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PubMed2003

Differential responses of serum gamma-glutamyltransferase to alcohol intake in Japanese males.

We studied the association of gamma-glutamyltransferase (GGT) and other serum markers of liver injury with daily alcohol consumption in a healthy population of 1,043 Japanese males. A positive correlation between daily alcohol consumption and biochemical markers, such as log GGT (r = 0.432), log AST (r = 0.244) or log LAP (r = 0.246), was seen in all drinkers. However, there was a negative correlation, such as log GGT (r = -0.434), log AST (r = -0.424) or log LAP (r = -0.430), in heavy drinkers who consumed more than 70 g ethanol a day. On the other hand, a positive correlation, such as log GGT (r = 0.426), log AST (r = 0.247) or log LAP (r = 0.216) was found in moderate drinkers who consumed less than 70 g ethanol a day. Interestingly, there was a tendency toward negative association between alcohol consumption and the Tokyo University ALDH2 Phenotype Screening Test (TAST) score in the heavy drinkers, and there was a tendency toward positive association between GGT and TAST score in this group. Our results suggest that there are 2 groups of drinkers, those with elevated GGT (good responders) and those with normal GGT (poor responders) despite heavy drinking.

Adult↗
PubMed2003

Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair.

We present an oligonucleotide microarray ("MetaboChip") based on the arrayed primer extension (APEX) technique, allowing genotyping of single nucleotide polymorphisms (SNPs) in genes of interest for cancer susceptibility and pharmacogenetics. APEX consists of a sequencing reaction primed by an oligonucleotide anchored with its 5' end to a glass slide and terminating one nucleotide before the polymorphic site. The extension with one fluorescently labeled dideoxynucleotide complementary to the template reveals the polymorphism. Ninety-three SNPs in 42 genes were selected among those resequenced in the context of the SNP500 project, using a set of 102 reference DNA samples from the Coriell Biorepository. Selected SNPs belong to the following genes: ADH1B, ALDH2, APEX, CDKN2A, COMT, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C19, CYP2C9, CYP2E1, CYP3A4, DRD2, DRD4, EPHX1, ERCC1, ERCC2, ERCC4, ERCC5, GRPR, GSTA4, GSTM3, GSTP1, GSTT2, LIG3, MDM2, MGMT, MPO, NAT1, NAT2, NQO1, OGG1, PCNA, POLB, SLC6A3, SOD2, TP53, XRCC1, XRCC2, XRCC3, and XRCC9. We assessed the performance of APEX by comparing the results obtained with MetaboChip against those reported by the SNP500. Among 88 SNPs that yielded signals, 6 showed less than 99% of concordance, whereas 82 performed accurately, showing that APEX is a reliable and sensitive genotyping method.

DNA Repair↗
PubMed2004

Aptamer-dependent full-length cDNA synthesis by overlap extension PCR.

Sequencing of the human genome in combination with computational annotation has provided tremendous data on predicted genes. However, for most of them, no corresponding cDNAs are available yet. Furthermore, even where cDNA clones were obtained, gene transcripts often have many different splice variants that are not covered by current gene collections. For direct synthesis of cDNA clones corresponding to predicted genes, new splice variants, or any other gene of interest, we established optimal PCR conditions for the direct amplification of exons from genomic DNA, which require a specific Taq aptamer. PCR products comprising differently tagged exons were concatenated by overlap extension into full-length cDNAs. To prove the effectiveness of the approach, the 1900-bp full-length open reading frame of the human mitochondrial aldehyde dehydrogenase (ALDH2) gene was synthesized in a two-step reaction comprising all 13 exons. Thus, our conditions are of general value for in vitro synthesis of cDNAs and alternative splice variants from genomic DNA.

Aldehyde Dehydrogenase↗
PubMed2002

Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients.

