Association of cholecystokinin-A receptor gene polymorphism with alcohol dependence in a Japanese population

Abstract

Aims: Cholecystokinin (CCK), one of the most abundant neurotransmitter peptides, interacts with dopamine. Dopaminergic neurotransmission between the ventral tegmental area and the limbic forebrain is a critical neurobiological component of alcohol and drug self-administration. CCK modulates dopamine release in the nucleus accumbens via the CCK-A receptor (R). We recently determined the transcriptional start site of the human CCK-AR gene, and detected two sequence changes (-81A/G and -128G/T) in the promoter region. The aims of the present study were to determine the prevalence of the -81A/G and -128G/T polymorphism of the CCK-AR gene between alcoholics and normal control subjects and the occurrences of the polymorphisms in subtypes of alcoholics. Methods: The above polymorphisms were examined in 435 alcoholics and 1490 control subjects. We excluded subjects with inactive ALDH2 and employed the subjects with ALDH2* 1/2*1 (384 alcoholics and 792 controls). Results: The allelic frequency of -81G in the CCK-AR gene polymorphism (-81A/G) was significantly higher in alcoholics than in control subjects. However, there were no differences between the two groups with respect to the frequency of -128G/T. Alcoholic patients with antisocial personality disorder and with first-degree alcoholic relatives were significantly associated with a higher frequency of the -81G allele. In addition, the age of onset of alcohol dependence was significantly earlier in patients with this allele. Conclusions: The CCK-AR gene -81A/G polymorphism, especially in the -81G allele, may be associated with intractable alcoholism.