Japanese Alcoholics Research Articles

Trends in Gastrectomy and ADH1B and ALDH2 Genotypes in Japanese Alcoholic Men and Their Gene–gastrectomy, Gene–gene and Gene–age Interactions for Risk of Alcoholism

The life-time drinking profiles of Japanese alcoholics have shown that gastrectomy increases susceptibility to alcoholism. We investigated the trends in gastrectomy and alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) genotypes and their interactions in alcoholics. This survey was conducted on 4879 Japanese alcoholic men 40 years of age or older who underwent routine gastrointestinal endoscopic screening during the period 1996-2010. ADH1B/ALDH2 genotyping was performed in 3702 patients. A history of gastrectomy was found in 508 (10.4%) patients. The reason for the gastrectomy was peptic ulcer in 317 patients and gastric cancer in 187 patients. The frequency of gastrectomy had gradually decreased from 13.3% in 1996-2000 to 10.5% in 2001-2005 and to 7.8% in 2006-2010 (P < 0.0001). ADH1B*1/*1 was less frequent in the gastrectomy group than in the non-gastrectomy group (age-adjusted prevalence: 20.4 vs. 27.6%, P = 0.006). ALDH2 genotype distribution did not differ between the two groups. The frequency of inactive ALDH2*1/*2 heterozygotes increased slightly from 13.0% in 1996-2000 to 14.0% in 2001-2005 and to 15.4% in 2006-2010 (P < 0.08). Two alcoholism-susceptibility genotypes, ADH1B*1/*1 and ALDH2*1/*1, modestly but significantly tended not to occur in the same individual (P = 0.026). The frequency of ADH1B*1/*1 decreased with ascending age groups. The high frequency of history of gastrectomy suggested that gastrectomy is still a risk factor for alcoholism, although the percentage decreased during the period. The alcoholism-susceptibility genotype ADH1B*1/*1 was less frequent in the gastrectomy group, suggesting a competitive gene-gastrectomy interaction for alcoholism. A gene-gene interaction and gene-age interactions regarding the ADH1B genotype were observed.

Development of squamous neoplasia in esophageal iodine‐unstained lesions and the alcohol and aldehyde dehydrogenase genotypes of Japanese alcoholic men

We investigated the development of esophageal neoplasia in biopsy specimens of the distinct iodine-unstained lesions (DIULs) ≥ 5 mm detected in 280 of 2,115 Japanese alcoholic men who underwent screening by esophageal iodine staining. Low-grade intraepithelial neoplasia (LGIN) was diagnosed in 155 of them, high-grade intraepithelial neoplasia (HGIN) in 57, and invasive SCC in 35. The size of the DIULs increased with the degree of neoplasia. Most LGINs were flat and were missed before iodine staining. Some DIULs became a light pink color (PC) about 2 min after staining, and 2.6, 56.1 and 96.0% of the LGIN, HGIN and invasive SCC lesions, respectively, were PC-sign-positive. Multiple DIULs of any size markedly increased the risk of LGIN [adjusted OR (95%CI) = 10.1 (7.12-14.5)], HGIN [27.9 (14.6-53.4)] and invasive SCC [21.6 (10.1-46.4)], and were strongly associated with the presence vs. absence of DIULs ≥ 5 mm [13.3 (9.21-19.1)], inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) vs. ALDH2*1/*1 [2.60 (1.79-3.78)], and less-active alcohol dehydrogenase-1B (ADH1B*1/*1) vs. ADH1B*2 allele [2.61 (1.87-3.64)]. The combination of ALDH2*1/*2 and ADH1B*1/*1 synergistically increased the risk of LGIN [4.53 (2.17-9.47)], HGIN [10.4 (4.34-24.7)] and invasive SCC [21.7 (7.96-59.3)]. Esophageal neoplasia developed at earlier ages in those with ALDH2*1/*2. Biopsy-proven HGIN was diagnosed as invasive SCC in 15 (39.5%) of 38 patients after endoscopic mucosectomy or surgery. In conclusion, large size, non-flat appearance, positive PC sign and multiplicity of DIULs and ALDH2*1/*2 and ADH1B*1/*1 were associated with development of esophageal neoplasia in Japanese alcoholics. Biopsy-proven HGIN should be totally resected for both diagnostic and therapeutic purposes.

