Role of GABRA2 in moderating subjective responses to alcohol.
- Authors
- Roh, Sungwon; Matsushita, Sachio; Hara, Sachiko; Maesato, Hitoshi; Matsui, Toshifumi; Suzuki, Go; Miyakawa, Tomohiro; Ramchandani, Vijay A; Li, Ting-Kai; Higuchi, Susumu
- Year
- 2011
- Journal
- Alcoholism, clinical and experimental research
- PMID
- 21118274
- DOI
- 10.1111/j.1530-0277.2010.01357.x
- PMCID
- PMC3472524
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 Ξ³-aminobutyric acid A (GABA(A)) receptor Ξ±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 Β± 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.
Representative sample of breath alcohol concentration clamping paradigm. SS, Sensation Scale; BAES, Biphasic Alcohol Effects Scale.
Pattern of linkage disequilibrium (LD) within GABRA2 identified by SNPs 1 to 7. The numbers on the top correspond to each SNP as named in Table 2. Each number in the diamonds represents LD (Dβ²) values for the respective SNP pairs. β, Absolute LD (Dβ² = 1); 97, Dβ² = 0.97 between SNPs 1 and 4.
Estimated mean (SD) for the initial response measured by Sensation Scale by genotypes of ALDH2 and GABRA2 SNPs 4 and 5. (A) Among subjects with ALDH2*1 /*1, initial responses did not differ by the genotype of GABRA2 SNPs 4 and 5. (B) Among subjects with ALDH2*1 /*2, those with 1 or 2 copies of the SNP4 C-allele (SNP5 A-allele) of GABRA2 showed significantly more increased initial responses in Anesthetic (p = 0.015), Dynamic Peripheral (p = 0.030), and General (p = 0.021) subscales than those homozygous for the SNP4 A-allele (SNP5 G-allele). Asterisks indicate significant differences (p < 0.05). An, Anesthetic subscale; DP, Dynamic Peripheral subscale; Ge, General subscale.
Estimated mean (SD) for the initial response measured by Biphasic Alcohol Effects Scale by genotypes of ALDH2 and GABRA2 SNPs 4 and 5. (A) Among subjects with ALDH2*1 /*1, there was a trend for higher initial responses in Stimulant (p = 0.071) subscale among the SNP4 C-allele (SNP5 A-allele) carriers than the SNP4 A-allele (SNP5 G-allele) homozygotes. (B) Among subjects with ALDH2*1 /*2, there were no significant differences in the initial responses by the genotypes of GABRA2 SNPs 4 and 5.
Estimated mean (SD) for the initial response measured by Sensation Scale by genotypes of ALDH2 and GABRA2 SNP6. (A) Among subjects with ALDH2*1 /*1, there were significant differences in Anesthetic (p = 0.033) and Dynamic Peripheral (p = 0.016) subscale scores among the SNP6 TT, TC, and CC genotypes. (B) Among subjects with ALDH2*1 /*2, those with 1 or 2 copies of the SNP6 T-allele of GABRA2 showed significantly more increased initial responses in Anesthetic (p = 0.015), Dynamic Peripheral (p = 0.031), and General (p = 0.021) subscales than those homozygous for the SNP6 C-allele. Asterisks indicate significant differences (p < 0.05). An, Anesthetic subscale; DP, Dynamic Peripheral subscale; Ge, General subscale.
Estimated mean (SD) for the initial response measured by Biphasic Alcohol Effects Scale by genotypes of ALDH2 and GABRA2 SNP6. (A) Among subjects with ALDH2*1 /*1, there were no significant differences in the initial responses by GABRA2 SNP6. (B) Among subjects with ALDH2*1 /*2, there were also no significant differences in the initial responses by the genotype of GABRA2 SNP6.
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