed using the allele-specific real-time PCR.Results:Results indicated that both C/D indexes and equilibrium concentration levels depend onConclusions:The study demonstrates that

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Changes in DNA methylation persist over time in males with severe alcohol use disorder—A longitudinal follow‐up study

American Journal of Medical Genetics Part B Neuropsychiatric Genetics ◽

10.1002/ajmg.b.32833 ◽

2021 ◽

Author(s):

Soundarya Soundararajan ◽

Arpana Agrawal ◽

Meera Purushottam ◽

Shravanthi Daphne Anand ◽

Bhagyalakshmi Shankarappa ◽

...

Keyword(s):

Dna Methylation ◽

Alcohol Use ◽

Alcohol Use Disorder ◽

Follow Up Study ◽

Over Time

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The Effects of Attention-Deficit/Hyperactivity Disorder Symptom and Impulsivity on Abstinence Period of Male Patients with Alcohol Use Disorder

Journal of Korean Neuropsychiatric Association ◽

10.4306/jknpa.2016.55.4.443 ◽

2016 ◽

Vol 55 (4) ◽

pp. 443 ◽

Cited By ~ 1

Author(s):

Jung Min Jo ◽

Sung-Doo Won ◽

Kyung Hi Jung ◽

Dong Hyun Ahn

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Alcohol Use ◽

Attention Deficit ◽

Alcohol Use Disorder ◽

Hyperactivity Disorder ◽

Disorder Symptom ◽

Male Patients ◽

Abstinence Period

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Epigenetic Regulation of GABAergic Neurotransmission and Neurosteroid Biosynthesis in Alcohol Use Disorder

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa073 ◽

2020 ◽

Author(s):

Eleonora Gatta ◽

Alessandro Guidotti ◽

Vikram Saudagar ◽

Dennis R Grayson ◽

Dario Aspesi ◽

...

Keyword(s):

Dna Methylation ◽

Alcohol Use ◽

Promoter Region ◽

Alcohol Use Disorder ◽

Hydroxysteroid Dehydrogenase ◽

Fine Tuning ◽

Translocator Protein ◽

Gas Chromatography Mass Spectrometry ◽

Gabaergic Neurotransmission

Abstract Background Alcohol use disorder (AUD) is a chronic relapsing brain disorder. GABAA receptor (GABAAR) subunits are a target for the pharmacological effects of alcohol. Neurosteroids play an important role in the fine-tuning of GABAAR function in the brain. Recently, we have shown that AUD is associated with changes in DNA methylation mechanisms. However, the role of DNA methylation in the regulation of neurosteroid biosynthesis and GABAergic neurotransmission in AUD patients remains under-investigated. Methods In a cohort of postmortem brains from 20 male controls and AUD patients, we investigated the expression of GABAAR subunits and neurosteroid biosynthetic enzymes and their regulation by DNA methylation mechanisms. Neurosteroid levels were quantified by gas chromatography-mass spectrometry. Results The α 2 subunit expression was reduced due to increased DNA methylation at the gene promoter region in the cerebellum of AUD patients, a brain area particularly sensitive to the effects of alcohol. Alcohol-induced alteration in GABAAR subunits was also observed in the prefrontal cortex. Neurosteroid biosynthesis was also affected with reduced cerebellar expression of the 18kDa translocator protein and 3α-hydroxysteroid dehydrogenase mRNAs. Notably, increased DNA methylation levels were observed at the promoter region of 3α-hydroxysteroid dehydrogenase. These changes were associated with markedly reduced levels of allopregnanolone and pregnanolone in the cerebellum. Conclusion Given the key role of neurosteroids in modulating the strength of GABAAR-mediated inhibition, our data suggest that alcohol-induced impairments in GABAergic neurotransmission might be profoundly impacted by reduced neurosteroid biosynthesis most likely via DNA hypermethylation.

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