P53 protein accumulation, iodine-unstained lesions, and alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotypes in Japanese alcoholic men with esophageal dysplasia

Inactive heterozygous aldehyde dehydrogenase-2 ( ALDH2 *1/ *2 ) and less-active alcohol dehydrogenase-1B ( ADH1B *1/ *1 ) increase the risk of esophageal cancer in East Asian drinkers, and esophageal cancer multiplicity is strongly associated with ALDH2 *1/ *2 . p53 alterations are key molecular events in multifocal carcinogenesis in the esophagus. We studied 260 esophageal-cancer free Japanese alcoholics with esophageal dysplasia diagnosed by biopsy of distinct iodine-unstained lesions (DIULs) ⩾5 mm. The degree of p53 protein accumulation was positively associated with the degree of atypia ( p < 0.0001) and size ( p = 0.040) of DIULs and with the presence of multiple DIULs (p = 0.070), but not with ALDH2 *1/ *2 or ADH1B *1/ *1 .

Serotonin transporter gene polymorphism and psychiatric disorders: Is there a link?

Though still in infancy, the field of psychiatric genetics holds great potential to contribute to the development of new diagnostic and therapeutic options to treat these disorders. Among a large number of existing neurotransmitter systems, the serotonin system dysfunction has been implicated in many psychiatric disorders and therapeutic efficacy of many drugs is also thought to be based on modulation of serotonin. Serotonin transporter gene polymorphism is one of the most extensively studied polymorphisms in psychiatric behavioral genetics. In this article, we review the status of evidence for association between the serotonin gene polymorphism and some common mental disorders like affective disorders, post-traumatic stress disorder, obsessive-compulsive disorder, suicide, autism, and other anxiety and personality disorders. Going beyond traditional association studies, gene-environment interaction, currently gaining momentum, is also discussed in the review. While the existing information of psychiatric genetics is inadequate for putting into practice genetic testing in the diagnostic work-up of the psychiatric patient, if consistent in future research attempts, such results can be of great help to improve the clinical care of a vast majority of patients suffering from such disorders.

Electrospray Ionization-Mass Spectrometric Measurement of Sake, a Traditional Japanese Alcohol Beverage, for Characterization

A rapid method for the characterization of sake by measuring the ratio of the peak intensities of taste components in sake, using electrospray ionization/mass spectrometry (ESI/MS) has been developed. Twenty-six different kinds of sake samples were collected and analyzed by ESI/MS. The ESI/MS ion peaks were assigned to amino acids, organic acids, and sugars. Principal component analysis was performed using the respective peak intensities obtained by ESI/MS measurements. As a result, the cumulative proportion of the two first principal components was over 70%, and these components could be used for the characterization of sake.

O836 The anomalities of Japanese fetal alcohol effects (FAE) infants

O836 The anomalities of Japanese fetal alcohol effects (FAE) infants

Association Between Personality Traits and ALDH2 Polymorphism in Japanese Male Alcoholics

Alcoholics who have developed alcoholism despite a strong negative risk factor, that is, the inactive form of aldehyde dehydrogenase-2 (ALDH2), are considered advantageous for studying predisposing factors for alcoholism. This study aimed to compare personality profiles and clinical characteristics between alcoholics with active and inactive ALDH2. Subjects were 460 male Japanese alcoholics hospitalized in Kurihama Alcoholism Center. All patients underwent Cloninger's Tridimensional Personality Questionnaire and semi-structured interviews 4 to 8 weeks after admission to obtain data on personalities and clinical characteristics. ALDH2 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Sixty-six patients had the inactive form of ALDH2 (ALDH2*1/2*2) and 394 had the active form (ALDH2*1/2*1). Alcoholics with inactive ALDH2 had significantly higher novelty-seeking (NS) and lower harm-avoidance (HA) scores compared with those with active ALDH2. The inactive ALDH2 group experienced delirium tremens significantly less frequently than the active ALDH2 group. These results suggest that high NS and low HA scores in alcoholics with inactive ALDH2 are associated with an increased risk for developing alcoholism, despite a low enzymatic ability to eliminate toxic acetaldehyde in these subjects. A study of alcoholics with inactive ALDH2 is useful for detecting environmental or personality factors related to alcoholism.

