{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:58:15Z","timestamp":1790243895233,"version":"4.1.0"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T00:00:00Z","timestamp":1627257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      The risk of alcohol dependence (AD) in Japanese men and women was evaluated according to combinations of alcohol flushing and\n                      <jats:italic>aldehyde dehydrogenase-2<\/jats:italic>\n                      (\n                      <jats:italic>ALDH2<\/jats:italic>\n                      , rs671) and\n                      <jats:italic>alcohol dehydrogenase-1B<\/jats:italic>\n                      (\n                      <jats:italic>ADH1B<\/jats:italic>\n                      , rs1229984) genotypes, all of which are known to determine AD susceptibility in Asians. Previous studies have focused on men, since women account for a smaller proportion of AD subjects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Case control studies were conducted between 3721 male and 335 female AD Japanese and 610 male and 406 female controls who were asked about their current or former tendency to experience facial flushing after drinking a glass of beer and underwent\n                      <jats:italic>ALDH2<\/jats:italic>\n                      and\n                      <jats:italic>ADH1B<\/jats:italic>\n                      genotyping. The time at which alcohol-induced facial flushing tendencies had disappeared in former-flushing AD subjects was also evaluated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Current alcohol flushing, the inactive\n                      <jats:italic>ALDH2*1\/*2<\/jats:italic>\n                      genotype, and the fast-metabolizing\n                      <jats:italic>ADH1B*2<\/jats:italic>\n                      allele were less frequently found in the AD groups. Although alcohol flushing was strongly influenced by the\n                      <jats:italic>ALDH2<\/jats:italic>\n                      and\n                      <jats:italic>ADH1B<\/jats:italic>\n                      genotypes, multiple logistic model showed that never or former flushing and the genotype combinations were independent strong risk factors of AD in men and women. Never or former flushing (vs. current flushing) markedly increased the odds ratios of AD in carriers of each of the\n                      <jats:italic>ALDH2<\/jats:italic>\n                      and\n                      <jats:italic>ADH1B<\/jats:italic>\n                      genotype combinations. The temporal profiles for drinking and flushing in former-flushing AD subjects revealed that the flushing response disappeared soon after or before the start of habitual drinking during young adulthood, regardless of the\n                      <jats:italic>ALDH2<\/jats:italic>\n                      genotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Although alcohol flushing is influenced by the\n                      <jats:italic>ALDH2<\/jats:italic>\n                      and\n                      <jats:italic>ADH1B<\/jats:italic>\n                      genotypes, constitutional or acquired flushing tolerance is an independent susceptibility trait for AD. The combination of the alcohol flushing status and the\n                      <jats:italic>ALDH2<\/jats:italic>\n                      and\n                      <jats:italic>ADH1B<\/jats:italic>\n                      genotypes can provide a better new strategy for AD risk assessment than the alcohol flushing status alone or the genotypes alone in Asian men and women.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0255276","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T13:24:07Z","timestamp":1627305847000},"page":"e0255276","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":24,"title":["Combinations of alcohol-induced flushing with genetic polymorphisms of alcohol and aldehyde dehydrogenases and the risk of alcohol dependence in Japanese men and 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contribution of polymorphism in the alcohol dehydrogenase \u03b2 subunit to alcohol sensitivity in a Japanese population","volume":"97","author":"T Takeshita","year":"1996","journal-title":"Hum