Okubo Takehito, Harada Shoji, Higuchi Susumu, Matsushita Sachio
Institute of Community Medicine, University of Tsukuba, Japan.
Alcohol Clin Exp Res. 2002 Aug;26(8 Suppl):2S-5S. doi: 10.1097/01.ALC.0000026826.96191.FB.
Cholecystokinin (CCK) plays an important role in the function of the central nervous system by interacting with dopamine and other neurotransmitters. We previously reported genetic variations in the promoter and coding regions of the CCKA receptor (CCKAR), CCKBR, and CCK genes and a possible association between polymorphisms of the CCKAR gene and alcoholism. In this study, association analyses were re-examined between the polymorphisms of the promoter region of the CCKAR gene and patients with alcohol withdrawal symptoms, in addition to patients with alcoholic liver injury.
A total of 131 Japanese male patients with alcohol withdrawal symptoms, 70 Japanese patients with alcoholic liver injury, and 98 age-matched Japanese male controls (nonhabitual drinkers) were examined using polymerase chain reaction-based single strand conformational polymorphism and sequencing analyses.
Significant differences between patients with hallucination and controls were found in the allele frequencies at the -388 and -85 loci of the CCKAR gene (p = 0.0095, p = 0.0087, respectively), but these differences were not significant after Bonferroni correction for multiple testing. In contrast, the frequency of the homozygous genotype -85CC was significantly higher in hallucination-positive patients than in controls (p = 0.0031) and in patients with hallucination accompanying delirium tremens than in controls (p = 0.0022), and these differences were significant after Bonferroni correction.
The data from the case control suggest that polymorphisms of the promoter region of the CCKAR gene do not play a major role in the pathogenesis of alcohol withdrawal symptoms or alcoholic liver injury. However, a significant association was found between polymorphism at the -85 locus of the CCKAR gene and patients with hallucination, and especially patients with hallucination accompanying delirium tremens.
胆囊收缩素（CCK）通过与多巴胺及其他神经递质相互作用，在中枢神经系统功能中发挥重要作用。我们之前报道了CCKA受体（CCKAR）、CCKBR和CCK基因启动子及编码区的基因变异，以及CCKAR基因多态性与酒精中毒之间可能存在的关联。在本研究中，除了酒精性肝损伤患者外，还重新审视了CCKAR基因启动子区域多态性与酒精戒断症状患者之间的关联分析。
使用基于聚合酶链反应的单链构象多态性和测序分析，对131名有酒精戒断症状的日本男性患者、70名酒精性肝损伤的日本患者以及98名年龄匹配的日本男性对照（非习惯性饮酒者）进行了检查。
在CCKAR基因的-388和-85位点的等位基因频率上，幻觉患者与对照之间存在显著差异（分别为p = 0.0095，p = 0.0087），但在进行多重检验的Bonferroni校正后，这些差异并不显著。相比之下，幻觉阳性患者中纯合基因型-85CC的频率显著高于对照（p = 0.0031），伴有震颤谵妄的幻觉患者中该频率也显著高于对照（p = 0.0022） 在Bonferroni校正后，这些差异具有统计学意义。
病例对照数据表明，CCKAR基因启动子区域的多态性在酒精戒断症状或酒精性肝损伤的发病机制中不发挥主要作用。然而，发现CCKAR基因-85位点的多态性与幻觉患者，尤其是伴有震颤谵妄的幻觉患者之间存在显著关联。