Phenomenological Distinctions Needed in DSM-V: Delirium, Subsyndromal Delirium, and Dementias

Phenomenological Distinctions Needed in DSM-V: Delirium, Subsyndromal Delirium, and Dementias

Contribution of the alcohol dehydrogenase‐1B genotype and oral microorganisms to high salivary acetaldehyde concentrations in Japanese alcoholic men

The less-active homozygous alcohol dehydrogenase-1B (ADH1B*1/*1) and inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) increase the risk of upper aerodigestive tract cancer (UADTC) in Japanese alcoholics. We evaluated associations between ADH1B/ALDH2 genotypes and the blood and salivary ethanol/acetaldehyde levels of 80 Japanese alcoholic men in the morning when they first visited our hospital after drinking the day before. Higher levels of ethanol persisted in the blood for longer periods in ADH1B*1/*1 carriers (n = 25) than in ADH1B*2 allele carriers after adjustment for the amount and time of the preceding alcohol consumption and body weight [median (25th-75th %): 20.5 mM (15.5-52.4) vs. below detection level (<DL) (<DL-6.4), p = 0.0003]. The ethanol levels in blood and saliva were similar, but the acetaldehyde levels in saliva were strikingly higher than in the blood, and were higher in ADH1B*1/*1 carriers than in ADH1B*2 allele carriers [47.4 muM (22.2-87.6) vs. 1.60 (<DL-26.3) in the saliva, p = 0.009]. The salivary acetaldehyde levels were correlated with salivary acetaldehyde production (r = 0.34, p = 0.002). The oral bacteria and yeast counts were correlated with salivary acetaldehyde production. Both the microorganisms counts and acetaldehyde production decreased after 3 weeks of abstinence, and the decreases were correlated (r = 0.35, p = 0.042). No effect of inactive ALDH2 (n = 12) on ethanol lingering the next morning was observed. In conclusion, the high salivary acetaldehyde levels in the alcoholics were partly attributable to prolonged ethanol exposure because of the less-active ADH1B and increased salivary acetaldehyde production as a result of oral microorganism overgrowth, and may explain their high risk for UADTC.

Incidence of Alcoholic Pancreatitis in Japanese Alcoholics

To estimate the incidence of alcoholic pancreatitis, a dependence questionnaire survey was administered to male members of the sobriety association in Japan. Questionnaires asking about age, age at start of alcohol drinking, amount of alcohol consumption, duration of drinking, the initiated age of abstinence, medical history of pancreatitis, the age at diagnosis of pancreatitis, and the etiology of pancreatitis were sent to 7876 male members of a sobriety association in Japan. Of 4120 members who replied to the questionnaire, 857 (20.8%) had a medical history of pancreatitis. Of these 857 members, 418 (10.1%) had been diagnosed with alcoholic pancreatitis, 32 (0.8%) as gallstone pancreatitis, and 407 (9.9%) with unknown etiology or etiology forgotten. A clear history of pancreatitis and information on habitual heavy drinking and the consumed amount of alcohol could be obtained from 373 of the 418 members diagnosed with alcoholic pancreatitis and from 345 of the 407 members with pancreatitis of unknown etiology. These 718 respondents were considered to be true alcoholic pancreatitis cases, with an extrapolated incidence of 9.1% (718/7876) to 17.4% (718/4120) cases of alcoholic pancreatitis in alcoholics in Japan. Alcoholics with a history of pancreatitis began drinking at relatively younger age and consumed a significantly greater amount of alcohol per day compared with 3113 alcoholics without a medical history of pancreatitis. This survey suggests that the incidence of alcoholic pancreatitis in alcoholics is much higher than previously reported.