This paper lists the genotype frequencies of 50 polymorphisms of 37 genes (ALDH2, ADRB2, ADRB3, COMT, CD36, CXCR2, CCND1, COX2, CYP2A6, CYP17, CYP19, IGF1, IL-1A, IL-1B, IL-1RN, IL-1R1, IL-6, IL-8, IL-10, LEP, Le, L-myc, MPO, MTR, MTHFR, MAO-A, NQO1, OGG1, p53, p73, Se, SRD5A2, TGF-B, TNF-A, TNF-B, XPD, and XRCC1) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients. Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers, 15 polymorphisms (CD36 A52C, CXCR2 C785T, CCND1 G870A, IGF1 C/T at intron 2 and G2502T, IL-1A 46-bp VNTR, IL-1R1 C-116T, IL-6 Ins/Del 17C, IL-8 A-278T and C74T, IL- 10 T-819C, LEP A-2548G, SRD5A2 2-bp VNTR, XPD Lys751Gln, and XRCC1 Arg399Gln) and six sets of combined genotype frequencies (IL-1B C-31T and IL-1A C-889T, IL-1B C-31T and IL-1RN 86-bp VNTR, IL-1B C-31T and IL-1R1 C-116T, TNF-A G-308A and TNF-B A252G, SRD5A2 Val89Leu and 2-bp VNTR, and XRCC1 Arg399Gln and XPD Lys751Gln) were reported in this paper for the first time for Japanese. Although microarray technology will produce this kind of information in near future, this is the first document that reports the genotype/allele frequencies among Japanese for an archival purpose.

Alleles↗
PubMed2026

Integrated multi-omics analysis of metabolomics and proteomics uncovers dysregulated amino acid metabolism in HCC metastasis.

BACKGROUND: Metastasis is the primary cause of treatment failure and adverse prognosis in hepatocellular carcinoma (HCC), and the molecular basis of HCC metastasis remains poorly defined. This work investigated the potential mechanisms underlying HCC metastasis through integrated multi-omics analysis of metabolomics and proteomics. METHOD: This retrospective study included 105 individuals with HCC, with comparative analysis between metastatic and non-metastatic cases. We further evaluated the effects of metastasis on serum metabolomics and proteomics in HCC patients. RESULT: Widespread disturbances in amino acid metabolism were identified via untargeted metabolomics in HCC patients with metastasis, closely governing inflammation-related metabolic remodeling and oxidative stress responses. Specifically, we identified 91 and 59 distinct differential metabolites capable of indicating HCC metastasis, with the screening criteria set as log2 fold change > 1.5, adjusted P value < 0.05, and VIP > 1.5 in positive and negative modes, respectively. The alanine, aspartate and glutamate metabolism pathway correlated with HCC-associated lung metastasis, while the gluconeogenesis pathway was linked to HCC-associated bone metastasis. Compared with HCC (non-metastatic hepatocellular carcinoma), the key molecular alterations in the multi-omics network of HCC_M (HCC with metastasis) are implicated in inflammatory metabolic reprogramming, oxidative stress response, gluconeogenesis, glycolysis, and the tricarboxylic acid (TCA) cycle. Twenty-five proteins, including PKM2, PERCK, ALDH2, CPS1, GLS1, GLUD1, GOT1, and SLC38A2, were identified as potential biomarkers for HCC metastasis. CONCLUSION: By integrating untargeted metabolomic and proteomic profiling, we identified distinct metabolic and proteomic changes linked to HCC metastasis. This work also characterized the pathological characteristics and core pathways underlying HCC metastasis, while identifying potential therapeutic candidates.

Humans↗
PubMed2005

Evaluation in vinyl chloride monomer-exposed workers and the relationship between liver lesions and gene polymorphisms of metabolic enzymes.

