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Yokoyama A, Yokoyama T, Yumoto Y, Takimura T, Toyama T, Yoneda J, Nishimura K, Minobe R, Matsuzaki T, Kimura M, Matsushita S. History of mental comorbidities and their relationships with drinking milestones, hazardous drug use, suicide attempts, and the ADH1B and ALDH2 genotypes in 4116 Japanese men with alcohol dependence: An exploratory study. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2025; 49:804-817. [PMID: 40146027 DOI: 10.1111/acer.70014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 02/03/2025] [Indexed: 03/28/2025]
Abstract
BACKGROUND Alcohol dependence (AD) is often comorbid with other mental disorders. We assessed how comorbidities are associated with the clinical features of AD. METHODS Information on the history of mental comorbidities, hazardous drug use, suicide attempts, and drinking milestones was collected on a semi-structured medical history form from 4116 Japanese male AD inpatients (2007-2018); the subjects' ADH1B and ALDH2 genotypes (rs1229984/rs671) were also determined. RESULTS Of the total, 889 (21.60%) patients reported a history of mental comorbidities, including mood disorders (15.48%) and insomnia (2.89%); 202 (4.91%) reported a history of hazardous drug use, and 614 (14.92%) reported suicide attempts. Comorbidities were most commonly diagnosed around the time of onset of advanced alcohol use disorder (aAUD). Patients with comorbidities who began drinking regularly showed more rapid progression to aAUD and to the start of treatment for AD. Multivariate odds ratios (MORs [95%CI]) for the fast-metabolizing ADH1B*1/*2 and ADH1B*2/*2, protective against AD, were higher in patients with comorbidities [1.43 (1.16-1.76) and 1.35 (1.11-1.66)], drug use [1.64 (1.09-2.46) and 1.60 (1.07-2.38)], and suicide attempts [1.45 (1.13-1.85) and 1.49 (1.17-1.88)] compared with the ADH1B*1/*1. MORs for the inactive protective ALDH2*1/*2 were increased only in patients with insomnia [2.65 (1.75-4.02)] compared with the ALDH2*1/*1. MORs for smoking [0.74 (0.58-0.94)] and for age ≤15 years at first drink [0.66 (0.54-0.81)] were lower in patients with comorbidities. MORs for suicide attempts were 2.87 (2.36-3.48) in patients with comorbidities and 3.38 (2.47-4.62) in patients with drug use. CONCLUSIONS Mental comorbidities and a history of suicide attempts were frequent in Japanese patients with AD. Risk factors for AD (ADH1B*1/*1, smoking, early initiation of drinking) were negatively associated with the risk of comorbidities, suggesting interactions between comorbidities and AD risk factors. Insomnia was positively associated with the inactive ALDH2*1/*2. AD patients with mental comorbidities require multifaceted interventions, including suicide prevention.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Tetsuji Yokoyama
- Department of Health Promotion, National Institute of Public Health, Wako, Japan
| | - Yosuke Yumoto
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Tsuyoshi Takimura
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Tomomi Toyama
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Junichi Yoneda
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Kotaro Nishimura
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Ruriko Minobe
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Takanobu Matsuzaki
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Mitsuru Kimura
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Sachio Matsushita
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
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Yokoyama A, Yokoyama T, Yumoto Y, Takimura T, Toyama T, Yoneda J, Nishimura K, Minobe R, Matsuzaki T, Kimura M, Matsushita S. Associations of ADH1B and ALDH2 genotypes and alcohol flushing with drinking history, withdrawal symptoms, and ICD-10 criteria in Japanese alcohol-dependent men. Pharmacogenet Genomics 2024; 34:139-148. [PMID: 38465575 DOI: 10.1097/fpc.0000000000000528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
OBJECTIVES Given the high prevalence of fast-metabolizing alcohol dehydrogenase-1B*2 (ADH1B*2 ) and inactive aldehyde dehydrogenase-2*2 (ALDH2*2 ) alleles in East Asians, we evaluated how the ADH1B / ALDH2 genotypes and alcohol flushing might affect the development of alcohol dependence (AD). METHODS We evaluated how the ADH1B / ALDH2 genotypes and self-reported alcohol flushing affected history of drinking events and withdrawal symptoms and ICD-10 criteria in 4116 Japanese AD men. RESULTS The ADH1B*1/*1 group and ALDH2*1/*1 group were 1-5 years younger than the ADH1B*2 (+) and ALDH2*1/*2 groups, respectively, for all of the ages at onset of habitual drinking, blackouts, daytime drinking, uncontrolled drinking, withdrawal symptoms, and first treatment for AD, and the current age. Blackouts were more common in the ADH1B*1/*1 group and ALDH2*1/*1 group. Daytime drinking, uncontrolled drinking, and withdrawal symptoms, such as hand tremor, sweating, convulsions, and delirium tremens/hallucinations were more common in the ADH1B*1/*1 group. The ADH1B*1/*1 was positively associated with the ICD-10 criteria for 'tolerance' and 'withdrawal symptoms'. The ADH1B*1/*1 group and ALDH2*1/*2 group had a larger ICD-10 score. Never flushing was reported by 91.7% and 35.2% of the ALDH2*1/*1 and ALDH2*1/*2 carriers, respectively. After a 1-2-year delay in the onset of habitual drinking in the former-/current-flushing group, no differences in the ages of the aforementioned drinking milestones were found according to the flushing status. CONCLUSION The ADH1B*1/*1 and ALDH2*1/*1 accelerated the development of drinking events and withdrawal symptoms in Japanese AD patients. ICD-10 score was larger in the ADH1B*1/*1 group and ALDH2*1/*2 group. The effects of alcohol flushing on drinking events were limited.
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Affiliation(s)
- Akira Yokoyama
- Clinical Research Unit, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa
| | - Tetsuji Yokoyama
- Department of Health Promotion, National Institute of Public Health, Wako, Saitama, Japan
| | - Yosuke Yumoto
- Departemt of Psychiatry, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa
| | - Tsuyoshi Takimura
- Departemt of Psychiatry, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa
| | - Tomomi Toyama
- Departemt of Psychiatry, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa
| | - Junichi Yoneda
- Departemt of Psychiatry, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa
| | - Kotaro Nishimura
- Departemt of Psychiatry, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa
| | - Ruriko Minobe
- Departemt of Psychiatry, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa
| | - Takanobu Matsuzaki
- Departemt of Psychiatry, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa
| | - Mitsuru Kimura
- Departemt of Psychiatry, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa
| | - Sachio Matsushita
- Departemt of Psychiatry, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa
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Kukowka A, Brzuchalski B, Kurzawski M, Malinowski D, Białecka MA. ADH1B, ADH1B/C and CYP2E1 Gene Polymorphism and the Risk of Fetal Alcohol Spectrum Disorder. Genes (Basel) 2023; 14:1392. [PMID: 37510297 PMCID: PMC10379323 DOI: 10.3390/genes14071392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/24/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
Increasing alcohol consumption by women of childbearing age contributes to more frequent cases of fetal alcohol spectrum disorder. The cause of the syndrome is fetal alcohol exposure, particularly what is referred to as high prenatal alcohol exposure. Low metabolic activity of fetal enzymes shifts the burden of ethanol removal to maternal metabolism. One of the factors influencing the pathogenesis of FASD is the genetic background. It can determine the rate of elimination of ethanol, thus increasing or decreasing the time of fetal exposure to ethanol and also decreasing its concentration. Genetic polymorphisms could potentially play a significant role in these processes. In the present study, we considered three polymorphisms of genes implicated in the synthesis of enzymes involved in ethanol metabolism, i.e., ADH1b (rs1229984), ADH1b/c (rs1789891), and CYP2E1 (rs3813867). The studied group consisted of 303 children and 251 mothers. Both mothers' and children's genotypes were considered in our analysis. There were no statistically significant differences between the respective groups of genotypes of the studied polymorphisms. However, the genetic background of FASD is still elusive.
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Affiliation(s)
- Arnold Kukowka
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, Aleja Powstanców Wielkopolskich 72 St., 70-111 Szczecin, Poland (D.M.)
| | - Bogusław Brzuchalski
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, Aleja Powstanców Wielkopolskich 72 St., 70-111 Szczecin, Poland (D.M.)
| | - Mateusz Kurzawski
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Aleja Powstanców Wielkopolskich 72 St., 70-111 Szczecin, Poland;
| | - Damian Malinowski
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, Aleja Powstanców Wielkopolskich 72 St., 70-111 Szczecin, Poland (D.M.)
| | - Monika Anna Białecka
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, Aleja Powstanców Wielkopolskich 72 St., 70-111 Szczecin, Poland (D.M.)
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Luo Z, Cheng J, Wang Y. Effects of the genetic variants of alcohol-metabolizing enzymes on lipid levels in Asian populations: a systematic review and meta-analysis. Nutr Rev 2022:6960646. [PMID: 36565468 DOI: 10.1093/nutrit/nuac100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
CONTEXT Emerging evidence indicates that variants of alcohol-metabolizing enzymes may influence lipid metabolism. OBJECTIVE This study aimed to investigate whether the rs671 and rs1229984 variants affect lipid levels in East Asian individuals. DATA SOURCES PubMed, Foreign Medical Journal Service, Embase, Cochrane Library, Scopus, MEDLINE, Web of Science, Web of Knowledge, Wanfang, and Chinese Biomedical Literature databases were searched until December 31, 2021. DATA EXTRACTION Meta-analyses of studies that examined the effects of alcohol-metabolizing enzyme variants on lipid levels, as well as the interaction with alcohol intake, were selected. Data extraction was conducted independently by two investigators and confirmed by the third. DATA ANALYSIS In total, 86 studies (179 640 individuals) were analyzed. The A allele of rs671 (a functional variant in the ALDH2 gene) was linked to higher levels of low-density lipoprotein cholesterol (LDL-C) and lower levels of triglycerides and high-density lipoprotein cholesterol. In contrast, the A allele of the rs1229984 (a functional variant in the ADH2 gene) was associated only with lower levels of LDL-C. The effects of rs671 and rs1229984 on lipid levels were much stronger in Japanese than in Chinese individuals and in males than in females. Regression analysis indicated that the effects of rs671 on lipid levels were independent of alcohol intake in an integrated East Asian population (ie, Japanese, Chinese, and Korean individuals). Intriguingly, alcohol intake had a statistical influence on lipid levels when the sample analyzed was restricted to Japanese individuals or to males. CONCLUSIONS The rs671 and rs1229984 variants of alcohol-metabolizing enzymes have significant effects on lipid levels and may serve as genetic markers for lipid dyslipidemia in East Asian populations. Circulating lipid levels in Japanese individuals and in males were modulated by the interaction between rs671 and alcohol intake.
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Affiliation(s)
- Zhi Luo
- Department of General Medicine and Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Jun Cheng
- Department of General Medicine and Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.,Medical Research Institute of Wuhan University, Wuhan University, Wuhan, China
| | - Yanggan Wang
- Department of General Medicine and Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.,Medical Research Institute of Wuhan University, Wuhan University, Wuhan, China
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Mamluk L, Jones T, Ijaz S, Edwards HB, Savović J, Leach V, Moore THM, von Hinke S, Lewis SJ, Donovan JL, Lawlor DA, Davey Smith G, Fraser A, Zuccolo L. Evidence of detrimental effects of prenatal alcohol exposure on offspring birthweight and neurodevelopment from a systematic review of quasi-experimental studies. Int J Epidemiol 2021; 49:1972-1995. [PMID: 31993631 PMCID: PMC7825937 DOI: 10.1093/ije/dyz272] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 11/25/2019] [Accepted: 01/08/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Systematic reviews of prenatal alcohol exposure effects generally only include conventional observational studies. However, estimates from such studies are prone to confounding and other biases. OBJECTIVES To systematically review the evidence on the effects of prenatal alcohol exposure from randomized controlled trials (RCTs) and observational designs using alternative analytical approaches to improve causal inference. SEARCH STRATEGY Medline, Embase, Web of Science, PsychINFO from inception to 21 June 2018. Manual searches of reference lists of retrieved papers. SELECTION CRITERIA RCTs of interventions to stop/reduce drinking in pregnancy and observational studies using alternative analytical methods (quasi-experimental studies e.g. Mendelian randomization and natural experiments, negative control comparisons) to determine the causal effects of prenatal alcohol exposure on pregnancy and longer-term offspring outcomes in human studies. DATA COLLECTION AND ANALYSIS One reviewer extracted data and another checked extracted data. Risk of bias was assessed using customized risk of bias tools. A narrative synthesis of findings was carried out and a meta-analysis for one outcome. MAIN RESULTS Twenty-three studies were included, representing five types of study design, including 1 RCT, 9 Mendelian randomization and 7 natural experiment studies, and reporting on over 30 outcomes. One study design-outcome combination included enough independent results to meta-analyse. Based on evidence from several studies, we found a likely causal detrimental role of prenatal alcohol exposure on cognitive outcomes, and weaker evidence for a role in low birthweight. CONCLUSION None of the included studies was judged to be at low risk of bias in all domains, results should therefore be interpreted with caution. SYSTEMATIC REVIEW REGISTRATION This study is registered with PROSPERO, registration number CRD42015015941.
