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Susumu Higuchi

Publications and source records attributed to Susumu Higuchi.

At least 19 recordsLinked to original sources
PubMed2006

Association analysis of the dopamine receptor D2 (DRD2) SNP rs1076560 in alcoholic patients.

The dopamine system plays a well-established role in alcoholism. In this study, we examined the association between the single-nucleotide polymorphism (SNP) rs1076560 of the dopamine receptor D2 (DRD2) gene and susceptibility to alcoholism. SNP rs1076560 (C/A) is located in intron 6 of DRD2, where it is 1.4 kb downstream from alternative exon 6 and 83 bp upstream from exon 7. A total of 248 alcoholic patients and 322 healthy controls, all Japanese males, were genotyped for rs1076560 polymorphism by direct sequencing and allele-specific PCR. Data were analyzed using standard chi(2) statistics and a backwards logistic regression approach to adjust for the contribution of aldehyde dehydrogenase-2 (ALDH2) genotype status. The DRD2 risk allele A was more prevalent in the alcoholic patients (40.1%) than in the healthy controls (34.0%) (P=0.034, odds ratio=1.300, 95% confidence interval=1.020-1.657). These data identify SNP rs1076560 as a potentially important variable in the development of alcoholism.

Alcoholism↗
PubMed2006

Melanosis and squamous cell neoplasms of the upper aerodigestive tract in Japanese alcoholic men.

Melanosis is frequently observed in the upper aerodigestive tract of Japanese alcoholic men, and the prevalences of squamous cell dysplasia and SCC in the upper aerodigestive tract of Japanese alcoholic men are high. This study evaluated associations between melanosis and both neoplasms of the upper aerodigestive tract and factors contributing to the development of melanosis in Japanese alcoholic men. Endoscopic screening of 643 Japanese alcoholic men (aged 50-79 years) was combined with oropharyngolaryngeal inspection and esophageal iodine staining, and ALDH2 genotyping was carried out in 425 of them. Melanosis was frequently (20.8%) observed in the upper aerodigestive tract. The palate was the most common site of melanosis (11.2%), followed by the pharynx (9.5%), and by the esophagus (7.0%). The incidence of melanosis was higher in those with esophageal dysplasia (31/126, 24.6%), esophageal SCC (19/42, 45.2%), and oropharyngolaryngeal SCC (8/14, 54.1%) than in cancer- and dysplasia-free controls (69/437, 15.8%). The presence of melanosis was associated with a higher risk of esophageal dysplasia, esophageal SCC, and oropharyngolaryngeal SCC (OR 1.69, 4.03, and 6.61, respectively). Multivariate analysis showed that older age, heavier smoking, and heterozygosity for inactive ALDH2 were positively associated with the presence of melanosis. The presence of melanosis indicates a high risk for neoplasms in the upper aerodigestive tract of Japanese alcoholic men. Melanosis and neoplasms have the same causes, including older age, heavy smoking, and high acetaldehyde exposure.

Aged↗
PubMed2006

p53 Protein accumulation, cancer multiplicity, and aldehyde dehydrogenase-2 genotype in Japanese alcoholic men with early esophageal squamous cell carcinoma.

Synchronous multiple intra-esophageal squamous cell carcinomas (SCCs) or oropharyngolaryngeal SCCs are common in alcoholics with esophageal SCC, and more frequently found in those with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2). p53 alterations have been suspected as key molecular events in such multifocal esophageal carcinogenesis. We studied 95 Japanese alcoholic men with Tis and mucosal invasive esophageal SCC and found very high levels of p53 protein accumulation occurring in early esophageal SCC. Synchronous cancer multiplicity in the upper aerodigestive tract was found in 40 patients. p53 expression was not correlated with either cancer multiplicity or ALDH2 genotype. The risk for cancer multiplicity was associated with inactive heterozygous ALDH2 alone (OR=4.22) among the risk factors investigated, which also included smoking, less-active alcohol dehydrogenase-1B, and macrocytosis, enhancing the validity of the link between acetaldehyde exposure and cancer multiplicity.

Alcoholism↗
PubMed2006

Dynamin-binding protein gene on chromosome 10q is associated with late-onset Alzheimer's disease.