AIM: To analyze occupational health hazards exposure to doses lower than the Chinese occupational health standard in a selected VC polymerization plant in China, and also to elucidate the relationship between genetic polymorphisms and genetic susceptibility on liver lesions of workers exposed to vinyl chloride monomer(VCM). METHODS: In order to explore the mechanism of VCM-related health effects, we used a case-control design to investigate the association between the genetic polymorphisms of metabolic enzymes and liver lesions in workers occupationally exposed to VCM. Genotypes of CYP2E1, GSTT1, GSTM1, ALDH2 and ADH2 were identified using PCR and PCR-RFLP. RESULTS: Even when the concentration of VCM was lower than the current Chinese occupational health standard, neurasthenia, pharyngeal irritation, liver ultrasonography abnormalities and hemoglobin disorders were significantly higher in exposure subjects compared to non-exposure subjects, and the relative risks (RR and 95% CI) were 1.74 (1.06-2.85), 1.97 (1.56-2.48), 10.69 (4.38-26.12), and 2.07 (1.20-3.57). CYP2E1 c1c2/c2c2 genotype was significantly associated with liver damages (OR 3.29, 95% CI 1.51-7.20, P<0.01). CONCLUSION: The incidences of neurasthenia and liver ultrasonography abnormalities significantly increase when the cumulative exposure dose increases. The genotypes of metabolic enzymes (CYP2E1 c1c2/c2c2, null GSTT1 and ADH2 1-1) play important roles in VCM metabolism. Polymorphisms of CYP 2E1, GSTT1 and ADH2 may be a major reason of genetic susceptibility in VCM-induced hepatic damage.

Case-Control Studies↗
PubMed2005

CD14 promoter polymorphism in Chinese alcoholic patients with cirrhosis of liver and acute pancreatitis.

AIM: To investigate the relationship between genetic polymorphism of the CD14 promoter and the occurrence of alcoholic cirrhosis and alcoholic pancreatitis, and to challenge the conclusion made earlier that the patients with acute alcoholic pancreatitis and patients with alcoholic cirrhosis of liver are two different subpopulations. METHODS: Using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, we determined the polymorphism of CD14 gene and aldehyde dehydrogenase gene 2 (ALDH 2) in 335 alcoholic patients with different organ complications i.e., cirrhosis of liver (n = 100), acute pancreatitis (n = 100), esophageal cancer (n = 82) and avascular necrosis of hip joint (AVN) (n = 53) and 194 non-alcoholic controls in a Chinese group. RESULTS: The results showed that the carriage of T allele was not different among alcoholic patients with cirrhosis of liver, alcoholic patients with other complication and non-alcoholic controls. On the other hand, the carriage of the C allele was significantly more prevalent for alcoholic pancreatitis than for esophageal cancer (0.79 vs 0.60, P<0.001), alcoholic AVN (0.79 vs 0.65, P<0.025) and non-alcoholic controls (0.79 vs 0.68, P<0.025). Furthermore, when only subjects with ALDH2 1-1 genotype were examined, the C allele frequency was significantly more prevalent for alcoholic pancreatitis than for alcoholic liver cirrhosis (0.82 vs 0.69, P<0.025), esophageal cancer (0.82 vs 0.61, P<0.01), alcoholic AVN (0.82 vs 0.64, P<0.01) and non-alcoholic controls (0.82 vs 0.69, P<0.05). CONCLUSION: The C allele may be associated with some mechanism, which is important in the pathogenesis of alcoholic pancreatitis, and that alcoholic patients with acute pancreatitis and cirrhosis of liver are probably two different subpopulations.

Adult↗
PubMed1999

Eukaryotic aldehyde dehydrogenase (ALDH) genes: human polymorphisms, and recommended nomenclature based on divergent evolution and chromosomal mapping.