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Affiliation(s)
- Loubaba Mamluk
- MRC Integrative Epidemiology Unit, Department of Population Health Sciences, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- NIHR ARC West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Timothy Jones
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- NIHR ARC West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Sharea Ijaz
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- NIHR ARC West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Hannah B Edwards
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- NIHR ARC West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Jelena Savović
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- NIHR ARC West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Verity Leach
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- NIHR ARC West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Theresa H M Moore
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- NIHR ARC West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Stephanie von Hinke
- Department of Economics, School of Economics, Finance and Management, University of Bristol, Bristol, UK
| | - Sarah J Lewis
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Jenny L Donovan
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- NIHR ARC West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Deborah A Lawlor
- MRC Integrative Epidemiology Unit, Department of Population Health Sciences, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- NIHR ARC West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
- NIHR Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust, University of Bristol, Bristol, UK
| | - George Davey Smith
- MRC Integrative Epidemiology Unit, Department of Population Health Sciences, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- NIHR Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust, University of Bristol, Bristol, UK
| | - Abigail Fraser
- MRC Integrative Epidemiology Unit, Department of Population Health Sciences, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- NIHR Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust, University of Bristol, Bristol, UK
| | - Luisa Zuccolo
- MRC Integrative Epidemiology Unit, Department of Population Health Sciences, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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Yokoyama A, Omori T, Yokoyama T. Risk factors for esophageal iodine-unstained lesions and changing trends among Japanese alcohol-dependent men (2003-2018). Cancer Sci 2020; 112:734-743. [PMID: 33249700 PMCID: PMC7894006 DOI: 10.1111/cas.14753] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/25/2020] [Accepted: 11/25/2020] [Indexed: 12/16/2022] Open
Abstract
Globally, a decreasing incidence of male esophageal squamous cell carcinoma (ESCC) has been observed in recent decades. We evaluated the determinants of esophageal distinct iodine-unstained lesions (DIULs), high-cancer-risk lesions and ESCC, among 3858 Japanese alcohol-dependent men (40-79 years) who underwent chromoendoscopic screening between 2003 and 2018. The initial screening detected DIULs ≥ 5 mm in 541 patients (dysplasia in 319 and SCC in 129) and multiple DIULs in 640. The detection rates for DIULs and chronic atrophic gastritis (CAG), pack-years, and the mean corpuscular volume (MCV) decreased over the course of the study period, while the detection of hiatal hernia and/or columnar-lined esophagus (HH/CLE) and the carriers of inactive heterozygous aldehyde dehydrogenase-2 (ALDH2, rs671) increased. Multiple logistic regression analyses showed that an older age, larger number of pack-years, smaller body mass index, larger MCV, presence of a slow-metabolizing alcohol dehydrogenase-1B genotype (rs1229984), presence of an inactive heterozygous ALDH2 genotype, and more advanced degree of CAG increased the odds ratios (ORs) for DIULs, while the 2008-2013 and 2014-2018 screening periods had lower ORs for DIULs than the 2003-2007 screening period. The presence of HH/CLE decreased the OR for multiple DIULs and was associated with a more proximal location of ESCC. In conclusion, the detection of DIULs in an alcohol-dependent population decreased between 2003 and 2018. In addition to reported determinants of ESCC, CAG and HH/CLE were associated with the risk of DIULs. Enigmatically, however, the decline in the detection of DIULs was not adequately explained by these factors and warrants further research.
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Affiliation(s)
- Akira Yokoyama
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai Omori
- Endoscopy Center, Kawasaki Municipal Ida Hospital, Kanagawa, Japan
| | - Tetsuji Yokoyama
- Department of Health Promotion, National Institute of Public Health, Saitama, Japan
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Yokoyama A, Omori T, Yokoyama T. Changing trends in cancer incidence of upper aerodigestive tract and stomach in Japanese alcohol-dependent men (1993-2018). Cancer Med 2020; 9:837-846. [PMID: 31957322 PMCID: PMC6970038 DOI: 10.1002/cam4.2737] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 11/12/2019] [Accepted: 11/14/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC), head and neck SCC (HNSCC), and gastric adenocarcinoma (GA) are frequently detected at an early stage using endoscopic screening in Japanese alcohol-dependent men. METHODS We performed endoscopic screening with esophageal iodine staining and oropharyngolaryngeal inspection in 7582 Japanese alcohol-dependent men (40-79 years) during 1993-2018, and retrospectively investigated their initial screening results. RESULTS The 2008-2018 screening showed lower detection rates for ESCC (2.6% vs 4.0%, P = .0009) and GA (0.5% vs 1.4%, P < .0001) for all age brackets, compared with the 1993-2007 screening. The HNSCC detection rate did not change (1.0% vs 1.1%). Multiple logistic regression analyses showed that the 2008-2018 screening had a reduced OR (95% CI) for ESCC (0.34 [0.25-0.47]) and GA (0.19 [0.10-0.35]), compared with the 1993-2007 screening. The reduction in H pylori infection is probably the main reason for the decrease in GA detection over time. Declining trends in pack-years and gastric atrophy and increasing trends in age and body mass index (BMI) were found over time. The presence of advanced gastric atrophy increased the risk for ESCC as well as GA. The inactive heterozygous aldehyde dehydrogenase-2*1/*2 genotype was a strong risk factor for ESCC, HNSCC, and GA. Fewer pack-years and a larger BMI decreased the ESCC risk. However, these confounders cannot fully explain why the incidence of ESCC has decreased markedly over the recent decade. CONCLUSIONS The detection rates of ESCC and GA have markedly decreased during the past decade in the alcohol-dependent population. The enigmatic declining trend of ESCC warrants research on this topic.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Medical and Addiction CenterKanagawaJapan
| | - Tai Omori
- Endoscopy CenterKawasaki Municipal Ida HospitalKanagawaJapan
| | - Tetsuji Yokoyama
- Department of Health PromotionNational Institute of Public HealthSaitamaJapan
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Yokoyama A, Yokoyama T, Omori T, Maesato H, Takimura T, Iwahara C, Kimura M, Matsui T, Mizukami T, Maruyama K. Endoscopic screening using esophageal iodine staining and genotypes of ADH1B and ALDH2 in Japanese alcohol-dependent women. PLoS One 2019; 14:e0210546. [PMID: 30629674 PMCID: PMC6328133 DOI: 10.1371/journal.pone.0210546] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 12/27/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The presence of large or multiple esophageal distinct iodine-unstained lesions (DIULs) is a strong predictor of field cancerization in the upper aerodigestive tract. Several risk factors for DIULs, including genetic polymorphisms of alcohol and aldehyde dehydrogenases (ADH1B, rs1229984; ALDH2, rs671), have been demonstrated in Japanese alcohol-dependent men. However, few evaluations of alcohol-dependent women have been conducted in this field. METHODS Using multiple logistic regression models, we investigated the results of screening using esophageal iodine staining and the identification of determinants for esophageal DIULs in 472 Japanese alcohol-dependent women. RESULTS DIULs ≥5 mm, multiple DILUs, and both characteristics were observed in 35 (7.4%), 31 (6.6%), and 16 (3.4%) patients, respectively. DIULs ≥5 mm were histologically diagnosed as low-grade intraepithelial neoplasia in 26 patients and superficial squamous cell carcinoma in 9 patients. Although the inactive heterozygous ALDH2*1/*2 genotype was more common (33.3% vs. 11.4%, p = 0.002) in the group with DIULs ≥5 mm than in the group without DIULs ≥5 mm, no significant differences in the results of a questionnaire asking about current and past facial flushing after a glass of beer were seen between the groups with and without DIULs ≥5 mm. When individuals with current or former flushing were assumed to have inactive ALDH2, the sensitivity and specificity of current or former flushing to identify the presence of inactive ALDH2 were 50.0% and 93.5%, respectively; these values were previously reported to be 88% and 92%, respectively, in a Japanese general female population. The low sensitivity in the present study suggests that a lack of alcohol flushing may play a crucial role in the development of alcohol dependence in women with inactive ALDH2. No significant differences in age, usual alcohol consumption, or smoking habits were observed according to ADH1B and ALDH2 genotypes. Multiple logistic regression analyses showed that the slow-metabolizing ADH1B*1/*1 genotype (odds ratio [95% confidence interval], 12.5 [4.82-32.4] and 9.89 [3.50-27.9]), the inactive heterozygous ALDH2*1/*2 genotype (2.94 [1.18-7.38] and 3.79 [1.40-10.3]), a lower body mass index per -1 kg/m2 (1.17 [1.02-1.35] and 1.38 [1.14-1.67]), and a mean corpuscular volume ≥106 fl (3.70 [1.56-8.81] and 3.27 [1.24-8.64]) increased the risk of DIULs ≥5 mm and multiple DIULs, respectively. The combination of ADH1B*1/*1 and ALDH2*1/*2 markedly increased the risk of esophageal DIULs ≥5 mm (39.3 [10.6-146]). CONCLUSIONS Japanese alcohol-dependent women shared several common risk factors for esophageal squamous cell neoplasia with alcohol-dependent men, but with considerably different magnitudes.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Tetsuji Yokoyama
- Department of Health Promotion, National Institute of Public Health, Wako, Saitama, Japan
| | - Tai Omori
- Endoscopy Center, Kawasaki Municipal Ida Hospital, Kawasaki, Kanagawa, Japan
| | - Hitoshi Maesato
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Tsuyoshi Takimura
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Chie Iwahara
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Mitsuru Kimura
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Toshifumi Matsui
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Takeshi Mizukami
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Katsuya Maruyama
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
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Chi YC, Lee SL, Lee YP, Lai CL, Yin SJ. Modeling of Human Hepatic and Gastrointestinal Ethanol Metabolism with Kinetic-Mechanism-Based Full-Rate Equations of the Component Alcohol Dehydrogenase Isozymes and Allozymes. Chem Res Toxicol 2018; 31:556-569. [PMID: 29847918 DOI: 10.1021/acs.chemrestox.8b00003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Alcohol dehydrogenase (ADH) is the principal enzyme responsible for the metabolism of ethanol. Human ADH constitutes a complex family of isozymes and allozymes with striking variation in kinetic properties and tissue distribution. The liver and the gastrointestinal tract are the major sites for first-pass metabolism (FPM). The quantitative contributions of ADH isozymes and ethnically distinct allozymes to cellular ethanol metabolism remain poorly understood. To address this issue, kinetic mechanism and the steady-state full-rate equations for recombinant human class I ADH1A, ADH1B (including allozymes ADH1B1, ADH1B2, and ADH1B3), ADH1C (including allozymes ADH1C1 and ADH1C2), class II ADH2, and class IV ADH4 were determined by initial velocity, product inhibition, and dead-end inhibition experiments in 0.1 M sodium phosphate at pH 7.5 and 25 °C. Models of the hepatic and gastrointestinal metabolisms of ethanol were constructed by linear combination of the numerical full-rate equations of the component isozymes and allozymes in target organs. The organ simulations indicate that in homozygous ADH1B*1/*1 livers, a representative genotype among ethnically distinct populations due to high prevalence of the allele, major contributors at 1 to 10 mM ethanol are ADH1B1 (45% to 24%) and the ADH1C allozymes (54% to 40%). The simulated activities at 1 to 50 mM ethanol for the gastrointestinal tract (total mucosae of ADH1C*1/*1-ADH4 stomach and the ADH1C*1/*1-ADH2 duodenum and jejunum) account for 0.68%-0.76% of that for the ADH1B*1/*1-ADH1C*1/*1 liver, suggesting gastrointestinal tract plays a relatively minor role in the human FPM of ethanol. Based on the flow-limited sinusoidal perfusion model, the simulated hepatic Kmapp, Vmaxapp, and Ci at a 95% clearance of ethanol for ADH1B*1/*1-ADH1C*1/*1 livers are compatible to that documented in hepatic vein catheterization and pharmacokinetic studies with humans that controlled for the genotypes. The model simulations suggest that slightly higher or similar ethanol elimination rates for ADH1B*2/*2 and ADH1B*3/*3 individuals compared with those for ADH1B*1/*1 individuals may result from higher hepatocellular acetaldehyde.
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Affiliation(s)
- Yu-Chou Chi
- Department of Biochemistry , National Defense Medical Center , 161 Minchuan East Road Section 6 , Taipei 11490 , Taiwan
| | - Shou-Lun Lee
- Department of Biological Science and Technology , China Medical University , 91 Hsueh-Shih Road , Taichung 40402 , Taiwan
| | - Yung-Ping Lee
- Department of Biochemistry , National Defense Medical Center , 161 Minchuan East Road Section 6 , Taipei 11490 , Taiwan
| | - Ching-Long Lai
- Department of Nursing , Chang Gung University of Science and Technology , 261 Wenhwa First Road , Taoyuan City 33303 , Taiwan
| | - Shih-Jiun Yin
- Department of Biochemistry , National Defense Medical Center , 161 Minchuan East Road Section 6 , Taipei 11490 , Taiwan
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Way MJ, Ali MA, McQuillin A, Morgan MY. Genetic variants in ALDH1B1 and alcohol dependence risk in a British and Irish population: A bioinformatic and genetic study. PLoS One 2017; 12:e0177009. [PMID: 28594837 PMCID: PMC5464525 DOI: 10.1371/journal.pone.0177009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 04/20/2017] [Indexed: 12/30/2022] Open
Abstract
Alcohol is metabolized in the liver via the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Polymorphisms in the genes encoding these enzymes, which are common in East Asian populations, can alter enzyme kinetics and hence the risk of alcohol dependence and its sequelae. One of the most important genetic variants, in this regards, is the single nucleotide polymorphism (SNP) rs671 in ALDH2, the gene encoding the primary acetaldehyde metabolizing enzyme ALDH2. However, the protective allele of rs671 is absent in most Europeans although ALDH1B1, which shares significant sequence homology with ALDH2, contains several, potentially functional, missense SNPs that do occur in European populations. The aims of this study were: (i) to use bioinformatic techniques to characterize the possible effects of selected variants in ALDH1B1 on protein structure and function; and, (ii) to genotype three missense and one stop-gain, protein-altering, non-synonymous SNPs in 1478 alcohol dependent cases and 1254 controls of matched British and Irish ancestry. No significant allelic associations were observed between the three missense SNPs and alcohol dependence risk. The minor allele frequency of rs142427338 (Gln378Ter) was higher in alcohol dependent cases than in controls (allelic P = 0.19, OR = 2.98, [0.62–14.37]) but as this SNP is very rare the study was likely underpowered to detect an association with alcohol dependence risk. This potential association will needs to be further evaluated in other large, independent European populations.