The apolipoprotein E (APOE) gene has been consistently shown to be a major genetic risk factor; however, all cases of Alzheimer's disease (AD) cannot be attributed to the epsilon4 variant of APOE, because about half of AD patients have the APOE-epsilon3*3 genotype. To identify an additional genetic risk factor(s), we performed large-scale single nucleotide polymorphism (SNP)-based association analysis of 1526 late-onset AD patients and 1666 control subjects in a Japanese population. We prepared two independent sets consisting of exploratory and validation samples, respectively, with only the APOE-epsilon3*3 genotype, and first carried out genotyping for the exploratory set with 1206 SNPs in the region between 60 and 107 Mb on chromosome 10q that is implicated by linkage studies as containing an AD susceptibility locus. Thirty-five SNPs that showed significant values (P<0.01) were followed-up to detect any association with the validation samples. Finally, six SNPs exhibited replicated significant associations (P=0.000035-0.00048) on meta-analysis of both sets. These SNPs were clustered in a locus spanning 220 kb at genomic position 101 Mb, and three of the six SNPs were located in the dynamin-binding protein (DNMBP) gene. Quantitative real-time RT-PCR analysis demonstrated that neuropathologically confirmed AD brains exhibit a significant reduction of DNMBP mRNA compared with age-matched ones (P<0.0169). Thus, we confirmed the association of DNMBP with AD individuals with the APOE-epsilon3*3 genotype or lacking the epsilon4 allele, and DNMBP may be one of the susceptibility genes for AD.

Aged↗
PubMed2006

ALDH2 promoter polymorphism has no effect on the risk for alcoholism.

AIM: To test for the possible association between mitochondrial aldehyde dehydrogenase (ALDH2) promoter polymorphism and alcoholism. METHODS: Genotyping to identify the polymorphisms in 515 alcoholic patients and 361 normal controls was performed. RESULTS: There were no significant differences between the genotype and allele frequencies of the -357A/G polymorphism in alcoholics and normal controls. Linkage disequilibrium was observed between the promoter and exon 12 polymorphisms. CONCLUSION: These results suggest the ALDH2 promoter polymorphism does not affect the risk for alcoholism.

Adult↗
PubMed2006

New findings on the genetic influences on alcohol use and dependence.

PURPOSE OF REVIEW: Alcohol dependence is a complex disorder with a well documented highly hereditary nature. This article reviews the recent advances in our understanding of the direct and indirect genetic influences on alcohol use and dependence. RECENT FINDINGS: Recent findings can be summarized as follows: (a) twin studies have defined and estimated the risks of general and specific alcohol-related vulnerabilities. (b) Linkage studies have provided largely inconsistent findings, though several chromosomal regions have been implicated. (c) Quantitative trait loci analyses in animals have identified that the Mpdz gene predisposes to alcohol dependence and withdrawal. (d) Examination of family-based samples has identified several genes including GABRA2 and CHRM2 thought to be associated with alcohol dependence. SUMMARY: Despite great advances in understanding of genetic vulnerability in alcohol use disorders, only two gene complexes, ADH and ALDH2, have been identified as having defined effects on alcohol use and liability to dependence in humans. New genes associated with increased risks for the disorder will certainly be added to this list in the near future. Neurobiological analyses of the effects of these genes will surely contribute to further understanding of the cause of alcohol dependence and the interindividual differences in risks.

Alcoholism↗
PubMed2006

Risk of squamous cell carcinoma of the upper aerodigestive tract in cancer-free alcoholic Japanese men: an endoscopic follow-up study.

Asian case-control studies have shown a strong relationship between the development of squamous cell carcinoma (SCC) of the esophagus and alcohol consumption combined with inactive aldehyde dehydrogenase-2 (ALDH2*1/*2), less-active alcohol dehydrogenase-1B (ADH1B*1/*1), high mean corpuscular volume (MCV), and self-reported facial flushing in response to alcohol. However, little is known about whether these risk factors prospectively influence cancer development in cancer-free alcoholics. Between 1993 and 2005, 808 Japanese alcoholic men diagnosed as cancer-free by an initial endoscopic screening examination received follow-up examinations ranging from 1 to 148 months (median, 31 months) later, and SCC of the upper aerodigestive tract was diagnosed in 53 of them (esophagus in 33 and oropharyngolarynx in 30). Cox proportional hazards analysis showed that the age-adjusted relative hazard for SCC was 11.55 [95% confidence interval (95% CI), 5.73-23.3] in ALDH2*1/*2 heterozygotes compared with ALDH2*1/*1 homozygotes, 2.02 (95% CI, 1.02-4.02) in ADH1B*1/*1 homozygotes compared with ADH1B*1/*2 heterozygotes or *2/*2 homozygotes, 2.64 (95% CI, 1.49-4.67) in patients with flushing compared with those who had never experienced flushing, 2.91 (95% CI, 1.63-5.20) in those with an MCV >or= 106 compared with those with an MCV < 106, 2.52 (95% CI, 1.22-5.22) in those who smoked >or=30 cigarettes per day compared with those who smoked 0 to 19 cigarettes per day, 7.26 (95% CI, 3.99-13.23) in those with esophageal dysplasia compared with those without distinct iodine-unstained lesions >or=5 mm, and 0.28 (95% CI, 0.09-0.85) in those with body mass index >or= 23.2 (highest quartile) compared with those with body mass index < 19.0 (lowest quartile). These predictors are useful for selecting appropriately patients for careful follow-up examinations.