As currently being performed with an increasing number of superfamilies, a standardized gene nomenclature system is proposed here, based on divergent evolution, using multiple alignment analysis of all 86 eukaryotic aldehyde dehydrogenase (ALDH) amino-acid sequences known at this time. The ALDHs represent a superfamily of NAD(P)(+)-dependent enzymes having similar primary structures that oxidize a wide spectrum of endogenous and exogenous aliphatic and aromatic aldehydes. To date, a total of 54 animal, 15 plant, 14 yeast, and three fungal ALDH genes or cDNAs have been sequenced. These ALDHs can be divided into a total of 18 families (comprising 37 subfamilies), and all nonhuman ALDH genes are named here after the established human ALDH genes, when possible. An ALDH protein from one gene family is defined as having approximately < or = 40% amino-acid identity to that from another family. Two members of the same subfamily exhibit approximately > or = 60% amino-acid identity and are expected to be located at the same subchromosomal site. For naming each gene, it is proposed that the root symbol 'ALDH' denoting 'aldehyde dehydrogenase' be followed by an Arabic number representing the family and, when needed, a letter designating the subfamily and an Arabic number denoting the individual gene within the subfamily; all letters are capitalized in all mammals except mouse and fruit fly, e.g. 'human ALDH3A1 (mouse, Drosophila Aldh3a1).' It is suggested that the Human Gene Nomenclature Guidelines (http://++www.gene.ucl.ac.uk/nomenclature/guidelines.h tml) be used for all species other than mouse and Drosophila. Following these guidelines, the gene is italicized, whereas the corresponding cDNA, mRNA, protein or enzyme activity is written with upper-case letters and without italics, e.g. 'human, mouse or Drosophila ALDH3A1 cDNA, mRNA, or activity'. If an orthologous gene between species cannot be identified with certainty, sequential naming of these genes will be carried out in chronological order as they are reported to us. In addition, 20 human ALDH variant alleles that have been reported to date are listed herein and are recommended to be given numbers (or a number plus a capital letter) following an asterisk (e.g. 'ALDH3A2*2, ALDH2*4C'). It is anticipated that this eukaryotic ALDH gene nomenclature system will be extended to include bacterial genes within the next 2 years and that this nomenclature system will require updating on a regular basis; an ALDH Web site has been established for this purpose (http://++www.uchsc.edu/sp./sp./alcdbase/a ldhcov.html) and will serve as a medium for interaction amongst colleagues in this field.

Aldehyde Dehydrogenase↗
PubMed2000

[Genetics of addictive disorders].

Given the spectacular advances of genetics during the last five years, it seems appropriate to revisit the important subject of genetics of alcoholism and substance abuse. In recent studies alcohol abuse was shown to have an hereditability of roughly 38%, whereas psychostimulant and opiate use exhibit hereditabilities of 11 to 45%. The hereditability of smoking was found to be around 50%. There is a strong comorbidity between alcoholism and smoking. More than 80% of alcoholics smoke cigarettes in the U.S.A. Other genetic methods such as linkage analysis, allele sharing methods, association studies and analysis of inbred, transgenic and gene-knockout rodents, have partially agreed in showing that the 5HT-1B serotonin receptor and the DRD1, DRD2 and DRD4 dopamine receptors, as well as the dopamine transporter DAT, play an important role in behaviors related to alcoholism and substance abuse. Some neurochemical markers, as for example monoamine oxidase and adenylate cyclase have also been implicated in addictive disorders. The aldehyde dehydrogenase allele ALDH2*2 has a protective effect against alcoholism. Two whole genome linkage studies have shown linkage to chromosomal regions that are in the proximity of the DRD4 dopamine receptor, the GABA receptor gene cluster and the alcohol dehydrogenase gene cluster.

Alcoholism↗
PubMed2002

Low-penetrance genes and their involvement in colorectal cancer susceptibility.

This report focuses on low-penetrance genes that are associated with colorectal adenoma and/or cancer or that are in strong linkage disequilibrium with colorectal adenoma and/or cancer causing variants. A pooled analysis was performed for 30 polymorphisms in 20 different genes that have been reported in more than one colorectal adenoma or cancer study. An association with colorectal cancer was found for seven polymorphisms in seven genes reported in more than one study; no associations were found with colorectal adenoma. Four of the polymorphisms exhibited an increased colorectal cancer risk [GSTT1, NAT2 (phenotype), HRAS1, and ALDH2]. Two others [MTHFR, Tp53 (intron 3)] exhibited a decreased risk. For the tumor necrosis factor (TNF)a polymorphism of the TNF-alpha gene, one allele was associated with an increased risk (a2 allele) and two other TNFa alleles with decreased risks (a5 and a13 allele). No association with colorectal adenoma and/or cancer was detected for 23 other polymorphisms in 15 genes. However, of all 30 polymorphisms, only three pooled analyses had sufficiently large samples to confirm (MTHFR) or to exclude (GSTM1 and NAT2 genotype) the association with a P < 0.0026 and a power of 90%. Eighteen polymorphisms in 15 genes were each described in only one study, all with very small sample sizes. For 11 polymorphisms in 10 of these genes, an association with colorectal adenoma and/or cancer was found. Only simultaneous genotyping and combined analysis of different polymorphisms in large numbers of patients and controls, stratified by ethnicity, gender, and tumor localization and taking relevant dietary and lifestyle habits into account, will make it possible to describe the exact relations between polymorphisms and colorectal cancer susceptibility with an adequate power.