アルコール依存症日本人男性における膵臓内石灰化とその背景因子

アルコール依存症日本人男性における膵臓内石灰化とその背景因子

An Initial View of Self-Help Groups for Japanese Alcoholics: Danshukai in its Historical, Social, and Cultural Contexts

An Initial View of Self-Help Groups for Japanese Alcoholics: Danshukai in its Historical, Social, and Cultural Contexts

Mean Corpuscular Volume, Alcohol Flushing, and the Predicted Risk of Squamous Cell Carcinoma of the Esophagus in Cancer-Free Japanese Men

Because some of the causes of increased mean corpuscular volume (MCV) and esophageal squamous cell carcinoma (ESCC), including alcoholism, acetaldehyde exposure, smoking, and poor nutrition are common to both, macrocytosis has been used as a predictor of early ESCC in Japanese alcoholics. We examined whether this was also true in the Japanese general population. This study compared the MCV of 522 cancer-free Japanese men with his risk of ESCC as defined using drinking, smoking, dietary habits and aldehyde dehydrogenase-2 (ALDH2) genotype in a previous case-control study of ESCC involving them as control subjects. MCV was significantly correlated with ESCC risk predicted by drinking combined with ALDH2 genotype, smoking, or fruit intake. Men at higher risk of ESCC were more frequent in the groups with higher MCV (p < 0.0001 for trend). The replies to a questionnaire about facial flushing in response to alcohol showed that the trend was more prominent in men with current/former flushing, a surrogate marker for inactive ALDH2, than in men with no flushing (p < 0.0001). In comparison with the mean risk of men with MCV < or = 93 fl (lowest quartile), that of current/former flushing men with MCV > or = 99 fl (highest quartile) was 6.35-fold higher, whereas that of never-flushing men with MCV > or = 99 fl was 2.50-fold higher. The sensitivity and specificity of the combination of moderate-to-heavy drinking and either MCV > or = 99 fl or current/former flushing, either 30+ pack-years or MCV > or = 99 fl or either 30+ pack-years or current/former flushing for detection of high-risk persons ranking in the top 10%, was 85% and 84%, 94% and 76%, or 98% and 77%, respectively. MCV and alcohol flushing might be used to better select candidates to screen this high-mortality-rate cancer not only in alcoholics but also in nonalcoholic Japanese men.

Certain Background Factors Exhibit an Association With an Increased Risk for Pancreatic Calcification Among Japanese Male Alcoholics

This was a cross-sectional study conducted from April 2003 through March 2004 to investigate the background factors related to pancreatic calcification (PC) in male Japanese alcoholics. Helical computed tomography examination revealed PC in 44 of 263 alcoholics, and this group was further divisible into 3 subgroups: "scant" (n = 24), "moderate" (n = 6), and "extensive" PC subgroups (n = 14). The extensive subgroup was associated with larger daily ethanol consumption (P = 0.05) and high-alcohol beverages, such as whisky (P = 0.02). The moderate subgroup was associated with a longer duration of habitual drinking (P = 0.04), whereas the scant PC group was associated with never having smoked (P = 0.05) and with low-alcohol beverages, such as beer (P = 0.09). None of the 40 subjects with inactive mitochondrial aldehyde dehydrogenase (ALDH2*2 allele) exhibited PC (P = 0.004). Heterozygous alcohol dehydrogenase 2 genotype (ADH2*1/2*2) exhibited an association with the scant subgroup (P = 0.02). The TG12 repeats in the cystic fibrosis transmembrane conductance regulator (CFTR) gene tended to have a weak association with PC. Drinking behavior, smoking status, and genetic backgrounds are associated with PC and are likely to increase the risk for alcoholic chronic pancreatitis.