Adult↗
PubMed2005

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 exocrine pancreatic 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.

Adult↗
PubMed2005

Esophageal melanosis, an endoscopic finding associated with squamous cell neoplasms of the upper aerodigestive tract, and inactive aldehyde dehydrogenase-2 in alcoholic Japanese men.

BACKGROUND: Esophageal melanosis is often observed in alcoholic Japanese men, in whom the prevalence of squamous cell dysplasia and carcinoma (SCC) in the upper aerodigestive tract are high. This study evaluated the associations of esophageal melanosis with these neoplasms, and the factors contributing to the development of esophageal melanosis in this population. METHODS: Endoscopic screening was combined with esophageal iodine staining in 1535 alcoholic Japanese men (aged 40-79 years), of whom 1007 underwent aldehyde dehydrogenase-2 (ALDH2) genotyping. RESULTS: Fifty patients (3.3%) were diagnosed with esophageal melanosis, which had a higher incidence in those with noncancerous distinct iodine-unstained lesions (DIULs; 16/268; 6.0%), esophageal SCC (9/66; 13.6%), and oropharyngolaryngeal SCC (4/19; 21.1%) than in cancer- and DIUL-free controls (24/1182; 2.0%). The presence of esophageal melanosis was associated with higher risks for noncancerous DIULs, esophageal SCC, and oropharyngolaryngeal SCC (odds ratios, 2.81, 6.54, and 14.77, respectively). Men with the inactive ALDH2*1/2*2 genotype had a higher risk for esophageal melanosis (2.66-fold), as well as for DIULs and SCCs. CONCLUSIONS: The presence of esophageal melanosis in alcoholic Japanese men could indicate a high risk for DIULs and SCCs in the upper aerodigestive tract. The high incidence of esophageal melanosis may be partially linked to high acetaldehyde exposure, a consequence of drinking alcohol in persons with inactive ALDH2.

Adult↗
PubMed2005

Carboxylester lipase gene polymorphism as a risk of alcohol-induced pancreatitis.

OBJECTIVES: Alcohol abuse causes pancreatic damage in humans. However, only 5% of alcoholic patients have a clinical manifestation of pancreatitis, and the genetic predisposition of alcohol-associated pancreatitis remains elusive. Nonoxidative metabolites of ethanol, fatty acid ethyl esters (FAEEs), might play an important role in pancreatic damage. Carboxylester lipase (CEL) has been known to catalyze FAEE synthesis from fatty acids and ethanol. METHODS: The variable number of tandem repeat (VNTR) polymorphism in the coding region of the CEL gene was studied in patients with alcoholic pancreatitis (n = 100), in alcoholics without pancreatitis (n = 52), in patients with nonalcoholic pancreatitis (n = 50), in hyperlipidemia patients (n = 96), and control subjects (n = 435). RESULTS: The frequency of the NN-type (wild-type) gene was significantly decreased in patients with alcoholic pancreatitis than in other groups. The frequency of subjects who had the L allele in patients with alcoholic pancreatitis was significantly higher than in other groups. The distribution of the CEL gene polymorphism was not different among the control subjects, alcoholics without pancreatitis, patients with nonalcoholic pancreatitis, and patients with hyperlipidemia. CONCLUSIONS: The CEL gene polymorphism, especially an increase in the frequency of the L allele, was found to be associated with alcohol-induced pancreatitis.

Aged↗
PubMed2005

Certain background factors exhibit an association with an increased risk for pancreatic calcification among Japanese male alcoholics.

OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSION: Drinking behavior, smoking status, and genetic backgrounds are associated with PC and are likely to increase the risk for alcoholic chronic pancreatitis.

Adult↗
PubMed2005

Plasma homocysteine and risk of coexisting silent brain infarction in Alzheimer's disease.

BACKGROUND: Cerebrovascular disease is common in Alzheimer's disease (AD). Elevated plasma homocysteine (pHcy) levels are reported to be associated with an increased risk of poor cognition and dementia. OBJECTIVE: To determine whether high pHcy levels are associated with an increased risk of coexisting silent brain infarctions (SBIs) in AD. METHODS: Study population comprising 143 outpatients with clinical diagnosis of probable AD (73.3 +/- 7.0 years) were classified into 2 groups according to the presence or absence of SBIs on magnetic resonance imaging. RESULTS: SBIs were noted in 32.9% (47/143) of the AD patients. The pHcy levels in the AD with SBIs (14.0 +/- 4.5 micromol/l) were significant ly elevated compared with the AD without SBIs (11.7 +/- 4.7 micromol/l, p = 0.007). After adjusting for age and gender, high pHcy (>12.4 micromol/l), but not hypertension, was associated with an increased risk of developing SBIs in AD (OR = 4.61, 95% CI = 1.74-12.2, p = 0.002). However, age at onset, cognitive function, cerebrospinal tau or amyloid beta-peptide(1-42) levels were not significantly correlated with pHcy levels in AD. CONCLUSION: SBIs commonly coexist with AD, and may be a unique vascular condition in which homocysteine plays an important role. Homocysteine-lowering therapy rather than antihypertensive medication might be an appropriate strategy to prevent stroke associated with AD.

Aged↗
PubMed2005

[A proposal for diagnostic and clinical assessment criteria for Alzheimer's disease].

To clarify the risk and associated genes of Alzheimer's disease by genome-wide screening, a Japanese study group was organized in 2000 under Yasuo Ihara, Tokyo University, supported by a Grant-in-Aid for Science Research on Priority Areas (C) -Advanced Brain Science Project from Ministry of Education, Culture, Sports, Science and Technology, Japan. This is the first Japanese consortium study under permission of the ethical committees of the enrolled institutes based on the ethics guidelines for human genome/gene analysis research, Ministry of Education, Culture, Sports, Science and Technology Ministry of Health, Labor and Welfare Ministry of Economy, Trade and Industry. In this project, 2,000 genome samples from patients with Alzheimer's disease, 2,000 control subjects, and 200 siblings affected with Alzheimer's disease are collected and analyzed. For this purpose, it is necessary to analyze samples from accurately diagnosed Alzheimer patients and controls using standard criteria for diagnosis and neuropsychological evaluation, which have been confirmed by an evidence-based studying a Japanese population. Here, we propose criteria for the diagnosis and clinical assessment of Alzheimer's disease. This proposal consists of a definition of Alzheimer's disease based on recent advances in research, diagnostic criteria based on DSM-IV, NINCDS-ADRDA and ICD-10, exclusion criteria for other dementia disorders, routine and detailed tests for neuropsychological and laboratory evaluations, criteria for neuroimaging and biomarkers, definitive diagnostic criteria and classification of clinical subtypes.

Alzheimer Disease↗
PubMed2005

[The treatment cost at different stages of alcohol dependence in Japan].

The treatment costs of alcohol dependence were calculated by disease stage and by method of treatment. Alcohol-related problems, mainly alcohol dependence, can be divided into four stages for convenience: (1) abnormal values found in health examinations, (2) preventive treatment as an outpatient or short-term hospitalization for education and testing, (3) basic outpatient treatment, and (4) inpatient treatment. The following results were obtained. (1) One example of expenses required for a routine examination was 936 points when converted to health insurance points. (2) The number of points for outpatient group psychotherapy in the first education stage and five additional examinations was 5175 points (6255 points with a designated mental health physician). The number of points for the program of medical tests and initial education in one week of hospitalization was 10,787. (3) For alcoholics, continued outpatient visits for two years, the number of points for only prescription of a drug to inhibit drinking such as disulfiram with no testing was 14,790 (19,650 points with a designated mental health physician). When the patient participated in alcohol daycare, the total number of points for three months of daycare with one meal each time was 46,020. (4) In cases of three-month inpatient treatment in our hospital including ordinary medical testing, the number of points for the first month for one patient was 57,280 points, plus 35,000 points each month in the 2nd and 3rd months for a total of 127,280 points. However, the total in our hospital is an average of 160,200 points when drugs and additional tests are included. As expected, the expenses required at the primary prevention stage were low, while those required for treatment after onset were high. Placing stress on prevention, providing proper treatment for patients and reducing relapses will reduce the burden including social expenses.