Adenoma↗
PubMed2001

Gene-environment Interactions and Polymorphism Studies of Cancer Risk in the Hospital-based Epidemiologic Research Program at Aichi Cancer Center II (HERPACC-II).

Genetic polymorphisms may modify the effects of environmental risk factors on cancer occurrence. We have recently launched a comprehensive epidemiologic project, HERPACC II (Hospital-based Epidemiologic Research Program at Aichi Cancer Center II), including both lifestyle and polymorphism data, following HERPACC-I which solely concentrated on lifestyle data. As of April 2001, about 3000 samples of DNA are being stored to conduct case-control studies. Genotyping of 46 polymorphisms has been conducted at the laboratory of the Division of Epidemiology and Prevention. Twelve case-control studies and two papers on a new PCR method, PCR-CTPP (polymerase chain reaction with confronting two-pair primers), have been accepted for publication. Significant findings in Japanese were found for 1) gene-environment interaction for esophageal cancer between heavy drinking and aldehyde dehydrogenase 2 (ALDH2), 2) malignant lymphoma risk with methylenetetrahydrofalate reductase (MTHFR) and methionine synthase (MS), 3) interactions between smoking and two polymorphisms, interleukin 1B (IL-1B) and myeloperoxidase (MPO) for Helicobacter pylori infection, and 4) smoking habits with dopamine receptor D2 (DRD2) and IL-1B. Further studies on interactions with polymorphisms will continue to be conducted for Japanese, using larger sizes of samples.

Journal Article↗
PubMedDate not supplied

Current concepts in alcohol metabolism.

Alcohol metabolism is a complex process with large individual variations related to absorption, distribution and elimination. Among the multiple factors which influence these variations, genetic factors especially those related to the different alleles of ADH2 and ALDH2, are the most well known and are related to the development of alcohol dependence, particularly in some populations such as those of Asian origin. The importance of new polymorphisms such as those in the ALDH promotor region requires further study. Furthermore, the importance of other factors such as nutrition and gastric metabolism should be taken into account to explain the variations in ethanol metabolism. The metabolic alterations produced by alcohol in the liver are responsible for liver damage. The individual variations in the metabolism of alcohol are responsible for the different toxicity of alcohol in both the liver and other organs.

Central Nervous System Depressants↗
PubMed2004

Genotype announcement in a genetic polymorphism study for health checkup examinees at Nagoya University Hospital.

On June 9, 2003, we started free genetic tests of eight polymorphisms for health checkup examinees who attended a basic course at Nagoya University Hospital. They were informed of their genotypes within four weeks after blood donation for research purposes. The genotypes were those of alcohol dehydrogenase 2 (ADH2) Arg47His, aldehyde dehydrogenase 2 (ALDH2) Glu487Lys, NAD(P)H: quinone oxidoreductase (NQO1) C609T, glutathione S transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), interleukin-1B (IL-1B) C-31T, and tumor necrosis factor A (TNF-A) T-1031C, angiotensin-converting enzyme (ACE) Ins/Del. In the first three months, 227 (89.4%) out of 254 examinees participated in the free tests, having been informed of the research aims, after which they consented to our use of research data. To date, there have been no complaints from the participants, indicating that the announcement of polymorphism genotypes may be accepted differently from that of hereditary disease genotypes.

Alcohol Dehydrogenase↗
PubMed2004

Associations between disease risk and eight polymorphisms adopted for genotype announcements at Nagoya University Hospital.