Pancreatic Volume Associated with Endocrine and Exocrine Function of the Pancreas among Japanese Alcoholics

Background/Aims: The pancreas is often damaged by excessive alcohol consumption. Because alcohol-related problems and diabetes mellitus (DM) are increasing in Japan, this cross-sectional study was designed to investigate how pancreatic volume (PV, calculated using multi-slice helical computed tomography) represents alcohol consumption and both endocrine and exocrinepancreatic function among alcoholics. Methods: Consenting male and female inpatients undergoing psychiatric therapy for alcoholism from June 2003 to May 2004 were subjected to four-slice MCT to determine PV. Fasting plasma glucose (FPG) and serum lipase levels were examined for endocrine and exocrine pancreatic functions, respectively. Results: The average PVs of 535 male and 117 female patients (57.2 ± 21.91 ml and 54.5 ± 17.56 ml, respectively) were related to age and height (H) but not to body weight (W). Lipase values had a strong relationship with PV/W. Multiple regression analysis revealed weak associations between PV and both daily ethanol consumption and duration of habitual drinking. The diagnosis of DM in 109 of these alcoholics was more strongly associated with the PV/W value than with PV or PV/H. Conclusion: The association of PV with endocrine and exocrine functions suggests new markers, especially PV/W, for the assessment of DM among alcoholic patients.

INTERLEUKIN-1 GENE CLUSTER POLYMORPHISMS AND ALCOHOLISM IN SPANISH MEN

In an attempt to explain differences in susceptibility to alcoholism and alcohol liver disease (ALD), different genes have been analysed, among them those encoding inflammatory cytokines. Thus, it has been reported recently that both the interleukin 1 receptor antagonist (IL1RN) and the IL1beta (IL1B) genes may influence the risk of ALD in Japanese alcoholics. We analysed the distribution of single nucleotide polymorphisms (SNPs) located in the IL1A, IL1B, IL1R1 and IL1RN genes in alcoholic and non-alcoholic Spanish subjects. DNA samples were obtained from 139 male alcoholics, 78 of whom were diagnosed as alcohol dependent (32 patients with liver cirrhosis and 46 without ALD) and 61 as alcohol abusers (25 with liver cirrhosis and 36 without ALD). As a control, we studied 81 age- and sex-matched healthy volunteers. Alleles -511 IL1B*1 and IL1RN*1 were represented more in alcoholic patients than in the control group. We did not find any association of alcoholism or ALD with polymorphisms in the IL1A and IL1R1 genes. We conclude that the proteins encoded by the IL1RN and IL1B genes may be involved in susceptibility to alcoholism in Spanish men, probably through a different pathway from that involved in the regulation of the inflammatory response.

Low fasting serum insulin in Japanese alcohol consumers does not imply improved coronary risk factors

The effects of alcohol consumption on coronary risk factors (CRFs) and insulin resistance (IR) have seemed equivocal in previous studies. This study aimed to clarify the implications of low fasting blood insulin observed in alcohol consumers as related to CRFs and IR. A cross-sectional observation in 2133 middle-aged healthy Japanese men for associations of increases in alcohol consumption, fasting serum insulin concentration and serum gammaglutamyltransferase (GGT) activity with the major CRFs of high systolic blood pressure (SBP), fasting serum glucose, triglycerides (TG), total- and LDL-cholesterol (tCh&LDLc) and low serum HDL-cholesterol (HDLc). Increased alcohol consumption was related to higher SBP, serum GGT, glucose and HDLc, and lower serum LDLc and insulin. Although high serum insulin was significantly related to all of the CRFs in all nondrinkers, moderate drinkers consuming up to 59 ml of alcohol per day and excessive drinkers consuming more, the means of SBP, serum glucose and HDLc were significantly higher and serum LDLc was lower in drinkers than in nondrinkers at any level of serum insulin, indicating that the good and bad profiles of CRFs in alcohol consumers are independent of their low fasting serum insulin. High serum GGT related to increased alcohol consumption and/or body weight was significantly associated with high serum insulin and all of the CRFs in all categories of alcohol consumption. Low fasting serum insulin observed in drinkers does not imply improved CRFs, and thus may not imply improved IR. High serum GGT may reflect increased IR in both drinkers and nondrinkers.