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Affiliation(s)
- Michael J. Way
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, United Kingdom
- UCL Institute for Liver & Digestive Health, Department of Medicine, Royal Free Campus, University College London, London, United Kingdom
| | - M. Adam Ali
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, United Kingdom
- UCL Institute for Liver & Digestive Health, Department of Medicine, Royal Free Campus, University College London, London, United Kingdom
| | - Andrew McQuillin
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, United Kingdom
| | - Marsha Y. Morgan
- UCL Institute for Liver & Digestive Health, Department of Medicine, Royal Free Campus, University College London, London, United Kingdom
- * E-mail:
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Yokoyama A, Yokoyama T, Mizukami T, Matsui T, Kimura M, Matsushita S, Higuchi S, Maruyama K. Platelet Counts and Genetic Polymorphisms of Alcohol Dehydrogenase-1B and Aldehyde Dehydrogenase-2 in Japanese Alcoholic Men. Alcohol Clin Exp Res 2016; 41:171-178. [PMID: 27991683 DOI: 10.1111/acer.13283] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 10/25/2016] [Indexed: 01/08/2023]
Abstract
BACKGROUND Thrombocytopenia during intoxication, rebound thrombocytosis during 1 to 3 weeks of abstinence, and subsequent normalization of the platelet count are common in alcoholics. METHODS We evaluated 989 Japanese alcoholic men to identify the effects of genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B; rs1229984) and aldehyde dehydrogenase-2 (ALDH2; rs671) on platelet counts during an 8-week in-hospital abstinence period. RESULTS Thrombocytopenia (<15 × 104 /μl) was observed in 25.9% of the subjects upon admission. The platelet counts increased from 21.4 ± 0.3 × 104 /μl (mean ± SE) to 27.6 ± 0.3 × 104 /μl, and a rebound platelet increase of ≥10 × 104 /μl was observed in 28.6% of the patients during the first 2 weeks after admission. By 4 weeks, the mean platelet counts had returned to intermediate levels and remained stable thereafter. The reversible suppression and rebound increase in the platelet counts were more prominent in the slow-metabolizing ADH1B*1/*1 group than in the fast-metabolizing ADH1B*2 group. Throughout the 8 weeks, the mean platelet counts of the active ALDH2*1/*1 group were consistently lower than those in the inactive ALDH2*1/*2 group. Cirrhosis was a strong determinant of a lower platelet count. After adjustments for nongenetic factors including cirrhosis, multiple linear regression analyses showed that the ADH1B*1/*1 genotype was associated with a lower platelet count (partial regression coefficient = -1.3 × 104 /μl) on the admission day, but subsequently had a positive effect on the platelet count at 1 and 2 weeks after admission (+1.5 and +3.8 × 104 /μl, respectively). The ALDH2*1/*1 genotype was associated with a lower platelet count (-2.1 to -3.9 × 104 /μl) consistently throughout the 8 weeks. Multiple logistic regression analyses showed that the ADH1B*1/*1 genotype increased the risk of thrombocytopenia upon admission (odds ratio [95% confidence interval] = 1.61 [1.14 to 2.27]) and of a rebound platelet increase during the first 2 weeks (3.86 [2.79 to 5.34]). The ALDH2*1/*1 genotype increased the risk of thrombocytopenia upon admission (1.73 [1.06 to 2.82]). CONCLUSIONS In alcoholics, the ADH1B*1/*1 genotype increased the risk of thrombocytopenia upon admission and of a rebound platelet increase 2 weeks thereafter, while the ALDH2*1/*1 genotype was associated with lower platelet counts throughout the 8-week hospital stay.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Tetsuji Yokoyama
- Department of Health Promotion, National Institute of Public Health, Wako, Saitama, Japan
| | - Takeshi Mizukami
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Toshifumi Matsui
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan.,Department of Geriatric Medicine, Kyorin University Hospital, Mitaka, Tokyo, Japan
| | - Mitsuru Kimura
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Sachio Matsushita
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Susumu Higuchi
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Katsuya Maruyama
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
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12
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Murray J, Burgess S, Zuccolo L, Hickman M, Gray R, Lewis SJ. Moderate alcohol drinking in pregnancy increases risk for children's persistent conduct problems: causal effects in a Mendelian randomisation study. J Child Psychol Psychiatry 2016; 57:575-84. [PMID: 26588883 PMCID: PMC4855628 DOI: 10.1111/jcpp.12486] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/12/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Heavy alcohol use during pregnancy can cause considerable developmental problems for children, but effects of light-moderate drinking are uncertain. This study examined possible effects of moderate drinking in pregnancy on children's conduct problems using a Mendelian randomisation design to improve causal inference. METHODS A prospective cohort study (ALSPAC) followed children from their mother's pregnancy to age 13 years. Analyses were based on 3,544 children whose mothers self-reported either not drinking alcohol during pregnancy or drinking up to six units per week without binge drinking. Children's conduct problem trajectories were classified as low risk, childhood-limited, adolescence-onset or early-onset-persistent, using six repeated measures of the Strengths and Difficulties Questionnaire between ages 4-13 years. Variants of alcohol-metabolising genes in children were used to create an instrumental variable for Mendelian randomisation analysis. RESULTS Children's genotype scores were associated with early-onset-persistent conduct problems (OR = 1.29, 95% CI = 1.04-1.60, p = .020) if mothers drank moderately in pregnancy, but not if mothers abstained from drinking (OR = 0.94, CI = 0.72-1.25, p = .688). Children's genotype scores did not predict childhood-limited or adolescence-onset conduct problems. CONCLUSIONS This quasi-experimental study suggests that moderate alcohol drinking in pregnancy contributes to increased risk for children's early-onset-persistent conduct problems, but not childhood-limited or adolescence-onset conduct problems.
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Affiliation(s)
- Joseph Murray
- Department of PsychiatryUniversity of CambridgeCambridgeUK
| | - Stephen Burgess
- Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
| | - Luisa Zuccolo
- School of Social and Community MedicineUniversity of BristolBristolUK,MRC Integrative Epidemiology UnitUniversity of BristolBristolUK
| | - Matthew Hickman
- School of Social and Community MedicineUniversity of BristolBristolUK
| | - Ron Gray
- National Perinatal Epidemiology UnitNuffield Department of Population HealthUniversity of OxfordOxfordUK
| | - Sarah J. Lewis
- School of Social and Community MedicineUniversity of BristolBristolUK
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RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2016; 1859:1198-1217. [PMID: 27113289 DOI: 10.1016/j.bbagrm.2016.04.010] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 04/19/2016] [Accepted: 04/19/2016] [Indexed: 12/14/2022]
Abstract
The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known xenobiotic-sensing nuclear receptors with overlapping functions. However, there lacks a quantitative characterization to distinguish between the PXR and CAR target genes and signaling pathways in the liver. The present study performed a transcriptomic comparison of the PXR- and CAR-targets using RNA-Seq in livers of adult wild-type mice that were treated with the prototypical PXR ligand PCN (200mg/kg, i.p. once daily for 4days in corn oil) or the prototypical CAR ligand TCPOBOP (3mg/kg, i.p., once daily for 4days in corn oil). At the given doses, TCPOBOP differentially regulated many more genes (2125) than PCN (212), and 147 of the same genes were differentially regulated by both chemicals. As expected, the top pathways differentially regulated by both PCN and TCPOBOP were involved in xenobiotic metabolism, and they also up-regulated genes involved in retinoid metabolism, but down-regulated genes involved in inflammation and iron homeostasis. Regarding unique pathways, PXR activation appeared to overlap with the aryl hydrocarbon receptor signaling, whereas CAR activation appeared to overlap with the farnesoid X receptor signaling, acute-phase response, and mitochondrial dysfunction. The mRNAs of differentially regulated drug-processing genes (DPGs) partitioned into three patterns, namely TCPOBOP-induced, PCN-induced, as well as TCPOBOP-suppressed gene clusters. The cumulative mRNAs of the differentially regulated DPGs, phase-I and -II enzymes, as well as efflux transporters were all up-regulated by both PCN and TCPOBOPOP, whereas the cumulative mRNAs of the uptake transporters were down-regulated only by TCPOBOP. The absolute mRNA abundance in control and receptor-activated conditions was examined in each DPG category to predict the contribution of specific DPG genes in the PXR/CAR-mediated pharmacokinetic responses. The preferable differential regulation by TCPOBOP in the entire hepatic transcriptome correlated with a marked change in the expression of many DNA and histone epigenetic modifiers. In conclusion, the present study has revealed known and novel, as well as common and unique targets of PXR and CAR in mouse liver following pharmacological activation using their prototypical ligands. Results from this study will further support the role of these receptors in regulating the homeostasis of xenobiotic and intermediary metabolism in the liver, and aid in distinguishing between PXR and CAR signaling at various physiological and pathophysiological conditions. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
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Yokoyama A, Kamada Y, Imazeki H, Hayashi E, Murata S, Kinoshita K, Yokoyama T, Kitagawa Y. Effects of ADH1B and ALDH2 Genetic Polymorphisms on Alcohol Elimination Rates and Salivary Acetaldehyde Levels in Intoxicated Japanese Alcoholic Men. Alcohol Clin Exp Res 2016; 40:1241-50. [DOI: 10.1111/acer.13073] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 03/18/2016] [Indexed: 01/30/2023]
Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Medical and Addiction Center; Yokosuka Kanagawa Japan
| | - Yoko Kamada
- Suntory Business Expert Limited; Suntory World Research Center; Soraku-gun Kyoto Japan
| | - Hiromi Imazeki
- National Hospital Organization Kurihama Medical and Addiction Center; Yokosuka Kanagawa Japan
| | - Emiko Hayashi
- National Hospital Organization Kurihama Medical and Addiction Center; Yokosuka Kanagawa Japan
| | - Shigenori Murata
- School of Pharmaceutical Science; Mukogawa Women's University; Nishinomiya Hyogo Japan
| | - Kenji Kinoshita
- School of Pharmaceutical Science; Mukogawa Women's University; Nishinomiya Hyogo Japan
| | - Tetsuji Yokoyama
- Department of Health Promotion; National Institute of Public Health; Wako Saitama Japan
| | - Yoshinori Kitagawa
- Suntory Business Expert Limited; Suntory World Research Center; Soraku-gun Kyoto Japan
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15
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Ethanol-metabolizing activities and isozyme protein contents of alcohol and aldehyde dehydrogenases in human liver: phenotypic traits of the ADH1B*2 and ALDH2*2 variant gene alleles. Pharmacogenet Genomics 2016; 26:184-195. [PMID: 26863581 DOI: 10.1097/fpc.0000000000000205] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for the metabolism of ethanol. East Asian populations are unique in that they carry both a prevalent ADH1B*2 and a dominant-negative ALDH2*2 allele. A systematic investigation of ethanol-metabolizing activities in normal livers correlated with the corresponding functional allelic variations and protein contents of the relevant isozymes in respective enzyme families has been lacking. MATERIALS AND METHODS To obtain a reasonable sample size encompassing all possible genetic allelotypes of the ADH1B and ALDH2, 141 surgical liver specimens from adult Han Chinese were studied. Expression patterns and activities of ADH and ALDH were determined with stratification of the genetic phenotypes. Absolute protein contents as well as cellular localization of the activity and protein of ADH/ALDH isozymes were also investigated. RESULTS The activities of ADH1B*1/*2 and ADH1B*2/*2 allelic phenotypes were 5-6-fold those of the ADH1B*1/*1, suggesting that ADH1B*2 allele-encoded subunits are dominant over expression of hepatic ADH activity. The activities of the ALDH2-active phenotype were 90% higher than those of the ALDH2-inactive phenotype. Sex and age did not significantly influence the hepatic ADH and ALDH activities with specified genetic phenotypes. The isozyme protein contents were as follows in decreasing order: ADH1, ADH2, ALDH1A1, ALDH2, and ADH3. Both ADH1, but not ADH2/3, and ALDH1A1/2 showed a preferential expression in perivenular hepatocytes. CONCLUSION Functional correlations of ADH1B*2 and ALDH2*2 variant alleles in the liver provide a biochemical genetic basis suggesting their contribution toward variability in ethanol metabolism as well as susceptibility to alcoholism and alcohol-related diseases in East Asians.