Genetic polymorphisms have the potential to predict disease susceptibility. This may be especially useful among individuals with a high-risk lifestyle, so that the genotyping could be adopted for disease prevention through modifications toward a lower-risk lifestyle. We started a program of free genotype announcements in a polymorphism study among health checkup examinees at the Nagoya University Hospital on June 9, 2003. Since such announcements remain controversial for fear of unexpected harmful effects and counseling system, the accumulated evidence on the association between disease risk and genotypes announcements in our study was reviewed in this article. The genotypes used were those of alcohol dehydrogenase 2 (ADH2) Arg47His, aldelhyde dehydlrogenase 2 (ALDH2) Glu487Lys, NAD(P)H: quinone oxidoreductase (NQO1) C609T, glutathlione S transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), interleukin-1B (IL-1B) C-31T, and tumor necrosis factor A (TNF-A) T-1031C, angiotensin converting enzyme (ACE) Ins/Del. Since showed a potential for widespread use in health checkups, the information on the above polymorphisms seems worth documenting. Although there have been no complaints from the participants to date, careful treatments are requested.

Alcohol Dehydrogenase↗
PubMed2005

[Interrelationship among factors associated with drinking behaviors in dental students].

We analyzed the Kurihama Alcoholism Screening Test (KAST), the Adolescent Alcohol Involvement Scale (AAIS), the Fagerstroem Tolerance Questionnaire (FTQ), the Tokyo University ALDH2-Phenotype Screening Test (TAST), results of ethanol patch tests, the presence or absence of a smoking habit, and gender by "Hayashi's quantification theory, type II" in 415 senior students (232 males and 183 females) of a dental college between 2000 and 2003, and evaluated their relationships. When drinking education is given to dental students, both the prevention of acute alcohol intoxication by chugging and the prevention of alcohol dependence in students with drinking behavior suggesting this tendency are necessary. For acute alcohol intoxication, attention can be aroused in students with positive ethanol patch tests. However, there is no definite instruction method for the prevention of alcohol dependence. Therefore, we analyzed the relationships among drinking, smoking, and constitution based on data obtained during the 4 years when the above 3 types of surveys were performed. Plotting of the results of analysis showed that the students can be classified by the ethanol patch test and TAST into those with "alcohol-sensitive" constitution and those with "alcohol-tolerant" constitution. Most problem drinkers were "alcohol-tolerant". KAST showed plotting along the constitution axis from "normal drinking group" to "problem drinking borderline group" but a change in the angle to an L shape at the transfer point from "problem drinking borderline group" to "problem drinking group", showing more serious states along the smoking axis. These results suggest that drinking behavior is first regulated by alcohol- sensitive or alcohol-tolerate constitution, and alcohol-tolerate students with a smoking habit have alcohol dependence tendency, and tend to show serious problem drinking. Improvement in the drinking habit is necessary in alcohol-tolerate students with a smoking habit so that they will not develop alcohol dependence.

Adult↗
PubMed1989

The heredity of human alcohol abuse: myths and facts.

Myths and facts concerning the heredity of human alcohol abuse are discussed in this article. Familial aggregation, adoption studies, twin concordances, marker gene associations and, finally, recent biochemical and genetic evidence are examined critically. It is concluded that with the exception of a possible protective action of the ALDH2 gene in Japanese there is a lack of clear cut evidence with respect to the direct participation of genetic factors in human alcoholism.

Adoption↗
PubMed1988

[Human aldehyde dehydrogenase in a sample of the Costa Rican population].

This is an electrophoretic study of ALDH isozymes in post-mortem tissue extracts. Three different electrophoretic variants of the isozyme ALDH3 were found in the 100 individuals examined. One liver sample showed lack of ALDH1 activity, but it remains unknown whether this is due to genetic mechanisms. The other two isozymes--ALDH2 and ALDH4--did not show any variations.

Aldehyde Dehydrogenase↗
PubMed1986

Aldehyde dehydrogenase polymorphism in North American, South American, and Mexican Indian populations.

While about 40% of the South American Indian populations (Atacameños, Mapuche, Shuara) were found to be deficient in aldehyde dehydrogenase isozyme I (ALDH2 or E2), preliminary investigations showed very low incidence of isozyme deficiency among North American natives (Sioux, Navajo) and Mexican Indians (mestizo). Possible implications of such trait differences on cross-cultural behavioral response to alcohol drinking are discussed.

Aldehyde Dehydrogenase↗