Genet"},{"key":"pone.0255276.ref002","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1111\/j.1530-0277.1998.tb03697.x","article-title":"Self-reported flushing and genotypes of ALDH2, ADH2, and ADH3 among Taiwanese Han","volume":"22","author":"WJ Chen","year":"1998","journal-title":"Alcohol Clin Exp Res"},{"key":"pone.0255276.ref003","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1158\/1055-9965.EPI-05-0911","article-title":"Alcohol dehydrogenase 2 His47Arg polymorphism influences drinking habit independently of aldehyde dehydrogenase 2 Glu487Lys polymorphism: analysis of 2,299 Japanese subjects","volume":"15","author":"K Matsuo","year":"2006","journal-title":"Cancer Epidemiol Biomarkers 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alcohol-dependent men","volume":"30","author":"A Yokoyama","year":"2020","journal-title":"Pharmacogenet Genomics"},{"key":"pone.0255276.ref007","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1176\/ajp.152.8.1219","article-title":"Alcohol and aldehyde dehydrogenase polymorphism and the risk for alcoholism","volume":"152","author":"S Higuchi","year":"1995","journal-title":"Am J Psychiatry"},{"key":"pone.0255276.ref008","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1086\/302540","article-title":"Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism","volume":"65","author":"CC Chen","year":"1999","journal-title":"Am J Hum Genet"},{"key":"pone.0255276.ref009","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1037\/0033-2909.132.4.607","article-title":"Meta-analyses of ALDH2 and ADH1B with alcohol dependence in Asians","volume":"132","author":"SE Luczak","year":"2006","journal-title":"Psychol Bull"},{"key":"pone.0255276.ref010","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1093\/hmg\/ddm357","article-title":"Major genetic components underlying alcoholism in Korean population","volume":"17","author":"DJ Kim","year":"2008","journal-title":"Hum Mole Genetics"},{"key":"pone.0255276.ref011","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1093\/alcalc\/agw002","article-title":"Prevalence and trends in alcohol dependence and alcohol use disorders in Japanese adults; Results from periodical nationwide surveys","volume":"51","author":"Y Osaki","year":"2016","journal-title":"Alcohol Alcohol"},{"key":"pone.0255276.ref012","first-page":"1227","article-title":"Alcohol flushing, alcohol and aldehyde dehydrogenase genotypes, and risk for esophageal squamous cell carcinoma in Japanese men","volume":"12","author":"T Yokoyama","year":"2003","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"pone.0255276.ref013","volume-title":"International Statistical Classification of Diseases and Related Health Problems, 10th ed. rev. (ICD-10)","author":"World Health Organization","year":"1992"},{"key":"pone.0255276.ref014","volume-title":"Diagnostic and statistical manual of mental disorders","author":"American Psychiatric Association","year":"1994","edition":"4"},{"key":"pone.0255276.ref015","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/j.1530-0277.2006.00053.x","article-title":"Esophageal squamous cell carcinoma and aldehyde dehydrogenase-2 genotypes in Japanese females","volume":"30","author":"A Yokoyama","year":"2006","journal-title":"Alcohol Clin Exp Res"},{"issue":"Suppl","key":"pone.0255276.ref016","first-page":"11","article-title":"New strategy for detection of ALDH2 mutant","volume":"28","author":"S Harada","year":"1993","journal-title":"Alcohol Alcohol"},{"key":"pone.0255276.ref017","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/0888-7543(88)90004-3","article-title":"Genotyping of human alcohol dehydrogenases at the ADH2 and ADH3 loci following DNA sequence amplification","volume":"2","author":"Y Xu","year":"1998","journal-title":"Genomics"},{"key":"pone.0255276.ref018","volume-title":"AUDIT: The Alcohol Use Disorders Identification Test, Guidelines for Use in Primary Care","author":"TF Babor","year":"2001","edition":"2"},{"issue":"8138","key":"pone.0255276.ref019","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0140-6736(79)90381-7","article-title":"Blocking of alcohol-induced flush with a combination of H1 and H2 histamine antagonists","volume":"2","author":"OT Tan","year":"1979","journal-title":"The