Alcohol & Alcoholism Vol. 39, No. 1, pp. 25-28, 2004
© Medical Council on Alcohol 2004; all rights reserved
ASSOCIATION OF CHOLECYSTOKININ-A RECEPTOR GENE POLYMORPHISM WITH ALCOHOL DEPENDENCE IN A JAPANESE POPULATION
1 Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 2 Department of Epidemiology, National Institute for Longevity Sciences, Ohbu, 3 Division of Gastroenterology, National Kyushu Cancer Center, Fukuoka, 4 Institute of Clinical Research, National Alcoholism Center, 5 National Alcoholism Center, Kurihama Hospital and 6 Department of Biochemistry and Cell Biology, Institute of Gerontology, Nippon Medical School, Kanagawa, Japan
* Author to whom correspondence should be addressed at: Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho Itabashiku, Tokyo 173-0015, Japan. Tel.: +81 3964 3241 (ext. 3088); Fax: +81 3579 4776; E-mail: miyasaka{at}tmig.or.jp
(Received 20 May 2003; first review notified 31 July 2003; in revised form 20 August 2003; accepted 26 August 2003)
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.
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