Association of cholecystokinin-A receptor gene polymorphism with alcohol dependence in a Japanese population.
OBJECTIVE
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.
Miyasaka
Kyoko
K
Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. miyasaka@tmig.or.jp
Yoshida
Yuki
Y
Matsushita
Sachio
S
Higuchi
Susumu
S
Maruyama
Katsuya
K
Niino
Naoakira
N
Ando
Fujiko
F
Shimokata
Hiroshi
H
Ohta
Shigeo
S
Funakoshi
Akihiro
A
D000328:Adult; D000368:Aged; D019973:Alcohol-Related Disorders / Q000235:genetics* / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000483:Alleles; D002766:Cholecystokinin / Q000378:metabolism; D005787:Gene Frequency; D006801:Humans; D007564:Japan / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D043886:Receptor, Cholecystokinin A / Q000235:genetics* / Q000378:metabolism
D043886:Receptor, Cholecystokinin A; D002766:Cholecystokinin; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial