Investigation of quantitative trait loci in the CCKAR gene with susceptibility to alcoholism.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Institute of Community Medicine, University of Tsukuba, Japan. ta-okubu@bc4.so-net.ne.jp
Takehito
T
Okubo
Shoji
S
Harada
Susumu
S
Higuchi
Sachio
S
Matsushita
D000328:Adult; D000430:Alcohol Withdrawal Delirium / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics*; D000483:Alleles; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006212:Hallucinations / Q000235:genetics; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci / Q000235:genetics*; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000235:genetics*; D020539:Sequence Analysis, Protein
D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin