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Aims: Most of the acetaldehyde, a recognized animal carcinogen, generated during alcohol metabolism is eliminated by liver mitochondrial aldehyde dehydrogenase 2 (ALDH2). More than 40% of Japanese people have the inactive form of ALDH 2, and inactive ALDH2 is a risk factor for multiple cancer of the esophagus, as well as head and neck cancer. Possible associations between pancreatic cancer and ALDH2 gene polymorphism, as well as between colon cancer and ALDH2 gene polymorphism, in conjunction with smoking and/or drinking habits, were examined in a Japanese population. Methods: Patients with pancreatic cancer ( n = 187) and with colon cancer ( n = 49) were examined. The drinking (5 g ethanol consumption/day) and/or smoking habits as well as ALDH2 gene polymorphism were examined. The age-matched control subjects were recruited in the NILS Longitudinal Study of Aging (LSA). Results: Aging, smoking and inactive ALDH2, but not alcohol, are independent risk factors for pancreatic cancer. The frequency of smoking habits tended to be higher in patients with colon cancer compared with the patients without cancer. However, age, body mass index or the distribution of ALDH2 genotypes did not differ significantly among the patients with colon cancer, colon polyps and others. Conclusions: Inactive ALDH2 is an independent risk factor for pancreatic cancer, but inactive ALDH2 might not be a risk for colon cancer. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S120–S126. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background. The etiology of gallstone formation is multifactorial, and genetic factors are involved. The genetic variations of cholecystokinin A receptor (CCKAR) in patients having gallstones and the molecular mechanisms of this polymorhpism were examined. The involvement of CCK-AR in gallstone formation was confirmed using CCK-AR gene knockout mice. Methods. CCK-AR gene expression was determined by Northern transfer analysis in gallbladders with or without gallstones. Genetic variations were determined by Southern blot and by direct sequencing. Molecular mechanisms in terms of the transcriptional activity and methylation status were examined. Finally, we investigated whether gallstone formation was enhanced in CCK-AR gene knockout mice. Results. The gene expression of CCK-AR was significantly decreased in gallbladders with gallstones compared to those without gallstones. No genetic variations were detected in the coding region, but two sequence variations were detected in the promoter region in gallstone patients. However, no significant differences were found for the promoter activities of polymorphic promoter constructs. In contrast, less methylation in the promoter region was related to substantial expression of the CCK-AR gene. Gallstone formation was enhanced in CCK-AR gene knockout mice. The homozygote (GG/ TT) polymorphism of the CCK-AR gene showed a significantly higher percentage of body fat. Conclusions. Deteriorating gallbladder contractions, possibly induced by alterations in the CCK-AR gene, as well as CCK-AR gene polymorphism, promoted gallstone formation. [ABSTRACT FROM AUTHOR]

Background. We have previously shown that polymorphism in the promoter region of the human cholecystokinin type-A receptor (CCKAR) gene is a genetic factor affecting obesity. However, there have not yet been any reports of analysis of the promoter activity of CCKAR genes, and thus almost nothing is known about CCKAR transcriptional regulation. Methods. Using STC-1 cells, an enteroendocrine tumor cell line, we measured the promoter activity of the human CCKAR gene by a transient transfection method. Results. We showed that STC-1 cells expressed CCKAR as well as its peptideligand, CCK. Analysis of a series of 5'-deleted promoter constructs showed that the proximal 622-base region upstream from the initiation site, which contained two GC-box motifs, was important as a regulatory region for the transcriptional activity. However, no significant differences were found for the promoter activities of polymorphic promoter constructs. Conclusions. These results suggest that the reported polymorphism may not play a role in transcriptional regulation. Background. We have previously shown that polymorphism in the promoter region of the human cholecystokinin type-A receptor (CCKAR) gene is a genetic factor affecting obesity. However, there have not yet been any reports of analysis of the promoter activity of CCKAR genes, and thus almost nothing is known about CCKAR transcriptional regulation. Methods. Using STC-1 cells, an enteroendocrine tumor cell line, we measured the promoter activity of the human CCKAR gene by a transient transfection method. Results. We showed that STC-1 cells expressed CCKAR as well as its peptideligand, CCK. Analysis of a series of 5'-deleted promoter constructs showed that the proximal 622-base region upstream from the initiation site, which contained two GC-box motifs, was important as a regulatory region for the transcriptional activity. However, no significant differences were found for the promoter activities of polymorphic promoter constructs.... [ABSTRACT FROM AUTHOR]

Purpose: To study the association between Cholecystokinin A receptor (CCKAR) genotypes and intelligence in community-living men and women. Method: Subjects were 2251 community-dwelling Japanese men and women aged 40 to 79 years. The CCKAR gene promoter polymorphisms A-81G and G-128T were determined. Intelligence was assessed by Japanese Wechsler Adult Intelligence Scales – Revised Short Forms (JWAIS-R SF). The difference in intelligence between wild type and mutation was tested. Results: There were no subjects with AA/GT, AA/TT, or AG/TT genotypic combinations. Both A-81G and G-128T genotypes were related to intelligence quotient (IQ) estimated by JWAIS-R SF. The mean and SE of IQ levels of subjects with the wild-type allele and the mutation allele at nucleotide -128 were 103.4 ± 0.3 and 101.6 ± 0.6, respectively. There was a significant difference in IQ for G-128T (p=0.008). The difference in IQ for A-81G was also significant (p=0.011). The IQ level was 103.6 ± 0.4 in the subjects with the wild-type allele and 102.0 ± 0.5 in the subjects with the mutation. Differences in IQ levels by haplotypes for combinations of A-81G/G-128T were examined. IQ significantly decreased with an increasing number of mutation alleles (p=0.018). Conclusion: There were statistically significant differences in IQ for CCKAR gene promoter polymorphisms A-81G and G-128T in community-living Japanese. [Copyright &y& Elsevier]