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GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers.
Alcohol Clin Exp Res. 2017 Dec; 41(12):2025-2032.AC

Abstract

BACKGROUND

The heritable risk for alcohol use disorder (AUD) is expressed partly through alterations in subjective alcohol response. In this study, we investigated the effects of 2 AUD-risk-associated single nucleotide polymorphisms, GABRA2 rs279858 and GRIK1 rs2832407, on the subjective response to alcohol administered intravenously to healthy social drinkers in a laboratory setting.

METHODS

In total, 93 self-identified European American social drinkers underwent 3 blinded laboratory sessions in which they received intravenous infusions of ethanol at 3 target blood alcohol levels (0.00 mg%, 40 mg%, and 100 mg%) using a "clamp" procedure. The self-reported Biphasic Alcohol Effects Scale (BAES) stimulation and sedation subscales were the primary outcome measures. We examined the effects of these 2 genetic variants on subjective response to alcohol.

RESULTS

For the BAES stimulation subscale scores, adjusting for age, baseline scores, and time effects, individuals with 2 copies of the GABRA2 rs279858 C "risk" allele for AUD exhibited the greatest stimulant responses to high-dose alcohol compared to the other risk allele counts (dose-by-allele count interaction effect, p = 0.001, post hoc contrast for C-allele, p = 0.012). For the BAES sedation subscale scores, adjusting for the same covariates, we detected a dose-by-allele count interaction effect (p = 0.0044) such that subjects with 2 copies of the GRIK1 C "risk" allele reported the greatest sedative response to the higher alcohol dose.

CONCLUSIONS

This study suggests that gene variants contributing to the risk for AUD may alter features of the alcohol dose-response relationship in specific ways. GABRA2 rs279858*C enhances stimulant responses to higher levels of alcohol, while the GRIK1 rs2832407*C-allele increases sedative responses. In summary, GRIK1 and GABRA2 variants have distinct effects on the dose-related subjective response to intravenous alcohol in humans.

Authors+Show Affiliations

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Department of Veterans Affairs, Alcohol Research Center, VA Connecticut Healthcare System (116-A), West Haven, Connecticut.Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Department of Veterans Affairs, Alcohol Research Center, VA Connecticut Healthcare System (116-A), West Haven, Connecticut.Quinnipiac University, Hamden, Connecticut.Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Department of Veterans Affairs, Alcohol Research Center, VA Connecticut Healthcare System (116-A), West Haven, Connecticut.Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Department of Veterans Affairs, Alcohol Research Center, VA Connecticut Healthcare System (116-A), West Haven, Connecticut. Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, Connecticut.Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Department of Veterans Affairs, Alcohol Research Center, VA Connecticut Healthcare System (116-A), West Haven, Connecticut.

Pub Type(s)

Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

29131352

Citation

Yang, Bao-Zhu, et al. "GRIK1 and GABRA2 Variants Have Distinct Effects On the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers." Alcoholism, Clinical and Experimental Research, vol. 41, no. 12, 2017, pp. 2025-2032.
Yang BZ, Arias AJ, Feinn R, et al. GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers. Alcohol Clin Exp Res. 2017;41(12):2025-2032.
Yang, B. Z., Arias, A. J., Feinn, R., Krystal, J. H., Gelernter, J., & Petrakis, I. L. (2017). GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers. Alcoholism, Clinical and Experimental Research, 41(12), 2025-2032. https://doi.org/10.1111/acer.13516
Yang BZ, et al. GRIK1 and GABRA2 Variants Have Distinct Effects On the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers. Alcohol Clin Exp Res. 2017;41(12):2025-2032. PubMed PMID: 29131352.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers. AU - Yang,Bao-Zhu, AU - Arias,Albert J, AU - Feinn,Richard, AU - Krystal,John H, AU - Gelernter,Joel, AU - Petrakis,Ismene L, Y1 - 2017/11/13/ PY - 2017/03/01/received PY - 2017/09/18/accepted PY - 2017/11/14/pubmed PY - 2018/7/19/medline PY - 2017/11/14/entrez KW - BAES KW - GABRA2 KW - GRIK1 KW - Alcohol Use Disorder KW - Intravenous Ethanol SP - 2025 EP - 2032 JF - Alcoholism, clinical and experimental research JO - Alcohol Clin Exp Res VL - 41 IS - 12 N2 - BACKGROUND: The heritable risk for alcohol use disorder (AUD) is expressed partly through alterations in subjective alcohol response. In this study, we investigated the effects of 2 AUD-risk-associated single nucleotide polymorphisms, GABRA2 rs279858 and GRIK1 rs2832407, on the subjective response to alcohol administered intravenously to healthy social drinkers in a laboratory setting. METHODS: In total, 93 self-identified European American social drinkers underwent 3 blinded laboratory sessions in which they received intravenous infusions of ethanol at 3 target blood alcohol levels (0.00 mg%, 40 mg%, and 100 mg%) using a "clamp" procedure. The self-reported Biphasic Alcohol Effects Scale (BAES) stimulation and sedation subscales were the primary outcome measures. We examined the effects of these 2 genetic variants on subjective response to alcohol. RESULTS: For the BAES stimulation subscale scores, adjusting for age, baseline scores, and time effects, individuals with 2 copies of the GABRA2 rs279858 C "risk" allele for AUD exhibited the greatest stimulant responses to high-dose alcohol compared to the other risk allele counts (dose-by-allele count interaction effect, p = 0.001, post hoc contrast for C-allele, p = 0.012). For the BAES sedation subscale scores, adjusting for the same covariates, we detected a dose-by-allele count interaction effect (p = 0.0044) such that subjects with 2 copies of the GRIK1 C "risk" allele reported the greatest sedative response to the higher alcohol dose. CONCLUSIONS: This study suggests that gene variants contributing to the risk for AUD may alter features of the alcohol dose-response relationship in specific ways. GABRA2 rs279858*C enhances stimulant responses to higher levels of alcohol, while the GRIK1 rs2832407*C-allele increases sedative responses. In summary, GRIK1 and GABRA2 variants have distinct effects on the dose-related subjective response to intravenous alcohol in humans. SN - 1530-0277 UR - https://www.unboundmedicine.com/medline/citation/29131352/GRIK1_and_GABRA2_Variants_Have_Distinct_Effects_on_the_Dose_Related_Subjective_Response_to_Intravenous_Alcohol_in_Healthy_Social_Drinkers_ L2 - https://doi.org/10.1111/acer.13516 DB - PRIME DP - Unbound Medicine ER -