Severe chronic pancreatitis and severe liver cirrhosis have different frequencies and are independent risk factors in male Japanese alcoholics

Chronic pancreatitis and liver cirrhosis are major alcohol-related diseases in most countries. Neither their specific etiologies nor the relationship between them is fully understood. This study was designed to examine a possible association between alcoholic chronic pancreatitis (ACP) and alcoholic liver cirrhosis (ALC), and to identify factors relating to them. The subjects were 141 consenting participants from 1087 male patients consecutively admitted to Kurihama National Hospital from July 2000 to November 2002. All were negative for major medical disorders (e.g., viral hepatitis, operative history, malignancy), except for ACP and ALC. Analysis of each subject included background information (collected by face-to-face interview, regarding quantity and duration of drinking, usual alcoholic drinks, smoking, education, employment, and marital status) and signs of ACP detected on endoscopic retrograde cholangiopancreatography (ERCP) and ALC indicated by Child-Pugh classification. Subjects consenting to genome analyses ( n = 83) were genotyped for two key alcohol-metabolizing enzymes: alcohol dehydrogenase-2 and aldehyde dehydrogenase-2. Grouping patients by ERCP grading and Child classification revealed a nonparallel relationship between the severities of the two diseases. This relationship held, even after controlling for several pertinent background variables (sociofamilial, drinking, clinical, and genetic factors) by logistic regression analysis. The drinking of spirits and a high daily consumption of alcohol were independent risk factors for ACP, while never-married status was the only risk factor identified with ALC among these male Japanese patients. Different risk factors may confer susceptibility to ACP versus ALC, which may explain the nonparallel relationship between the severities of the two diseases in Japanese alcoholics.

Homozygous (TG)11 Allele in Intron 8 of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene has a Protective Role against Bicarbonate Decrease in Pure Pancreatic Juice among Japanese Male Alcoholics

Heavy drinkers have a high incidence of chronic pancreatitis (CP), but the mechanism of alcohol-related CP is largely unknown. Exocrine pancreatic insufficiency exists in about 90% of the patients with cystic fibrosis (CF), which results from an abnormal cystic fibrosis transmembrane conductance regulator gene (CFTR). To investigate in Japanese alcoholics the association between bicarbonate concentration in pure pancreatic juice and one of the polymorphisms of the CFTR gene, the (TG)m Tn tract length in intron 8. Fifty-six patients under treatment for alcohol dependence were stimulated by intravenous injection of secretin during endoscopic retrograde cholangiopancreatography to provide pancreatic juice specimens. Individual maximum bicarbonate concentrations (MBC) were compared with (TG)m Tn tract polymorphisms identified by directly sequencing lymphocyte DNA. Among the 41 patients able to provide adequate pancreatic juice specimens, 15 had low MBC and 26 had normal MBC. The frequencies of the six haplotypes identified in these patients were 17.1% (TG)11T7/(TG)llT7, 46.3% (TG)11T7/(TG)12T7, 29.3% (TG)12T7/(TG)12T7, 2.4% (TG)10T9/(TG)11T7, 2.4% (TG)12T5/(TG)11T7, and 2.4% (TG)12T6/(TG)12T7. Among the 92.7% of patients who had the common (TG) miT7/(TG)m2T7 haplotype, all of the 7 with homozygous (TG)11 alleles had normal MBC (p<0.05). Alcoholics with homozygous (TG)11 alleles in intron 8 of the CFTR gene appear to be protected against decreased MBC, compared with those who have the (TG)11/(TG)12 and (TG)12/(TG)12 genotypes, suggesting a role for CFTR gene polymorphism in the progression of alcohol-related pancreatic disease.

Low Fasting Serum Insulin in Japanese Alcohol Consumers Does Not Imply Improved Coronary Risk Factors

Low Fasting Serum Insulin in Japanese Alcohol Consumers Does Not Imply Improved Coronary Risk Factors