Hikino Keiko, Otsuka Ikuo, Oshima Shunji, Hishimoto Akitoyo, Ozaki Kouichi, Liu Xiaoxi, Ishikawa Yuki, Mushiroda Taisei, Matsushita Sachio, Terao Chikashi
Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan.
Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan.
Neuropsychopharmacology. 2025 Jun 21. doi: 10.1038/s41386-025-02147-7.
While numerous studies have examined the subjective response to alcohol as an intermediate phenotype to understand its variability, heritability, and predictive capacity for alcohol-related disorders, in-depth analyses linking alcohol reactivity indicators to genetic factors within a large cohort have been absent. Our study aimed to quantify the exact contribution of each genetic variant relevant to the alcohol metabolism to the variability in alcohol response. Specifically, we focused on two primary genes involved in alcohol metabolism (ALDH2 and ADH1B) and three additional loci (ALDH1B1, ALDH1A1, and GCKR) that have been shown to have significant associations with drinking behaviors in Japanese individuals. We conducted the first study to assess the relationship between subjective response to alcohol (SR), evaluated by various assessment subscales, and genetic factors using an intravenous clamp technique in 429 healthy Japanese young adults. By reducing the dimensionality of the data to assess similarity structures, we identified three distinct clusters of SRs and participants. Each participant cluster exhibited a distinct alcohol response profile shaped by specific genetic contributions. Participant cluster 1 demonstrated the strongest response, followed by participant cluster 2, and then participant cluster 3. Participant cluster 1 may also be the most strongly influenced by the allelic status of ALDH2 and ADH1B. SR patterns varied accordingly, and the enrichment of the ALDH22 and ADH1B2, differed across both participant and subscale clusters. Notably, the three participant clusters closely aligned with the three subscale clusters, highlighting a consistent genotype-phenotype relationship. Furthermore, the proportion of variance explained by these genes also varied across subscale clusters. Contrary to known functions, ADH1B showed associations at later timings when ALDH2 associations attenuate. Our three-cluster classification may improve prevention by enabling early identification of individuals at health risk.
虽然众多研究已将对酒精的主观反应作为一种中间表型进行考察，以了解其变异性、遗传性以及对酒精相关障碍的预测能力，但尚未有针对大型队列中酒精反应指标与遗传因素之间关系的深入分析。我们的研究旨在量化与酒精代谢相关的每个基因变异对酒精反应变异性的确切贡献。具体而言，我们聚焦于两个参与酒精代谢的主要基因（乙醛脱氢酶2基因和乙醇脱氢酶1B基因）以及另外三个位点（乙醛脱氢酶1B1基因、乙醛脱氢酶1A1基因和葡萄糖激酶调节蛋白基因），这些基因已被证明与日本人群的饮酒行为存在显著关联。我们开展了第一项研究，采用静脉钳夹技术，在429名健康的日本年轻成年人中评估通过各种评估子量表评估的酒精主观反应（SR）与遗传因素之间的关系。通过降低数据维度以评估相似性结构，我们识别出了SR和参与者的三个不同聚类。每个参与者聚类都呈现出由特定遗传贡献塑造的独特酒精反应特征。参与者聚类1表现出最强的反应，其次是参与者聚类2，然后是参与者聚类3。参与者聚类1可能也最受乙醛脱氢酶2基因和乙醇脱氢酶1B基因等位基因状态的影响。SR模式相应地有所不同，乙醛脱氢酶2基因2和乙醇脱氢酶1B基因2的富集情况在参与者聚类和子量表聚类中均存在差异。值得注意的是，这三个参与者聚类与三个子量表聚类紧密对应，突出了一致的基因型 - 表型关系。此外，这些基因所解释的方差比例在子量表聚类中也有所不同。与已知功能相反，当乙醛脱氢酶2基因的关联减弱时，乙醇脱氢酶1B基因在较晚时间点显示出关联。我们的三聚类分类法可能通过能够早期识别有健康风险的个体来改进预防工作。