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16
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Yokoyama A, Brooks PJ, Yokoyama T, Mizukami T, Matsui T, Kimura M, Matsushita S, Higuchi S, Maruyama K. Blood Leukocyte Counts and Genetic Polymorphisms of Alcohol Dehydrogenase-1B and Aldehyde Dehydrogenase-2 in Japanese Alcoholic Men. Alcohol Clin Exp Res 2016; 40:507-17. [PMID: 26917006 DOI: 10.1111/acer.12983] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 12/03/2015] [Indexed: 12/23/2022]
Abstract
BACKGROUND Roughly 40% of East Asians have inactive aldehyde dehydrogenase-2 (ALDH2) encoded by the ALDH2*2 allele, and 90% have highly active alcohol dehydrogenase-1B (ADH1B) encoded by the ADH1B*2 allele. Macrocytosis and macrocytic anemia in alcoholics have been associated with ADH1B and ALDH2 gene variants which increase acetaldehyde (AcH) levels. METHODS We investigated the relationship between ADH1B*2, ALDH2*2, and leukocyte counts of Japanese alcoholic men (N = 1,661). RESULTS After adjusting for age, drinking habits, smoking habits, body mass index, presence of liver cirrhosis, and serum levels of C-reactive protein, we found that total and differential leukocyte counts were lower in the presence of the ALDH2*1/*2 genotype (vs. ALDH2*1/*1 genotype). ALDH2*2/*2 carriers were not found in our study population. Leukocyte, granulocyte, and monocyte counts were also lower in the presence of ADH1B*2 (vs. ADH1B*1/*1 genotype), but the lymphocyte count was higher. The ALDH2*1/*2 genotype was associated with leukocytopenia (<4,000/μl; adjusted odds ratio [95% confidence interval] = 1.89 [1.27 to 2.80]), granulocytopenia (<2,000/μl; 1.86 [1.22 to 2.82]), monocytopenia (<250/μl; 2.22 [1.49 to 3.29]), and lymphocytopenia (<1,000/μl; 1.93 [1.32 to 2.83]). In contrast, the ADH1B*2 had the opposite effect on lymphocytopenia (0.65 [0.46 to 0.93]). Considering genotype effects under conditions of immune stimulation, we observed suppressive effects of ADH1B*2 allele on leukocytosis (≥9,000/μl; 0.69 [0.50 to 0.97]), granulocytosis (≥6,500/μl; 0.66 [0.47 to 0.93]), and monocytosis (≥750/μl; 0.56 [0.39 to 0.79]). The ADH1B*2 plus ALDH2*1/*2 combination had the greatest suppressive effects on the leukocyte, granulocyte, and monocyte counts. CONCLUSIONS The total and differential blood leukocyte counts of Japanese alcoholics were strongly affected by their ADH1B and ALDH2 gene variants. High AcH exposure levels probably play a critical role in the suppression of blood leukocyte counts in alcoholics.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Medical and Addiction Center, Kanagawa, Japan
| | - Philip J Brooks
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland
| | - Tetsuji Yokoyama
- Department of Health Promotion, National Institute of Public Health, Saitama, Japan
| | - Takeshi Mizukami
- National Hospital Organization Kurihama Medical and Addiction Center, Kanagawa, Japan
| | - Toshifumi Matsui
- National Hospital Organization Kurihama Medical and Addiction Center, Kanagawa, Japan.,Department of Geriatric Medicine, Kyorin University Hospital, Tokyo, Japan
| | - Mitsuru Kimura
- National Hospital Organization Kurihama Medical and Addiction Center, Kanagawa, Japan
| | - Sachio Matsushita
- National Hospital Organization Kurihama Medical and Addiction Center, Kanagawa, Japan
| | - Susumu Higuchi
- National Hospital Organization Kurihama Medical and Addiction Center, Kanagawa, Japan
| | - Katsuya Maruyama
- National Hospital Organization Kurihama Medical and Addiction Center, Kanagawa, Japan
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Hashimoto M, Watanabe M, Uematsu Y, Hattori S, Miyai N, Utsumi M, Oka M, Hayashida M, Kinoshita K, Arita M, Takeshita T. Relationships of alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) genotypes with alcohol sensitivity, drinking behavior and problem drinking in Japanese older men. Environ Health Prev Med 2016; 21:138-48. [PMID: 26825972 DOI: 10.1007/s12199-016-0507-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 01/11/2016] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES Many East Asians have the genetic polymorphisms rs1229984 in alcohol dehydrogenase 1B (ADH1B) and rs671 in aldehyde dehydrogenase 2 (ALDH2). Here we analyzed the relationships of the two genotypes with alcohol sensitivity, drinking behavior and problem drinking among older and younger men living in rural areas of Japan. METHODS The subjects were 718 Japanese men aged 63.3 ± 10.8 (mean ± SD), categorized into the older (≥65 years, n = 357) and younger (<65 years, n = 361) groups. Facial flushing frequency, drinking behavior and positive CAGE results were compared among the genotypes using Bonferroni-corrected χ(2) test and a multivariate logistic regression analysis adjusting for age, BMI and lifestyle factors. RESULTS The frequency of 'always' facial flushing among the ADH1B*1/*2 carriers was significantly lower than that among the ADH1B*2/*2 carriers in the older group (P < 0.01). The alcohol consumption (unit/day) in the ADH1B*1/*2 carriers tended to be higher compared with that in the ADH1B*2/*2 carriers among the older group (P = 0.050). In the younger group, no significant differences in alcohol sensitivity and drinking habits were generally found among the ADH1B genotypes. The ADH1B*1/*1 genotype tended to be positively associated with problem drinking in the older group (P = 0.080) but not in the younger group. The ALDH2 genotypes consistently and strongly affected the alcohol sensitivity, drinking behavior and problem drinking in both the younger and older group. CONCLUSIONS We for the first time observed a significant difference in alcohol sensitivity between ADH1B*1/*2 and ADH1B*2/*2 in older men aged 65 and above.
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Affiliation(s)
- Marowa Hashimoto
- Department of Public Health, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, 641-8509, Japan
| | - Masutaka Watanabe
- Department of Public Health, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, 641-8509, Japan
| | - Yuji Uematsu
- School of Health and Nursing Sciences, Wakayama Medical University, Wakayama, Wakayama, Japan
| | - Sonomi Hattori
- School of Health and Nursing Sciences, Wakayama Medical University, Wakayama, Wakayama, Japan
| | - Nobuyuki Miyai
- School of Health and Nursing Sciences, Wakayama Medical University, Wakayama, Wakayama, Japan
| | - Miyoko Utsumi
- School of Health and Nursing Sciences, Wakayama Medical University, Wakayama, Wakayama, Japan
| | - Mayumi Oka
- School of Health and Nursing Sciences, Wakayama Medical University, Wakayama, Wakayama, Japan
| | - Mariko Hayashida
- School of Pharmaceutical Sciences, Mukogawa Woman's University, Nishinomiya, Hyogo, Japan
| | - Kenji Kinoshita
- School of Pharmaceutical Sciences, Mukogawa Woman's University, Nishinomiya, Hyogo, Japan
| | - Mikio Arita
- School of Health and Nursing Sciences, Wakayama Medical University, Wakayama, Wakayama, Japan
| | - Tatsuya Takeshita
- Department of Public Health, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, 641-8509, Japan.
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18
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Peng GS, Chen YC, Wang MF, Lai CL, Yin SJ. ALDH2*2 but not ADH1B*2 is a causative variant gene allele for Asian alcohol flushing after a low-dose challenge: correlation of the pharmacokinetic and pharmacodynamic findings. Pharmacogenet Genomics 2015; 24:607-17. [PMID: 25365528 DOI: 10.1097/fpc.0000000000000096] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVE It has been well documented that variant alleles of both ADH1B*2 of alcohol dehydrogenase (ADH) and ALDH2*2 of aldehyde dehydrogenase (ALDH) protect against the development of alcoholism in East Asians. However, it remains unclear whether ADH1B*2 contributes significantly toward the accumulation of systemic blood acetaldehyde and whether it plays a critical role in the alcohol flushing reaction. PARTICIPANTS AND METHODS Sixty-one adult Han Chinese men were recruited and divided into six combinatorial genotypic groups: ALDH2*1/*1-ADH1B*1/*1 (12), ALDH2*1/*1-ADH1B*1/*2 (11), ALDH2*1/*1-ADH1B*2/*2 (11); ALDH2*1/*2-ADH1B*1/*1 (9), ALDH2*1/*2-ADH1B*1/*2 (9), and ALDH2*1/*2-ADH1B*2/*2 (9). After ingesting 0.3 g/kg of alcohol, blood ethanol, acetaldehyde, and acetate concentrations, as well as the facial skin blood flow (FSBF) and pulse rate were measured for 130 min. RESULTS The ALDH2*1/*2 heterozygotes carrying three ADH1B allelotypes showed significantly higher peak levels and areas under the concentration curve (AUCs) of the blood acetaldehyde as well as significantly greater increases in the peak pulse rate and peak FSBF compared with the ALDH2*1/*1 homozygotes. However, no significant differences in peak levels and AUCs of blood ethanol, acetaldehyde or acetate, or the peak cardiovascular responses, were found between the ADH1B allelotypes carrying ALDH2*1/*1 or between those with ALDH2*1/*2. Partial correlation analyses showed that peak blood acetaldehyde, rather than the blood ethanol or acetate, was correlated significantly with the peak responses of pulse rate and FSBF. CONCLUSION Findings indicate that ALDH2*2, rather than ADH1B2*2, is a causal variant allele for the accumulation of blood acetaldehyde and the resultant facial flushing during low alcohol consumption.
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Affiliation(s)
- Giia-Sheun Peng
- aDepartment of Neurology, Tri-Service General Hospital bDepartment of Biochemistry, National Defense Medical Center, Taipei cDepartment of Psychiatry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City dDepartment of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan
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Aldehyde Dehydrogenase Polymorphisms and Blood Pressure Elevation in the Japanese: A Cross-Sectional and a Longitudinal Study over 20 Years in the Shimane CoHRE Study. DISEASE MARKERS 2015; 2015:825435. [PMID: 26185357 PMCID: PMC4491569 DOI: 10.1155/2015/825435] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 06/02/2015] [Accepted: 06/09/2015] [Indexed: 12/27/2022]
Abstract
PURPOSE Effects of a genetic polymorphism in the aldehyde dehydrogenase-2 (ALDH2) on blood pressure (BP) were investigated in a cross-sectional and a longitudinal study over 20 years on Japanese rural residents. METHODS Health examinations were held through 2006 to 2012, and 3,202 participates were recruited for this study. Among these participants, 560 individuals had medical records that were obtained in a health examination 20 years ago. Genomic DNA of participants was extracted from blood and the genotype of a polymorphism in ALDH2 was determined by the TaqMan method. Multivariate regression analyses were performed to examine association between BP and the genetic polymorphism in the ALDH2 gene. RESULTS Systolic and diastolic BP were higher in the ALDH2 (∗)1/(∗)1 than the others (ALDH2 (∗)1/(∗)2 or ALDH2 (∗)2/(∗)2). Genetic variation of the ALDH2 gene apparently influenced drinking behavior as the number of the drinkers was significantly reduced in the ALDH2 (∗)2/(∗) 2 after 20 years of the observation period. This polymorphism, however, did not confer a risk for BP increase in the longitudinal observation. CONCLUSION The present cross-sectional study confirmed a genetic effect of the ALDH2 gene on BP. In contrast, no significant effects on BP were identified in a longitudinal study, which may require a careful consideration.
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Way M, McQuillin A, Saini J, Ruparelia K, Lydall GJ, Guerrini I, Ball D, Smith I, Quadri G, Thomson AD, Kasiakogia-Worlley K, Cherian R, Gunwardena P, Rao H, Kottalgi G, Patel S, Hillman A, Douglas E, Qureshi SY, Reynolds G, Jauhar S, O'Kane A, Dedman A, Sharp S, Kandaswamy R, Dar K, Curtis D, Morgan MY, Gurling HMD. Genetic variants in or near ADH1B and ADH1C affect susceptibility to alcohol dependence in a British and Irish population. Addict Biol 2015; 20:594-604. [PMID: 24735490 DOI: 10.1111/adb.12141] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Certain single nucleotide polymorphisms (SNPs) in genes encoding alcohol dehydrogenase (ADH) enzymes confer a significant protective effect against alcohol dependence syndrome (ADS) in East Asian populations. Recently, attention has focused on the role of these SNPs in determining ADS risk in European populations. To further elucidate these associations, SNPs of interest in ADH1B, ADH1C and the ADH1B/1C intergenic region were genotyped in a British and Irish population (ADS cases n = 1076: controls n = 1027) to assess their relative contribution to ADS risk. A highly significant, protective association was observed between the minor allele of rs1229984 in ADH1B and ADS risk [allelic P = 8.4 × 10(-6) , odds ratio (OR) = 0.26, 95 percent confidence interval, 0.14, 0.49]. Significant associations were also observed between ADS risk and the ADH1B/1C intergenic variant, rs1789891 [allelic P = 7.2 × 10(-5) , OR = 1.4 (1.2, 1.6)] and three non-synonymous SNPs rs698, rs1693482 and rs283413 in ADH1C. However, these associations were not completely independent; thus, while the ADH1B rs1229984 minor allele association was independent of those of the intergenic variant rs1789891 and the three ADH1C variants, the three ADH1C variants were not individually independent. In conclusion, the rare ADH1B rs1229984 mutation provides significant protection against ADS in this British and Irish population; other variants in the ADH gene cluster also alter ADS risk, although the strong linkage disequilibrium between SNPs at this location precluded clear identification of the variant(s) driving the associations.
