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Role of GABRA2 in moderating subjective responses to alcohol.

ABSTRACT: BACKGROUND:Human twin studies have shown that certain responses to alcohol, including subjective perceptions, are genetically influenced. Previous studies have provided evidence that a low level of response to alcohol predicts future alcohol use disorders in humans. Recent genetic studies suggest an association between alcohol dependence and genetic variation in the ?-aminobutyric acid A (GABA(A)) receptor ?2 subunit gene (GABRA2). Based on a haplotypic association of alcohol dependence with GABRA2, we investigated whether GABRA2 alleles are associated with the subjective responses to clamped alcohol concentration. METHODS:One hundred and ten healthy social drinkers (53 men) underwent the alcohol clamp. Fifteen minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 50 ± 5 mg/dl for 165 minutes. Subjective physiologic responses to alcohol and stimulant and sedative effects of alcohol were measured repeatedly during the alcohol clamp. Because aldehyde dehydrogenase 2 (ALDH2) has been shown to have a great impact on the subjective responses to alcohol, we divided subjects by ALDH2 genotype for further analyses. To examine the role of genetic variation in GABRA2, 7 single nucleotide polymorphisms (SNPs) that were informative in association studies were included as factors in the analysis. RESULTS:Among these 7 SNPs, 3 SNPs (rs279869, rs279858, and rs279837) located in the middle of the GABRA2 gene showed significant associations with subjective effects of alcohol. Subjects with 1 or 2 copies of the more common allele showed greater subjective responses to alcohol than did individuals homozygous for the alcohol dependence-associated allele regardless of ALDH2 genotype. CONCLUSIONS:These findings confirm and extend the observation that the GABRA2 alleles affect the subjective responses to alcohol, and suggest that the genetic variations in GABRA2 might play a role in the risk of alcohol use disorders by moderating the subjective effects of alcohol.

SUBMITTER: Roh S

PROVIDER: S-EPMC3472524 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Role of GABRA2 in moderating subjective responses to alcohol.

Roh Sungwon S Matsushita Sachio S Hara Sachiko S Maesato Hitoshi H Matsui Toshifumi T Suzuki Go G Miyakawa Tomohiro T Ramchandani Vijay A VA Li Ting-Kai TK Higuchi Susumu S

Alcoholism, clinical and experimental research 20101130 3

<h4>Background</h4>Human twin studies have shown that certain responses to alcohol, including subjective perceptions, are genetically influenced. Previous studies have provided evidence that a low level of response to alcohol predicts future alcohol use disorders in humans. Recent genetic studies suggest an association between alcohol dependence and genetic variation in the γ-aminobutyric acid A (GABA(A)) receptor α2 subunit gene (GABRA2). Based on a haplotypic association of alcohol dependence ...[more]

PMID: 21118274

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Project description:BACKGROUND:Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. METHODS:One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol "clamp," during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response. RESULTS:Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. CONCLUSIONS:Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol.

Project description:Aims:Converging evidence has implicated perturbed inflammatory signaling in alcohol use disorders (AUDs), and both animal and human studies suggest that alcohol-induced inflammatory signaling is mediated by Toll-Like Receptor 4 (TLR4). We previously demonstrated that TLR4 is hypermethylated in subjects with AUD compared to control individuals. Examining the relationship between TLR4 methylation and subjective alcohol responses could shed light on the role of TLR4 in promoting AUDs, thereby highlighting its potential as a treatment target. Short summary:Significant interactions were demonstrated between Toll-like Receptor 4 (TLR4) methylation and human alcohol consumption patterns, such that greater methylation was associated with decreased positive and negative self-reported arousal during an alcohol infusion among light-to-moderate drinkers, but increased self-reported positive arousal and physiological arousal (i.e. systolic blood pressure) among heavy drinkers. Methods:Latent growth models were used to examine the relationship between TLR4 methylation and subjective responses and physiological measures of arousal during an alcohol infusion across 222 drinkers. Results:We observed significant interactions of TLR4 methylation and alcohol use (drinks per week) on intercepts for self-report and physiological arousal measures. Specifically, light-to-moderate drinkers had positive associations between methylation and stimulation and tension (r's = 0.21-0.24), and heavy drinkers had negative associations (r's = -0.15 to -0.21). There were also significant interaction effects on changes in tension (? = 0.31, P < 0.01), systolic blood pressure (? = 0.74, P < 0.01) and marginal effects on stimulation (? = 0.15, P = 0.07) during the infusion, such that methylation was associated with decreased arousal among light-to-moderate drinkers (r's = -0.12 to -0.25) but stable or increased arousal among heavy drinkers (r's = 0.05-0.19). Conclusions:Findings suggest that the relationship between TLR4 methylation and subjective and physiological arousal during acute alcohol intoxication depends upon on self-reported alcohol use. These data demonstrate the influence of TLR4 on subjective responses to alcohol, thereby supporting the need for further research on its potential as a pharmacological treatment target.

Project description:BackgroundsThe oldest-old population is increasing sharply in China, and intergenerational support has been their primary source of caregiving. Although intergenerational support has been found to be associated with wellbeing of older people in previous study, most analysis were from the perspective of children's characteristics and exchange patterns. This study aims to investigate the impact of different types of intergenerational support on subjective wellbeing among Chinese oldest-old and the variation across groups of different economic status, based on their five-tier of needs (physiological needs, safety needs, love/belonging needs, esteem needs, and self-actualization needs).MethodsWe included older adults aged ≥ 80 years from the 2018 Chinese longitudinal Healthy Longevity Survey (CLHLS). We assessed older people's subjective wellbeing by their life satisfaction and psychological health. We evaluated four types of intergenerational support: parents provide financial support, receive financial, instrumental and emotional support. We applied binary logistic regression analysis to analyze the association between different intergenerational support and older people's subjective wellbeing and the moderating effect of self-rated economic status on this relationship.ResultsA total of 8.794 participants were included, with a mean age of 91,46 years (standard deviation:7.60). Older adults who provide financial support (OR: 1.37, 95% CI: 1.01, 1.85) and receive emotional support (OR: 1.99, 95% CI: 1.40, 2.83) report better subjective wellbeing. However, receiving instrumental support depressed psychological health (OR: 0.67, 95% CI: 0.56, 0.79) while improved life satisfaction (OR: 1.42, 95% CI: 1.04, 1.55). Receiving emotional support promoted parents' psychological health among all combinations of support, and receiving all the three types together raised their subjective wellbeing most.ConclusionsOur study recognizes that higher level of subjective wellbeing for oldest-old is related to providing financial support, receiving emotional and certain instrumental support. In addition, higher economic status can moderate these associations.

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Role of GABRA2 in moderating subjective responses to alcohol.

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Role of GABRA2 in moderating subjective responses to alcohol.

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