Alcoholism↗
PubMed2005

[Nationwide survey of alcohol drinking and alcoholism among Japanese adults].

PURPOSE: To investigate the characteristics of alcohol use among Japanese adults and prevalence of alcohol dependence in Japan, we conducted a nationwide survey on alcohol drinking behavior and alcohol dependence among Japanese adults using a representative sampling method. METHODS: We sampled 3500 adults from throughout the entire country using a stratified random sampling method with two-step stratification, and carried out a home visit interview survey. A total of 2547 people (72.8%) responded to the survey. The survey period was June, 2003. The questionnaire contained questions about the frequency and quantity of alcohol use, 'hazardous use of alcohol' and 'alcohol dependence' according to the ICD-10 definition, several screening scales on problem use of alcohol (CAGE, KAST, AUDIT), life-time prevalence of 24 alcohol related diseases, smoking status, dysgryphia, and nightcap drinking. RESULTS: The number of respondents was, 1184 males, and 1363 females. Lifetime alcohol drinking, and weekly drinking, and daily drinking rates were 95.1%, 64.4%, and 36.2% for males, 79.0%, 27.5%, and 7.5% for females, respectively. Average daily alcohol consumption was 3.7 units for males, and 2.0 units for females (1 unit = 10 g pure alcohol). The proportion of drinkers who drank alcohol 4 units or more daily was 28.9% for males, and 7.6% for females, and that for 6 units or more was 12.7% for males, and 3.4% for females. The proportion of flasher was 41.2% for males, and 35.0% for females. Among screening questions, problem drinking was most frequently identified using AUDIT (score 12 points or more, 150 persons), followed by KAST (2 points or more, 100 persons) and CAGE (2 points or more, 98 persons). The number of subjects who met the ICD-10 criteria for alcohol dependence was 24, while the number who engaged in hazardous alcohol use was 64. CONCLUSIONS: This study revealed that problem drinking and alcohol dependence are a serious problem in Japanese general population. The problem of females drinking may be growing. The government should emphasize the prevention of alcohol drinking problems in adults and continue the conduct of nationwide prevalence surveys to monitor the problem.

Adult↗
PubMed2004

Serotonin transporter regulatory region polymorphism is associated with anorexia nervosa.

Several lines of evidence support possible serotonin transporter (5-HTT) involvement in modulating eating disorders (ED). The 5-HTT gene is a good candidate for genetic studies on the course of ED, despite controversy concerning the association between polymorphism in the 5-HTT gene promoter region (5-HTTLPR) and ED. Comparison of 5-HTTLPR distribution in 195 female Japanese ED patients and 290 age- and gender-matched control subjects facilitated examining the association between the course of the disease and 5-HTTLPR in 138 of 195 ED subjects. The 5-HTTLPR S allele frequency was significantly higher in subjects with anorexia nervosa (AN) than in control subjects. Among subjects observed > or =3 years, the S allele frequency was significantly higher in those diagnosed as AN at ED onset than in those diagnosed as AN in this study. The 5-HTTLPR S allele might play some role in the development of AN with persistent disease.

Adult↗
PubMed2004

Association of aldehyde dehydrogenase-2 polymorphism with alcoholic polyneuropathy in humans.

Persons who have the Glu-487-->Lys mutation (single nucleotide polymorphism) of the aldehyde dehydrogenase-2 (ALDH2) gene have less ability to metabolize the alcohol breakdown product acetaldehyde. In order to clarify whether acetaldehyde is associated with the pathogenesis of alcoholic polyneuropathy, we compared nerve conduction data as well as clinical signs and symptoms of neuropathy between alcoholics with ALDH2*2 (Lys-487) heterozygotes and those with ALDH2*1 (Glu-487) homozygotes. Alcoholics with ALDH2*2 heterozygotes showed significantly lower sensory nerve action potential amplitudes of the sural and median nerves than those with ALDH2*1 homozygotes, suggesting that the accumulation of acetaldehyde due to ALDH2 inactivity is associated with alcoholic polyneuropathy.

Action Potentials↗