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Affiliation(s)
- Michael Way
- Molecular Psychiatry Laboratory; Mental Health Sciences Unit; Faculty of Brain Sciences; University College London; UK
| | - Andrew McQuillin
- Molecular Psychiatry Laboratory; Mental Health Sciences Unit; Faculty of Brain Sciences; University College London; UK
| | - Jit Saini
- UCL Institute for Liver & Digestive Health; Royal Free Campus; University College London Medical School; UK
| | - Kush Ruparelia
- UCL Institute for Liver & Digestive Health; Royal Free Campus; University College London Medical School; UK
| | - Gregory J. Lydall
- Molecular Psychiatry Laboratory; Mental Health Sciences Unit; Faculty of Brain Sciences; University College London; UK
| | - Irene Guerrini
- National Addiction Centre and Social Genetic and Developmental Psychiatry Centre; Institute of Psychiatry; UK
- Bexley Substance Misuse Services; South London & Maudsley NHS Trust; UK
| | - David Ball
- National Addiction Centre and Social Genetic and Developmental Psychiatry Centre; Institute of Psychiatry; UK
| | - Iain Smith
- Kershaw Unit; Gartnavel Royal Hospital; UK
| | - Giorgia Quadri
- Molecular Psychiatry Laboratory; Mental Health Sciences Unit; Faculty of Brain Sciences; University College London; UK
| | - Allan D. Thomson
- Molecular Psychiatry Laboratory; Mental Health Sciences Unit; Faculty of Brain Sciences; University College London; UK
| | - Katherine Kasiakogia-Worlley
- Molecular Psychiatry Laboratory; Mental Health Sciences Unit; Faculty of Brain Sciences; University College London; UK
- Kershaw Unit; Gartnavel Royal Hospital; UK
| | - Raquin Cherian
- Gatehouse Alcohol Clinic and Max Glatt Unit; Central and North West London NHS Foundation Trust; St Bernard's Hospital; UK
| | - Priyanthi Gunwardena
- Gatehouse Alcohol Clinic and Max Glatt Unit; Central and North West London NHS Foundation Trust; St Bernard's Hospital; UK
| | - Harish Rao
- City and Hackney Centre for Mental Health; East London NHS Foundation Trust; UK
| | - Girija Kottalgi
- Gatehouse Alcohol Clinic and Max Glatt Unit; Central and North West London NHS Foundation Trust; St Bernard's Hospital; UK
| | - Shamir Patel
- Gatehouse Alcohol Clinic and Max Glatt Unit; Central and North West London NHS Foundation Trust; St Bernard's Hospital; UK
| | | | | | | | - Gerry Reynolds
- Homeless Addictions Team; NHS Greater Glasgow and Clyde; UK
| | | | | | - Alex Dedman
- Molecular Psychiatry Laboratory; Mental Health Sciences Unit; Faculty of Brain Sciences; University College London; UK
| | - Sally Sharp
- Molecular Psychiatry Laboratory; Mental Health Sciences Unit; Faculty of Brain Sciences; University College London; UK
| | - Radhika Kandaswamy
- Molecular Psychiatry Laboratory; Mental Health Sciences Unit; Faculty of Brain Sciences; University College London; UK
| | - Karim Dar
- Gatehouse Alcohol Clinic and Max Glatt Unit; Central and North West London NHS Foundation Trust; St Bernard's Hospital; UK
| | - David Curtis
- Molecular Psychiatry Laboratory; Mental Health Sciences Unit; Faculty of Brain Sciences; University College London; UK
- City and Hackney Centre for Mental Health; East London NHS Foundation Trust; UK
| | - Marsha Y. Morgan
- UCL Institute for Liver & Digestive Health; Royal Free Campus; University College London Medical School; UK
| | - Hugh M. D. Gurling
- Molecular Psychiatry Laboratory; Mental Health Sciences Unit; Faculty of Brain Sciences; University College London; UK
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21
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Genetic polymorphisms of alcohol dehydrogense-1B and aldehyde dehydrogenase-2, alcohol flushing, mean corpuscular volume, and aerodigestive tract neoplasia in Japanese drinkers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 815:265-79. [PMID: 25427912 DOI: 10.1007/978-3-319-09614-8_15] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) modulate exposure levels to ethanol/acetaldehyde. Endoscopic screening of 6,014 Japanese alcoholics yielded high detection rates of esophageal squamous cell carcinoma (SCC; 4.1%) and head and neck SCC (1.0%). The risks of upper aerodigestive tract SCC/dysplasia, especially of multiple SCC/dysplasia, were increased in a multiplicative fashion by the presence of a combination of slow-metabolizing ADH1B*1/*1 and inactive heterozygous ALDH2*1/*2 because of prolonged exposure to higher concentrations of ethanol/acetaldehyde. A questionnaire asking about current and past facial flushing after drinking a glass (≈180 mL) of beer is a reliable tool for detecting the presence of inactive ALDH2. We invented a health-risk appraisal (HRA) model including the flushing questionnaire and drinking, smoking, and dietary habits. Esophageal SCC was detected at a high rate by endoscopic mass-screening in high HRA score persons. A total of 5.0% of 4,879 alcoholics had a history of (4.0%) or newly diagnosed (1.0%) gastric cancer. Their high frequency of a history of gastric cancer is partly explained by gastrectomy being a risk factor for alcoholism because of altered ethanol metabolism, e.g., by blood ethanol level overshooting. The combination of H. pylori-associated atrophic gastritis and ALDH2*1/*2 showed the greatest risk of gastric cancer in alcoholics. High detection rates of advanced colorectal adenoma/carcinoma were found in alcoholics, 15.7% of 744 immunochemical fecal occult blood test (IFOBT)-negative alcoholics and 31.5% of the 393 IFOBT-positive alcoholics. Macrocytosis with an MCV≥106 fl increased the risk of neoplasia in the entire aerodigestive tract of alcoholics, suggesting that poor nutrition as well as ethanol/acetaldehyde exposure plays an important role in neoplasia.
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Hominids adapted to metabolize ethanol long before human-directed fermentation. Proc Natl Acad Sci U S A 2014; 112:458-63. [PMID: 25453080 DOI: 10.1073/pnas.1404167111] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Paleogenetics is an emerging field that resurrects ancestral proteins from now-extinct organisms to test, in the laboratory, models of protein function based on natural history and Darwinian evolution. Here, we resurrect digestive alcohol dehydrogenases (ADH4) from our primate ancestors to explore the history of primate-ethanol interactions. The evolving catalytic properties of these resurrected enzymes show that our ape ancestors gained a digestive dehydrogenase enzyme capable of metabolizing ethanol near the time that they began using the forest floor, about 10 million y ago. The ADH4 enzyme in our more ancient and arboreal ancestors did not efficiently oxidize ethanol. This change suggests that exposure to dietary sources of ethanol increased in hominids during the early stages of our adaptation to a terrestrial lifestyle. Because fruit collected from the forest floor is expected to contain higher concentrations of fermenting yeast and ethanol than similar fruits hanging on trees, this transition may also be the first time our ancestors were exposed to (and adapted to) substantial amounts of dietary ethanol.
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23
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Zhang Y, Gu N, Miao L, Yuan H, Wang R, Jiang H. Alcohol dehydrogenase-1B Arg47His polymorphism is associated with head and neck cancer risk in Asian: a meta-analysis. Tumour Biol 2014; 36:1023-7. [PMID: 25323582 DOI: 10.1007/s13277-014-2727-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 10/08/2014] [Indexed: 02/06/2023] Open
Abstract
Head and neck cancers (HNCs) include cancers which arise in oral cavity, pharynx, and larynx. Recent studies have demonstrated that alcohol drinking is an established risk factor for HNC. The alcohol dehydrogenase-1B (ADH1B) plays a major role in the oxidized process of alcohol. To investigate the association of ADH1B Arg47His with HNC in Asian populations, we combined all available studies into a meta-analysis. A total of 2186 cases and 4488 controls were analyzed for this meta-analysis. We used odds ratios (ORs) to assess the strength of the association and 95% confidence intervals (CIs) to give a sense of the precision of the estimate. The ADH1B*47Arg allele was found to be associated with increased risk of HNC in Asians, with the pooled odds ratios (ORs) (Arg/Arg vs. Arg/His + His/His: OR = 2.35, 95% CI = 1.56-3.55, P < 0.0001) in all eight studies. In the subgroup analysis by alcohol consumption, the Arg/Arg vs. Arg/His + His/His genotype was found to be interacted with alcohol consumption, with the OR = 2.44, 95% CI = 1.85-3.20 among ever drinkers. Besides, no significant association was found in non-drinkers. This meta-analysis revealed that ADH1B Arg47His (rs1229984) polymorphism could increase the risk of HNC in Asians significantly.
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Affiliation(s)
- Yu Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
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24
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Kumari M, Holmes MV, Dale CE, Hubacek JA, Palmer TM, Pikhart H, Peasey A, Britton A, Horvat P, Kubinova R, Malyutina S, Pajak A, Tamosiunas A, Shankar A, Singh-Manoux A, Voevoda M, Kivimaki M, Hingorani AD, Marmot MG, Casas JP, Bobak M. Alcohol consumption and cognitive performance: a Mendelian randomization study. Addiction 2014; 109:1462-71. [PMID: 24716453 PMCID: PMC4309480 DOI: 10.1111/add.12568] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Revised: 11/18/2013] [Accepted: 03/31/2014] [Indexed: 02/02/2023]
Abstract
AIMS To use Mendelian randomization to assess whether alcohol intake was causally associated with cognitive function. DESIGN Mendelian randomization using a genetic variant related to alcohol intake (ADH1B rs1229984) was used to obtain unbiased estimates of the association between alcohol intake and cognitive performance. SETTING Europe. PARTICIPANTS More than 34 000 adults. MEASUREMENTS Any versus no alcohol intake and units of intake in the previous week was measured by questionnaire. Cognitive function was assessed in terms of immediate and delayed word recall, verbal fluency and processing speed. FINDINGS Having consumed any versus no alcohol was associated with higher scores by 0.17 standard deviations (SD) [95% confidence interval (CI) = 0.15, 0.20] for immediate recall, 0.17 SD (95% CI = 0.14, 0.19) for delayed recall, 0.17 SD (95% CI = 0.14, 0.19) for verbal fluency and 0.12 SD (95% CI = 0.09, 0.15) for processing speed. The minor allele of rs1229984 was associated with reduced odds of consuming any alcohol (odds ratio = 0.87; 95% CI = 0.80, 0.95; P = 0.001; R(2) = 0.1%; F-statistic = 47). In Mendelian randomization analysis, the minor allele was not associated with any cognitive test score, and instrumental variable analysis suggested no causal association between alcohol consumption and cognition: -0.74 SD (95% CI = -1.88, 0.41) for immediate recall, -1.09 SD (95% CI = -2.38, 0.21) for delayed recall, -0.63 SD (95% CI = -1.78, 0.53) for verbal fluency and -0.16 SD (95% CI = -1.29, 0.97) for processing speed. CONCLUSIONS The Mendelian randomization analysis did not provide strong evidence of a causal association between alcohol consumption and cognitive ability.
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Affiliation(s)
- Meena Kumari
- Department of Epidemiology and Public Health, University College LondonLondon, UK
- ISER, University of EssexColchester, UK
| | - Michael V Holmes
- Department of Epidemiology and Public Health, University College LondonLondon, UK
- Department of Surgery, Division of Transplantation and Clinical Epidemiology Unit, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of PennsylvaniaPhiladelphia, PA, USA
| | | | - Jaroslav A Hubacek
- Centre for Experimental Medicine, Institute for Clinical and Experimental MedicinePrague, Czech Republic
| | - Tom M Palmer
- Division of Health Sciences, Warwick Medical School, University of WarwickCoventry, UK
| | - Hynek Pikhart
- Department of Epidemiology and Public Health, University College LondonLondon, UK
| | - Anne Peasey
- Department of Epidemiology and Public Health, University College LondonLondon, UK
| | - Annie Britton
- Department of Epidemiology and Public Health, University College LondonLondon, UK
| | - Pia Horvat
- Department of Epidemiology and Public Health, University College LondonLondon, UK
| | | | - Sofia Malyutina
- Institute of Internal Medicine, Russian Academy of Medical ScienceNovobrisk, Russia
- Novosibirsk State UniversityNovosibirsk, Russia
| | - Andrzej Pajak
- Department of Epidemiology and Population Studies, Jagiellonian University Medical CollegeKrakow, Poland
| | | | - Aparna Shankar
- Department of Epidemiology and Public Health, University College LondonLondon, UK
| | - Archana Singh-Manoux
- Department of Epidemiology and Public Health, University College LondonLondon, UK
- INSERM, U1018, AP-HPVillejuif, France
| | - Mikhail Voevoda
- Institute of Internal Medicine, Russian Academy of Medical ScienceNovobrisk, Russia
| | - Mika Kivimaki
- Department of Epidemiology and Public Health, University College LondonLondon, UK
| | - Aroon D Hingorani
- Department of Epidemiology and Public Health, University College LondonLondon, UK
- Institute of Cardiovascular Science, University College LondonLondon, UK
| | - Michael G Marmot
- Department of Epidemiology and Public Health, University College LondonLondon, UK
| | - Juan P Casas
- London School of Hygiene and Tropical MedicineLondon, UK
- Institute of Cardiovascular Science, University College LondonLondon, UK
| | - Martin Bobak
- Department of Epidemiology and Public Health, University College LondonLondon, UK
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Sun Y, Meng S, Li J, Shi J, Lu L. Advances in genetic studies of substance abuse in China. SHANGHAI ARCHIVES OF PSYCHIATRY 2014; 25:199-211. [PMID: 24991158 PMCID: PMC4054556 DOI: 10.3969/j.issn.1002-0829.2013.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Summary The importance of genetic factors in substance addiction has long been established. The rationale for this work is that understanding of the function of addiction genes and delineation of the key molecular pathways of these genes would enhance the development of novel therapeutic targets and biomarkers that could be used in the prevention and management of substance abuse. Over the past few years, there has been a substantial increase in the number of genetic studies conducted on addiction in China; these studies have primarily focused on heroin, alcohol, and nicotine dependence. Most studies of candidate genes have concentrated on the dopamine, opioid, and serotonin systems. A number of genes associated with substance abuse in Caucasians are also risk factors in Chinese, but several novel genes and genetic risk factors associated with substance abuse in Chinese subjects have also been identified. This paper reviews the genetic studies of substance abuse performed by Chinese researchers. Genotypes and alleles related to addictive behavior in Chinese individuals are discussed and the contributions of Chinese researchers to the international corpus of knowledge about the genetic understanding of substance abuse are described.
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Affiliation(s)
- Yan Sun
- National Institute on Drug Dependence, Peking University, Beijing, China
| | - Shiqiu Meng
- National Institute on Drug Dependence, Peking University, Beijing, China
| | - Jiali Li
- National Institute on Drug Dependence, Peking University, Beijing, China
| | - Jie Shi
- National Institute on Drug Dependence, Peking University, Beijing, China
| | - Lin Lu
- Institute of Mental Health, Peking University, Beijing, China
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Maeda S, Mure K, Mugitani K, Watanabe Y, Iwane M, Mohara O, Takeshita T. Roles of the ALDH2 and ADH1B genotypes on the association between alcohol intake and serum adiponectin levels among Japanese male workers. Alcohol Clin Exp Res 2014; 38:1559-66. [PMID: 24749767 DOI: 10.1111/acer.12406] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 02/10/2014] [Indexed: 11/30/2022]
Abstract
BACKGROUND Adiponectin secreted from adipose tissue is assumed to mediate protective effects on development of metabolic syndrome (MetS) and MetS-related diseases such as cardiovascular diseases and cancer. Relationship between alcohol intake and circulating adiponectin levels is not consistent among the several previous studies. In the present study, we investigated effects of alcohol intake and the alcohol-related polymorphisms on serum adiponectin levels among Japanese male workers. METHODS We conducted a cross-sectional design study with 541 male workers aged 51.5 ± 5.9 (mean ± SD) years in a Japanese plant. Information on alcohol intake and other lifestyles was obtained by a self-administered questionnaire. Serum total adiponectin (T-Ad), high-molecular-weight adiponectin (HMW-Ad), medium-molecular-weight adiponectin (MMW-Ad), and low-molecular-weight adiponectin (LMW-Ad) levels were measured by the enzyme-linked immune assay system kit. Two genotypes in the alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) genes were determined using blood sample. In multivariate regression analyses, we adjusted for age, body mass index, smoking, and physical exercise. RESULTS Among all subjects, high alcohol consumption of 12 units (1 unit contains 22.9 g of ethanol) a week or more was negatively associated with T-Ad levels in the multivariate model, although not significant. When we performed analyses separately for each genotype, high alcohol consumption was negatively associated with T-Ad, HMW-Ad, and LMW-Ad levels only in those with ADH1B *2/*2. Such relationships were not observed in each ALDH2 genotype group. CONCLUSIONS High alcohol consumption was inversely associated with T-Ad, HMW-Ad, and LMW-Ad levels in those with ADH1B *2/*2 genotype, but not in those with the other ADH1B genotypes. To our knowledge, this is the first study that reports combined effects of the alcohol-related polymorphisms and alcohol intake on serum adiponectin levels. Additional studies are required to confirm the present finding.
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Affiliation(s)
- Shinya Maeda
- Department of Public Health, Wakayama Medical University School of Medicine, Wakayama, Japan; Wakayama Wellness Foundation, Wakayama, Japan
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27
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Yokoyama A, Yokoyama T, Brooks PJ, Mizukami T, Matsui T, Kimura M, Matsushita S, Higuchi S, Maruyama K. Macrocytosis, macrocytic anemia, and genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 in Japanese alcoholic men. Alcohol Clin Exp Res 2014; 38:1237-46. [PMID: 24588059 DOI: 10.1111/acer.12372] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 01/13/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND Oxidation of ethanol by alcohol dehydrogenase (ADH) generates acetaldehyde (AcH), which is converted to acetate by aldehyde dehydrogenase-2 (ALDH2). Roughly 40% of East Asians are ALDH2-deficient due to an inactive enzyme encoded by the ALDH2*2 allele. ALDH2-deficient individuals have a dramatically elevated risk of esophageal cancer from alcohol consumption. METHODS We investigated the relationship between ALDH2*2, ADH1B*2 (encoding a highly active ADH) and erythrocyte abnormalities, in a population of Japanese alcoholic men (N = 1,238). RESULTS Macrocytosis (mean corpuscular volume [MCV] ≥100 fl) and macrocytic anemia (MCV ≥100 fl and hemoglobin <13.5 g/dl) were found in 62.4 and 24.1% of the subjects, respectively. Age-adjusted daily alcohol consumption did not differ according to ADH1B and ALDH2 genotypes. However, macrocytosis and macrocytic anemia were strongly associated with the ALDH2*1/*2 genotype multivariate odds ratios (ORs; 95% confidence interval [CI] = 2.85 [1.95 to 4.18] and 3.68 [2.64 to 5.15], respectively, versus ALDH2*1/*1). In comparison with the ADH1B*1/*1 and ALDH2*1/*1 genotype combination, the ADH1B*1/*1 and ALDH2*1/*2 genotype combination and the ADH1B*2 allele and ALDH2*1/*2 genotype combination increased stepwise the ORs (95% CI) for macrocytosis (1.65 [0.92 to 2.94] and 4.07 [2.33 to 7.11], respectively, p for difference in OR = 0.015) and macrocytic anemia (2.80 [1.52 to 5.15] and 5.32 [3.29 to 8.62], respectively, p for difference in OR = 0.045). Genotype effects were more prominent on the risks of the more advanced erythrocyte abnormalities. Older age, cigarette smoking, and low body mass index independently increased the risks of the erythrocyte abnormalities. Consumption of beer, which contains folate, decreased the risks, whereas consumption of alcoholic beverages lacking folate did not. CONCLUSIONS These results suggest that the erythrocyte abnormalities in alcoholics are attributable to high AcH exposure as well as to nutritional deficiencies and may be prevented by folate.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Medical and Addiction Center, Kanagawa, Japan
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Zuccolo L, Lewis SJ, Davey Smith G, Sayal K, Draper ES, Fraser R, Barrow M, Alati R, Ring S, Macleod J, Golding J, Heron J, Gray R. Prenatal alcohol exposure and offspring cognition and school performance. A 'Mendelian randomization' natural experiment. Int J Epidemiol 2013; 42:1358-70. [PMID: 24065783 PMCID: PMC3807618 DOI: 10.1093/ije/dyt172] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2013] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND There is substantial debate as to whether moderate alcohol use during pregnancy could have subtle but important effects on offspring, by impairing later cognitive function and thus school performance. The authors aimed to investigate the unconfounded effect of moderately increased prenatal alcohol exposure on cognitive/educational performance. METHODS We used mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) and performed both conventional observational analyses and Mendelian randomization using an ADH1B variant (rs1229984) associated with reduced alcohol consumption. Women of White European origin with genotype and self-reported prenatal alcohol consumption, whose offspring's IQ score had been assessed in clinic (N=4061 pairs) or Key Stage 2 (KS2) academic achievement score was available through linkage to the National Pupil Database (N=6268), contributed to the analyses. RESULTS Women reporting moderate drinking before and during early pregnancy were relatively affluent compared with women reporting lighter drinking, and their children had higher KS2 and IQ scores. In contrast, children whose mothers' genotype predisposes to lower consumption or abstinence during early pregnancy had higher KS2 scores (mean difference +1.7, 95% confidence interval +0.4, +3.0) than children of mothers whose genotype predisposed to heavier drinking, after adjustment for population stratification. CONCLUSIONS Better offspring cognitive/educational outcomes observed in association with prenatal alcohol exposure presumably reflected residual confounding by factors associated with social position and maternal education. The unconfounded Mendelian randomization estimates suggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes.
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Affiliation(s)
- Luisa Zuccolo
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Sarah J Lewis
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - George Davey Smith
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Kapil Sayal
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Elizabeth S Draper
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Robert Fraser
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Margaret Barrow
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Rosa Alati
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Sue Ring
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - John Macleod
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Jean Golding
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Jon Heron
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Ron Gray
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, School of Social and Community Medicine, University of Bristol, Bristol, UK, Section of Developmental Psychiatry, University of Nottingham, Nottingham, UK, Department of Health Sciences, University of Leicester, Leicester, UK, School of Medicine, University of Sheffield, Sheffield, UK, Clinical Genetics, University Hospitals of Leicester, Leicester, UK, School of Population Health, University of Queensland, Brisbane, Queensland, Australia and National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
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Yokoyama A, Yokoyama T, Mizukami T, Matsui T, Kimura M, Matsushita S, Higuchi S, Maruyama K. Blood Ethanol Levels of Nonabstinent Japanese Alcoholic Men in the Morning After Drinking and Their ADH1B and ALDH2 Genotypes. Alcohol Alcohol 2013; 49:31-7. [DOI: 10.1093/alcalc/agt136] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Morey TE, Wasdo S, Wishin J, Quinn B, van der Straten A, Booth M, Gonzalez D, Derendorf H, Melker RJ, Dennis DM. Feasibility of a Breath Test for Monitoring Adherence to Vaginal Administration of Antiretroviral Microbicide Gels. J Clin Pharmacol 2013; 53:103-11. [DOI: 10.1177/0091270011434157] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Accepted: 11/30/2011] [Indexed: 11/15/2022]
Affiliation(s)
- Timothy E. Morey
- Department of Anesthesiology; University of Florida College of Medicine; Gainesville, FL; USA
| | - Scott Wasdo
- Department of Anesthesiology; University of Florida College of Medicine; Gainesville, FL; USA
| | - Judith Wishin
- Department of Anesthesiology; University of Florida College of Medicine; Gainesville, FL; USA
| | | | | | - Matthew Booth
- Department of Anesthesiology; University of Florida College of Medicine; Gainesville, FL; USA
| | - Daniel Gonzalez
- Department of Pharmaceutics; University of Florida College of Pharmacy; Gainesville, FL; USA
| | - Hartmut Derendorf
- Department of Pharmaceutics; University of Florida College of Pharmacy; Gainesville, FL; USA
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Zhang WS, Xu L, Schooling CM, Jiang CQ, Cheng KK, Liu B, Lam TH. Effect of alcohol and aldehyde dehydrogenase gene polymorphisms on alcohol-associated hypertension: the Guangzhou Biobank Cohort Study. Hypertens Res 2013; 36:741-6. [PMID: 23615284 PMCID: PMC3734527 DOI: 10.1038/hr.2013.23] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Revised: 12/13/2012] [Accepted: 01/10/2013] [Indexed: 11/11/2022]
Abstract
The effects of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 genotypes on the alcohol–blood pressure association are unclear. We examined the association of ADH2 or ALDH2 genotypes with blood pressure in older Chinese men. Based on the Guangzhou Biobank Cohort Study (GBCS), 4792 men with valid ADH2, ALDH2 genotypes were included, and genotyping of rs1229984 ADH2 and rs671 ALDH2 (AA, AG/GA or GG) was performed using a Sequenom Mass-Array platform. Information on socio-demographics and lifestyle factors, including alcohol use, was obtained from a questionnaire, and blood pressure was measured. Among alcohol drinkers, systolic and diastolic blood pressure (SBP and DBP) and mean arterial pressure (MAP) were highest for men with the GG ADH2 genotype (136.6, 77.9 and 97.5 mm Hg, respectively), followed by those with the (AA/AG ADH2+GG ALDH2) genotype (133.4, 77.6 and 96.2 mm Hg, respectively) and then the (AA/AG ADH2+AA/AG ALDH2) genotype (SBP=132.6, DBP=76.6 and MAP=95.2 mm Hg) (P for trend ranged 0.025–0.035). After adjustment for potential confounders, as well as frequency or amount of alcohol use, men with the GG ADH2 genotype were more likely to have hypertension (odds ratio (OR)=1.62, 95% confidence interval 1.15–2.28) as were men with the (AA/AG ADH2+AA/AG ALDH2) genotype (OR=1.40, 95% confidence interval 1.01–1.96) compared with men with the (AA/AG ADH2+GG ALDH2) genotype). ADH2 or ALDH2 genotypes were unrelated to hypertension among those who never drink alcohol. ADH2 genotype influences blood pressure and risk of hypertension among male alcohol drinkers, suggesting that the hypertensive effect of alcohol is due to ethanol rather than acetaldehyde.
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Affiliation(s)
- Wei Sen Zhang
- Molecular Epidemiological Research Centre, Guangzhou No. 12 Hospital, Guangzhou, China
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Yokoyama A, Yokoyama T, Matsui T, Mizukami T, Kimura M, Matsushita S, Higuchi S, Maruyama K. 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. Alcohol Alcohol 2013; 48:146-52. [PMID: 23296215 DOI: 10.1093/alcalc/ags135] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Medical and Addiction Center, 5-3-1 Nobi, Yokosuka, Kanagawa 239-0841, Japan.
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Oral adherence monitoring using a breath test to supplement highly active antiretroviral therapy. AIDS Behav 2013; 17:298-306. [PMID: 23001413 DOI: 10.1007/s10461-012-0318-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
A breath-based adherence system to document ingestion of oral medications (e.g., HAART) was investigated. Specifically, the food additive 2-butanol, which can be easily packaged with a drug, is converted via alcohol dehydrogenase to the volatile metabolite 2-butanone that rapidly appears in breath, indicating adherence. In healthy adults using a portable sensor and GC-MS, the following experiments were performed: yield of 2-butanone in breath following ingestion of 2-butanol, adherence system accuracy, and potential interference of the adherence system by food or misplacement of 2-butanol on the tongue. During feasibility testing, every subject exhaled 2-butanone with 6.6 ± 1.5 min to peak concentrations of 548 ± 235 ppb following ingestion of 2-butanol (40 mg). ROC areas at 5 and 10 min were 0.95 (0.86-1.00) and 1.00 (1.00-1.00). Food did not interfere. Tongue application resulted in large concentrations of 2-butanol, but not 2-butanone. A breath test to provide definitive evidence of oral medication adherence appears technically feasible.
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Chiang CP, Wu CW, Lee SP, Ho JL, Lee SL, Nieh S, Yin SJ. Expression Pattern, Ethanol-Metabolizing Activities, and Cellular Localization of Alcohol and Aldehyde Dehydrogenases in Human Small Intestine. Alcohol Clin Exp Res 2012; 36:2047-58. [DOI: 10.1111/j.1530-0277.2012.01836.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Accepted: 03/09/2012] [Indexed: 12/12/2022]
Affiliation(s)
- Chien-Ping Chiang
- Department of Dermatology; Tri-Service General Hospital, National Defense Medical Center; Taipei; Taiwan
| | - Chew-Wun Wu
- Department of Surgery; Taipei Veterans General Hospital; Taipei; Taiwan
| | - Shiao-Pieng Lee
- Department of Dentistry; Tri-Service General Hospital, National Defense Medical Center; Taipei; Taiwan
| | - Ji-Lin Ho
- Department of Biochemistry; National Defense Medical Center; Taipei; Taiwan
| | - Shou-Lun Lee
- Department of Biological Science and Technology; China Medical University; Taichung; Taiwan
| | - Shin Nieh
- Department of Pathology; Tri-Service General Hospital, National Defense Medical Center; Taipei; Taiwan
| | - Shih-Jiun Yin
- Department of Biochemistry; National Defense Medical Center; Taipei; Taiwan
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Carrigan MA, Uryasev O, Davis RP, Zhai L, Hurley TD, Benner SA. The natural history of class I primate alcohol dehydrogenases includes gene duplication, gene loss, and gene conversion. PLoS One 2012; 7:e41175. [PMID: 22859968 PMCID: PMC3409193 DOI: 10.1371/journal.pone.0041175] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Accepted: 06/18/2012] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Gene duplication is a source of molecular innovation throughout evolution. However, even with massive amounts of genome sequence data, correlating gene duplication with speciation and other events in natural history can be difficult. This is especially true in its most interesting cases, where rapid and multiple duplications are likely to reflect adaptation to rapidly changing environments and life styles. This may be so for Class I of alcohol dehydrogenases (ADH1s), where multiple duplications occurred in primate lineages in Old and New World monkeys (OWMs and NWMs) and hominoids. METHODOLOGY/PRINCIPAL FINDINGS To build a preferred model for the natural history of ADH1s, we determined the sequences of nine new ADH1 genes, finding for the first time multiple paralogs in various prosimians (lemurs, strepsirhines). Database mining then identified novel ADH1 paralogs in both macaque (an OWM) and marmoset (a NWM). These were used with the previously identified human paralogs to resolve controversies relating to dates of duplication and gene conversion in the ADH1 family. Central to these controversies are differences in the topologies of trees generated from exonic (coding) sequences and intronic sequences. CONCLUSIONS/SIGNIFICANCE We provide evidence that gene conversions are the primary source of difference, using molecular clock dating of duplications and analyses of microinsertions and deletions (micro-indels). The tree topology inferred from intron sequences appear to more correctly represent the natural history of ADH1s, with the ADH1 paralogs in platyrrhines (NWMs) and catarrhines (OWMs and hominoids) having arisen by duplications shortly predating the divergence of OWMs and NWMs. We also conclude that paralogs in lemurs arose independently. Finally, we identify errors in database interpretation as the source of controversies concerning gene conversion. These analyses provide a model for the natural history of ADH1s that posits four ADH1 paralogs in the ancestor of Catarrhine and Platyrrhine primates, followed by the loss of an ADH1 paralog in the human lineage.
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Affiliation(s)
- Matthew A Carrigan
- Foundation for Applied Molecular Evolution, Gainesville, Florida, United States of America.
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Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human large bowel: association of the functional polymorphisms of ADH and ALDH genes with hemorrhoids and colorectal cancer. Alcohol 2012; 46:37-49. [PMID: 21940137 DOI: 10.1016/j.alcohol.2011.08.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Revised: 08/05/2011] [Accepted: 08/11/2011] [Indexed: 12/16/2022]
Abstract
Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol. Functional polymorphisms of ADH1B, ADH1C, and ALDH2 genes occur among racial populations. The goal of this study was to systematically determine the functional expressions and cellular localization of ADHs and ALDHs in human rectal mucosa, the lesions of adenocarcinoma and hemorrhoid, and the genetic association of allelic variations of ADH and ALDH with large bowel disorders. Twenty-one surgical specimens of rectal adenocarcinoma and the adjacent normal mucosa, including 16 paired tissues of rectal tumor, normal mucosae of rectum and sigmoid colon from the same individuals, and 18 surgical mixed hemorrhoid specimens and leukocyte DNA samples from 103 colorectal cancer patients, 67 hemorrhoid patients, and 545 control subjects recruited in previous study, were investigated. The isozyme/allozyme expression patterns of ADH and ALDH were identified by isoelectric focusing and the activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting using the corresponding purified class-specific antibodies; the cellular activity and protein localizations were detected by immunohistochemistry and histochemistry, respectively. Genotypes of ADH1B, ADH1C, and ALDH2 were determined by polymerase chain reaction-restriction fragment length polymorphisms. At 33mM ethanol, pH 7.5, the activity of ADH1C*1/1 phenotypes exhibited 87% higher than that of the ADH1C*1/*2 phenotypes in normal rectal mucosa. The activity of ALDH2-active phenotypes of rectal mucosa was 33% greater than ALDH2-inactive phenotypes at 200μM acetaldehyde. The protein contents in normal rectal mucosa were in the following order: ADH1>ALDH2>ADH3≈ALDH1A1, whereas those of ADH2, ADH4, and ALDH3A1 were fairly low. Both activity and content of ADH1 were significantly decreased in rectal tumors, whereas the ALDH activity remained unchanged. The ADH activity was also significantly reduced in hemorrhoids. ADH4 and ALDH3A1 were uniquely expressed in the squamous epithelium of anus at anorectal junctions. The allele frequencies of ADH1C*1 and ALDH2*2 were significantly higher in colorectal cancer and that of ALDH2*2 also significantly greater in hemorrhoids. In conclusion, ADH and ALDH isozymes are differentially expressed in mucosal cells of rectum and anus. The results suggest that acetaldehyde, an immediate metabolite of ethanol, may play an etiological role in pathogenesis of large bowel diseases.
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Alcohol and aldehyde dehydrogenase polymorphisms and a new strategy for prevention and screening for cancer in the upper aerodigestive tract in East Asians. Keio J Med 2011; 59:115-30. [PMID: 21187698 DOI: 10.2302/kjm.59.115] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The ethanol in alcoholic beverages and the acetaldehyde associated with alcohol consumption are Group 1 human carcinogens (WHO, International Agency for Research on Cancer). The combination of alcohol consumption, tobacco smoking, the inactive heterozygous aldehyde dehydrogenase-2 genotype (ALDH2*1/*2) and the less-active homozygous alcohol dehydrogenase-1B genotype (ADH1B*1/*1) increases the risk of squamous cell carcinoma (SCC) in the upper aerodigestive tract (UADT) in a multiplicative fashion in East Asians. In addition to being exposed to locally high levels of ethanol, the UADT is exposed to a very high concentration of acetaldehyde from a variety of sources, including that as an ingredient of alcoholic beverages per se and that found in tobacco smoke; acetaldehyde is also produced by salivary microorganisms and mucosal enzymes and is present as blood acetaldehyde. The inefficient degradation of acetaldehyde by weakly expressed ALDH2 in the UADT may be cri! tical to the local accumulation of acetaldehyde, especially in ALDH2*1/*2 carriers. ADH1B*1/*1 carriers tend to experience less intense alcohol flushing and are highly susceptible to heavy drinking and alcoholism. Heavy drinking by persons with the less-active ADH1B*1/*1 leads to longer exposure of the UADT to salivary ethanol and acetaldehyde. The ALDH2*1/*2 genotype is a very strong predictor of synchronous and metachronous multiple SCCs in the UADT. High red cell mean corpuscular volume (MCV), esophageal dysplasia, and melanosis in the UADT, all of which are frequently found in ALDH2*1/*2 drinkers, are useful for identifying high-risk individuals. We invented a simple flushing questionnaire that enables prediction of the ALDH2 phenotype. New health appraisal models that include ALDH2 genotype, the simple flushing questionnaire, or MCV are powerful tools for devising a new strategy for prevention and screening for UADT cancer in East Asians.
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Origins of the high catalytic activity of human alcohol dehydrogenase 4 studied with horse liver A317C alcohol dehydrogenase. Chem Biol Interact 2010; 191:42-7. [PMID: 21184752 DOI: 10.1016/j.cbi.2010.12.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2010] [Revised: 12/14/2010] [Accepted: 12/22/2010] [Indexed: 11/21/2022]
Abstract
The turnover numbers and other kinetic constants for human alcohol dehydrogenase (ADH) 4 ("stomach" isoenzyme) are substantially larger (10-100-fold) than those for human class I and horse liver alcohol dehydrogenases. Comparison of the primary amino acid sequences (69% identity) and tertiary structures of these enzymes led to the suggestion that residue 317, which makes a hydrogen bond with the nicotinamide amide nitrogen of the coenzyme, may account for these differences. Ala-317 in the class I enzymes is substituted with Cys in human ADH4, and locally different conformations of the peptide backbones could affect coenzyme binding. This hypothesis was tested by making the A317C substitution in horse liver ADH1E and comparisons to the wild-type ADH1E. The steady-state kinetic constants for the oxidation of benzyl alcohol and the reduction of benzaldehyde catalyzed by the A317C enzyme were very similar (up to about 2-fold differences) to those for the wild-type enzyme. Transient kinetics showed that the rate constants for binding of NAD(+) and NADH were also similar. Transient reaction data were fitted to the full Ordered Bi Bi mechanism and showed that the rate constants for hydride transfer decreased by about 2.8-fold with the A317C substitution. The structure of A317C ADH1E complexed with NAD(+) and 2,3,4,5,6-pentafluorobenzyl alcohol at 1.2 Å resolution is essentially identical to the structure of the wild-type enzyme, except near residue 317 where the additional sulfhydryl group displaces a water molecule that is present in the wild-type enzyme. ADH is adaptable and can tolerate internal substitutions, but the protein dynamics apparently are affected, as reflected in rates of hydride transfer. The A317C substitution is not solely responsible for the larger kinetic constants in human ADH4; thus, the differences in catalytic activity must arise from one or more of the other hundred substitutions in the enzyme.
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Yang SJ, Yokoyama A, Yokoyama T, Huang YC, Wu SY, Shao Y, Niu J, Wang J, Liu Y, Zhou XQ, Yang CX. Relationship between genetic polymorphisms of ALDH2 and ADH1B and esophageal cancer risk: A meta-analysis. World J Gastroenterol 2010; 16:4210-20. [PMID: 20806441 PMCID: PMC2932928 DOI: 10.3748/wjg.v16.i33.4210] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the contribution of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) polymorphisms to the risk of esophageal cancer.
METHODS: Nineteen articles were included by searching MEDLINE, EMBASE and the Chinese Biomedical Database, 13 on ADH1B and 18 on ALDH2. We performed a meta-analysis of case-control studies including 13 studies on ADH1B (cases/controls: 2390/7100) and 18 studies on ALDH2 (2631/6030).
RESULTS: The crude odds ratio [OR (95% confidence interval)] was 2.91 (2.04-4.14) for ADH1B*1/*1 (vs ADH1B*2/*2) and 1.32 (1.17-1.49) for ADH1B*1/*2. The crude OR for ALDH2*1/*2 (vs ALDH2*1/*1) was 2.52 (1.76-3.61). ADH1B*1/*1 increased the risk of esophageal cancer among never/rare [1.56 (0.93-2.61)], moderate [2.71 (1.37-5.35)], and heavy drinkers [3.22 (2.27-4.57)]. ADH1B*1/*2 was associated with a modest risk among moderate drinkers [1.43 (1.09-1.87)]. ALDH2*1/*2 increased the risk among never/rare [1.28 (0.91-1.80)], moderate [3.12 (1.95-5.01)], and heavy [7.12 (4.67-10.86)] drinkers, and among ex-drinkers [5.64 (1.57-20.25)]. ALDH2*2/*2 increased the risk among drinkers [4.42 (1.72-11.36)]. ADH1B*1/*1 plus ALDH2*1/*2 was associated with the highest risk for heavy drinkers [12.45 (2.9-53.46)]. The results of the meta-regression analysis showed that the effects of ADH1B*1/*1 and ALDH2*1/*2 increased with the level of alcohol consumption. ALDH2*1/*2 was associated with a high risk among Taiwan Chinese and Japanese drinkers, as opposed to a moderate risk among drinkers in high-incidence regions of Mainland China. ADH1B*1/*1 in heavy drinkers and ALDH2*1/*2 in moderate-to-heavy drinkers was associated with similarly high risk among both men and women.
CONCLUSION: ADH1B/ALDH2 genotypes affect the risk of esophageal cancer, and the risk is modified by alcohol consumption, ethnicity, and gender.
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Weng H, Weng Z, Lu Y, Nakayama K, Morimoto K. Effects of alcohol-drinking behaviour and ADH1B and ALDH2 polymorphisms on basal DNA damage in human mononuclear cells as determined by the comet assay. Mutat Res 2010; 701:132-6. [PMID: 20685249 DOI: 10.1016/j.mrgentox.2010.05.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2009] [Revised: 04/30/2010] [Accepted: 05/22/2010] [Indexed: 11/15/2022]
Abstract
The aim of this study was to investigate the effects of alcohol drinking and ADH1B and ALDH2 polymorphisms on basal DNA damage (measured by the alkaline comet assay) of mononuclear cells in 122 healthy Japanese workers. Our results showed that drinking frequency had a significant impact on the tail moment (TM) value, with the highest TM value observed in habitual drinkers. The presence of the ADH1B*2 or ALDH2*2 allele was associated with increased DNA damage in older habitual drinkers. Furthermore, habitual drinkers with a combined genotype of ADH1B*2/*2 and ALDH2*1/*2 demonstrated a significantly higher TM value than other groups. Moreover, the combination of drinking and smoking has a combined effect on DNA damage. Multiple regression analysis revealed that drinking frequency, smoking status, and ALDH2 polymorphisms significantly influence basal TM value, suggesting that these are important variables affecting individual basal DNA damage.
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Affiliation(s)
- Huachun Weng
- Department of Environmental and Preventive Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka 565-0871, Japan
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Yokoyama A, Tsutsumi E, Imazeki H, Suwa Y, Nakamura C, Yokoyama T. Polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 and the blood and salivary ethanol and acetaldehyde concentrations of Japanese alcoholic men. Alcohol Clin Exp Res 2010; 34:1246-56. [PMID: 20477767 DOI: 10.1111/j.1530-0277.2010.01202.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The effects of genetic polymorphism of aldehyde dehydrogenase-2 (ALDH2) on alcohol metabolism are striking in nonalcoholics, and the effects of genetic polymorphism of alcohol dehydrogenase-1B (ADH1B) are modest at most, whereas genetic polymorphisms of both strongly affect the susceptibility to alcoholism and upper aerodigestive tract (UADT) cancer of drinkers. METHODS We evaluated associations between ADH1B/ADH1C/ALDH2 genotypes and the blood and salivary ethanol and acetaldehyde levels of 168 Japanese alcoholic men who came to our hospital for the first time in the morning and had been drinking until the day before. RESULTS The ethanol levels in their blood and saliva were similar, but the acetaldehyde levels in their saliva were much higher than in their blood, probably because of acetaldehyde production by oral bacteria. Blood and salivary ethanol and acetaldehyde levels were both significantly higher in the subjects with the less active ADH1B*1/*1 genotype than in the ADH1B*2 carriers, but none of the levels differed according to ALDH2 genotype. Significant linkage disequilibrium was detected between the ADH1B and ADH1C genotypes, but ADH1C genotype did not affect the blood or salivary ethanol or acetaldehyde levels. High blood acetaldehyde levels were found even in the active ALDH2*1/*1 alcoholics, which were comparable with the levels of the inactive heterozygous ALDH2*1/*2 alcoholics with less active ADH1B*1/*1. The slope of the increase in blood acetaldehyde level as the blood ethanol level increased was significantly steeper in alcoholics with inactive heterozygous ALDH2*1/*2 plus ADH1B*2 allele than with any other genotype combinations, but the slopes of the increase in salivary acetaldehyde level as the salivary ethanol level increased did not differ between the groups of subjects with any combinations of ALDH2 and ADH1B genotypes. CONCLUSIONS The ADH1B/ALDH2 genotype affected the blood and salivary ethanol and acetaldehyde levels of nonabstinent alcoholics in a different manner from nonalcoholics, and clear effects of ADH1B genotype and less clear effects of ALDH2 were observed in the alcoholics. Alterations in alcohol metabolism as a result of alcoholism may modify the gene effects, and these findings provide some clues in regard to associations between the genotypes and the risks of alcoholism and UADT cancer.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan.
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Salaspuro M. Acetaldehyde as a common denominator and cumulative carcinogen in digestive tract cancers. Scand J Gastroenterol 2010; 44:912-25. [PMID: 19396661 DOI: 10.1080/00365520902912563] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The key issue in cancer prevention is the identification of specific aetiologic factors. Acetaldehyde, the first metabolite of ethanol oxidation, is carcinogenic in animals. ADH and ALDH2 gene mutations provide an exceptional human model to estimate the long-term effects of acetaldehyde exposure in man. These models provide strong evidence for the local carcinogenic potential of acetaldehyde also in humans. Ethanol is metabolized to acetaldehyde by both mucosal and microbial enzymes. Many microbes produce acetaldehyde from ethanol, but their capacity to eliminate acetaldehyde is low, which leads to the accumulation of acetaldehyde in saliva during an alcohol challenge. Acetaldehyde is the most abundant carcinogen in tobacco smoke, and it readily dissolves into saliva during smoking. Fermented food and many alcoholic beverages can also contain significant amounts of acetaldehyde. Thus acetaldehyde, derived from mucosal or microbial oxidation of ethanol, tobacco smoke, and/or diet, appears to act as a cumulative carcinogen in the upper digestive tract of humans. The evidence strongly suggests the importance of world-wide screening of acetaldehyde and ethanol levels in many beverages and foodstuffs, as well as an urgent need for regulatory measures and consumer guidance. Screening of the risk groups with enhanced acetaldehyde exposure, e.g. people with ADH and ALDH2 gene polymorphisms and hypochlorhydric atrophic gastritis, should also be seriously considered. Most importantly, the GRAS (generally regarded as safe) status of acetaldehyde, which allows it to be used as a food additive, should be re-evaluated, and the classification of acetaldehyde as a carcinogen should be upgraded.
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Affiliation(s)
- Mikko Salaspuro
- Research Unit on Acetaldehyde and Cancer, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
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Zuccolo L, Fitz-Simon N, Gray R, Ring SM, Sayal K, Smith GD, Lewis SJ. A non-synonymous variant in ADH1B is strongly associated with prenatal alcohol use in a European sample of pregnant women. Hum Mol Genet 2009; 18:4457-66. [PMID: 19687126 PMCID: PMC2766294 DOI: 10.1093/hmg/ddp388] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Pregnant women are advised to abstain from alcohol despite insufficient evidence on the fetal consequences of moderate prenatal alcohol use. Mendelian randomization could help distinguish causal effects from artifacts due to residual confounding and measurement errors; however, polymorphisms reliably associated with alcohol phenotypes are needed. We aimed to test whether alcohol dehydrogenase (ADH) gene variants were associated with alcohol use before and during pregnancy. Ten variants in four ADH genes were genotyped in women from South-West England. Phenotypes of interest were quantity and patterns of alcohol consumption before and during pregnancy, including quitting alcohol following pregnancy recognition. We tested single-locus associations between genotypes and phenotypes with regression models. We used Bayesian models (multi-locus) to take account of linkage disequilibrium and reanalyzed the data with further exclusions following two conservative definitions of ‘white ethnicity’ based on the woman's reported parental ethnicity or a set of ancestry-informative genetic markers. Single-locus analyses on 7410 women of white/European background showed strong associations for rs1229984 (ADH1B). Rare allele carriers consumed less alcohol before pregnancy [odds ratio (OR) = 0.69; 95% confidence interval (CI): 0.56–0.86, P = 0.001], were less likely to have ‘binged’ during pregnancy (OR = 0.55, 95% CI: 0.38–0.78, P = 0.0009), and more likely to have abstained in the first trimester of gestation (adjusted OR = 1.42, 95% CI: 1.12–1.80, P = 0.004). Multi-locus models confirmed these results. Sensitivity analyses did not suggest the presence of residual population stratification. We confirmed the established association of rs1229984 with reduced alcohol consumption over the life-course, contributing new evidence of an effect before and during pregnancy.
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Affiliation(s)
- Luisa Zuccolo
- Department of Social Medicine, University of Bristol, Bristol, UK.
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Gamnamoside, a Phenylpropanoid Glycoside from Persimmon Leaves (Diospyros kaki) with an Inhibitory Effect against an Alcohol Metabolizing Enzyme. B KOREAN CHEM SOC 2009. [DOI: 10.5012/bkcs.2009.30.5.1035] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Chase JR, Poolman MG, Fell DA. Contribution of NADH increases to ethanol's inhibition of retinol oxidation by human ADH isoforms. Alcohol Clin Exp Res 2009; 33:571-80. [PMID: 19183134 DOI: 10.1111/j.1530-0277.2008.00871.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND A decrease in retinoic acid levels due to alcohol consumption has been proposed as a contributor to such conditions as fetal alcohol spectrum diseases and ethanol-induced cancers. One molecular mechanism, competitive inhibition by ethanol of the catalytic activity of human alcohol dehydrogenase (EC 1.1.1.1) (ADH) on all-trans-retinol oxidation has been shown for the ADH7 isoform. Ethanol metabolism also causes an increase in the free reduced nicotinamide adenine dinucleotide (NADH) in cells, which might reasonably be expected to decrease the retinol oxidation rate by product inhibition of ADH isoforms. METHODS To understand the relative importance of these two mechanisms by which ethanol decreases the retinol oxidation in vivo we need to assess them quantitatively. We have built a model system of 4 reactions: (1) ADH oxidation of ethanol and NAD(+), (2) ADH oxidation of retinol and NAD(+), (3) oxidation of ethanol by a generalized Ethanol(oxidase) that uses NAD(+), (4) NADH(oxidase) which carries out NADH turnover. RESULTS Using the metabolic modeling package ScrumPy, we have shown that the ethanol-induced increase in NADH contributes from 0% to 90% of the inhibition by ethanol, depending on (ethanol) and ADH isoform. Furthermore, while the majority of flux control of retinaldehyde production is exerted by ADH, Ethanol(oxidase) and the NADH(oxidase) contribute as well. CONCLUSIONS Our results show that the ethanol-induced increase in NADH makes a contribution of comparable importance to the ethanol competitive inhibition throughout the range of conditions likely to occur in vivo, and must be considered in the assessment of the in vivo mechanism of ethanol interference with fetal development and other diseases.
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Affiliation(s)
- Jennifer R Chase
- School of Health Science, Northwest Nazarene University, Nampa, Idaho 83686, USA.
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Yang SJ, Wang HY, Li XQ, Du HZ, Zheng CJ, Chen HG, Mu XY, Yang CX. Genetic polymorphisms of ADH2 and ALDH2 association with esophageal cancer risk in southwest China. World J Gastroenterol 2007; 13:5760-4. [PMID: 17963305 PMCID: PMC4171265 DOI: 10.3748/wjg.v13.i43.5760] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the impact of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) polymorphisms on esophageal cancer risk.
METHODS: One hundred and ninety-one esophageal cancer patients and 198 healthy controls from Yanting County were enrolled in this study. ADH2 and ALDH2 genotypes were examined by polymerase-chain-reaction with the confronting-two-pair-primer (PCR-CTPP) method. Unconditional logistic regression was used to calculate the odds ratios (OR) and 95% confidence interval (95% CI).
RESULTS: Both ADH2*1 allele and ALDH2*1/*2 allele showed an increased risk of developing esophageal cancer. The adjusted OR (95% CI) for ADH2*1 allele compared with ADH2*2/*2 was 1.65 (95% CI = 1.02-2.68) and 1.67 (95% CI = 1.02-2.72) for ALDH2*1/*2 compared with ALDH2*1/*1. A significant interaction between ALDH2 and drinking was detected regarding esophageal cancer risk, the OR was 1.83 (95% CI = 1.13-2.95). Furthermore, when compared with ADH2*2/*2 and ALDH2*1/*1 carriers, ADH2*1 and ALDH2*2 carriers showed an elevated risk of developing esophageal cancer among non-alcohol drinkers (OR = 2.46, 95% CI = 0.98-6.14), and a significantly elevated risk of developing esophageal cancer among alcohol drinkers among alcohol drinkers (OR = 9.86, 95% CI = 3.10-31.38).
CONCLUSION: ADH2 and ALDH2 genotypes are associated with esophageal cancer risk. ADH2*1 allele and ALDH2*2 allele carriers have a much higher risk of developing esophageal cancer, especially among alcohol drinkers.
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Yin G, Kono S, Toyomura K, Moore MA, Nagano J, Mizoue T, Mibu R, Tanaka M, Kakeji Y, Maehara Y, Okamura T, Ikejiri K, Futami K, Yasunami Y, Maekawa T, Takenaka K, Ichimiya H, Imaizumi N. Alcohol dehydrogenase and aldehyde dehydrogenase polymorphisms and colorectal cancer: the Fukuoka Colorectal Cancer Study. Cancer Sci 2007; 98:1248-53. [PMID: 17517051 PMCID: PMC11159727 DOI: 10.1111/j.1349-7006.2007.00519.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Alcohol dehydrogenase and aldehyde dehydrogenase are key enzymes in alcohol metabolism and therefore may be of importance to colorectal cancer development. The present case-control study was conducted to determine the influence of ADH2, ADH3 and ALDH2 polymorphisms in Fukuoka, Japan, with 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly from the study area. Alcohol use was ascertained by in-person interview. Statistical adjustment was made for sex, age class, area, and alcohol use. Individuals with the allele 47Arg of the ADH2 polymorphism (slow metabolizers) had a statistically significant increase in risk, with an adjusted OR of 1.32 (95% CI = 1.07-1.63), compared with those having the ADH2*47His/His genotype. This association was not affected by the level of alcohol consumption. The ADH3 polymorphism showed no measurable association with the risk of colorectal cancer on either overall analysis or stratified analysis with alcohol use. The heterozygous ALDH2*487Glu/Lys genotype was not associated with an increase in the risk of colorectal cancer (adjusted OR 0.89, 95% CI = 0.71-1.13) compared with the ALDH2*487Glu/Glu genotype. Rather unexpectedly, the homozygous ALDH2*487Lys/Lys genotype was related to a statistically significantly decreased risk of colorectal cancer (adjusted OR 0.55, 95% CI = 0.33-0.93). It is unlikely that acetaldehyde metabolism determined by ALDH2 polymorphism contributes to the risk of colorectal cancer, whereas the role of ADH2 polymorphism deserves further investigation.
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Affiliation(s)
- Guang Yin
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Sakai Y, Matsuyama Y, Hasegawa Y, Yoshihara H, Nakamura H, Katayama Y, Imagama S, Ito Z, Ishiguro N, Hamajima N. Association of gene polymorphisms with intervertebral disc degeneration and vertebral osteophyte formation. Spine (Phila Pa 1976) 2007; 32:1279-86. [PMID: 17515815 DOI: 10.1097/brs.0b013e318059af8a] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Cross-sectional cohort study of elderly people. OBJECTIVES To examine the factors influencing osteophyte formation without lumbar disc degeneration and to estimate the implications of osteophytes from the viewpoint of low back pain and gene polymorphisms. SUMMARY OF BACKGROUND DATA The degenerative changes that occur in the intervertebral discs are the point of departure of osteophyte formation. Several studies on factors associated with genetic susceptibility to spinal osteophyte formation, such as VDR and TGF-beta1. However, there are no detailed studies concerning osteophytes not accompanied with disc degeneration. METHODS A total of 387 elderly persons were recruited, and disc degeneration and osteophyte formation were evaluated. The cases with osteophyte formation were classified into 3 groups: osteophyte formation with disc height narrowing (n = 217), osteophyte formation without disc height narrowing (n = 99), and control group defined as the cases without osteophyte formation (n = 71). Twelve genotypes were characterized. Correlations between these degenerative factors and the polymorphisms were analyzed. RESULTS The prevalence of low back pain was significantly greater in the group of osteophyte formation with disc height narrowing than the other 2 groups. In the polymorphism of alcohol dehydrogenase (ADH2), prevalence of osteophyte formation without disc height narrowing was less in His/Arg (odds ratio = 0.57, P = 0.041) and Arg/Arg (odds ratio = 0.41, P = 0.18) than His/His. CONCLUSIONS Patients with osteophyte formation preceding intervertebral disc narrowing had a lower risk of low back pain compared with those without osteophytes. The 47Arg polymorphism in the ADH2 may act to suppress osteophyte formation unaffected by disc degeneration.
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Affiliation(s)
- Yoshihito Sakai
- Department of Orthopaedic Surgery, Nagoya University School of Medicine, Nagoya, Japan.
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