Lancet"},{"key":"pone.0255276.ref020","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1111\/j.1365-2133.1982.tb00522.x","article-title":"Suppression of alcohol-induced flushing by a combination of H1 and H2 histamine antagonists","volume":"107","author":"OT Tan","year":"1982","journal-title":"Br J Dermatol"},{"key":"pone.0255276.ref021","doi-asserted-by":"crossref","first-page":"16","DOI":"10.15288\/jsa.1988.49.16","article-title":"Antihistamine blockade of alcohol-induced flushing in orientals","volume":"49","author":"NS Miller","year":"1988","journal-title":"J Stud Alcohol"},{"key":"pone.0255276.ref022","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1093\/alcalc\/34.2.141","article-title":"Alcohol-histamine interactions","volume":"34","author":"SM Zimatkin","year":"1999","journal-title":"Alcohol Alcohol"},{"key":"pone.0255276.ref023","first-page":"595","article-title":"Aspirin attenuation of alcohol-induced flushing and intoxication in Oriental and Occidental subjects","volume":"Supplment 1","author":"EB Truitt","year":"1987","journal-title":"Alcohol Alcohol"},{"key":"pone.0255276.ref024","first-page":"705","article-title":"Opiate antagonist nalmefene inhibits ethanol-induced flushing in Asians: a preliminary study","volume":"12","author":"SB Ho","year":"1998","journal-title":"Alcohol Clin Exp Res"},{"key":"pone.0255276.ref025","doi-asserted-by":"crossref","first-page":"4210","DOI":"10.3748\/wjg.v16.i33.4210","article-title":"Relationship between genetic polymorphisms of ALDH2 and ADH1B and esophageal cancer risk: A meta-analysis","volume":"16","author":"SJ Yang","year":"2010","journal-title":"World J Gastroenterol"},{"key":"pone.0255276.ref026","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/acer.14527","article-title":"Association between the aldehyde dehydrogenase-2 rs671 G>A polymorphism and head and neck cancer susceptibility: A meta-analysis in East Asians","volume":"45","author":"XY Du","year":"2021","journal-title":"Alcohol Clin Exp Res"},{"key":"pone.0255276.ref027","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1111\/j.1349-7006.2010.01709.x","article-title":"Past and current tendency for facial flushing after a small dose of alcohol is a marker for increased risk of upper aerodigestive tract cancer in Japanese drinkers","volume":"101","author":"A Yokoyama","year":"2010","journal-title":"Cancer Sci"},{"key":"pone.0255276.ref028","doi-asserted-by":"crossref","first-page":"170","DOI":"10.15288\/jsa.1992.53.170","article-title":"The relationship between low Km aldehyde dehydrogenase phenotype and drinking behavior in Japanese","volume":"53","author":"S Higuchi","year":"1992","journal-title":"J Stud Alcohol"},{"key":"pone.0255276.ref029","doi-asserted-by":"crossref","first-page":"553","DOI":"10.15288\/jsa.1992.53.553","article-title":"The relationship between three subtypes of the flushing response and DSM-III alcohol abuse in Japanese","volume":"53","author":"S Higuchi","year":"1992","journal-title":"J Stud Alcohol"},{"key":"pone.0255276.ref030","doi-asserted-by":"crossref","first-page":"e96","DOI":"10.1038\/ctg.2017.24","article-title":"Establishment of a quick and highly accurate breath test for ALDH2 genotyping","volume":"8","author":"I Aoyama","year":"2017","journal-title":"Clin Trans Gastroenterol"},{"key":"pone.0255276.ref031","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/acer.13569","article-title":"Validation of alcohol flushing questionnaires in determining inactive aldehyde dehydrogenase-2 and its clinical implication in alcohol-related diseases","volume":"42","author":"CM Shin","year":"2018","journal-title":"Alcohol Clin Exp Res"},{"key":"pone.0255276.ref032","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1111\/acer.14049","article-title":"Validation of alcohol flushing questionnaire to identify ALDH2 status in a case-control study of head and neck cancer","volume":"43","author":"JR Hsiao","year":"2019","journal-title":"Alcohol Clin Exp Res"},{"key":"pone.0255276.ref033","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1111\/j.1530-0277.1995.tb01552.x","article-title":"Is alcohol-related flushing a protective factor for alcoholism in Caucasians?","volume":"19","author":"WS Slutske","year":"1995","journal-title":"Alcohol Clin Exp Res"},{"key":"pone.0255276.ref034","doi-asserted-by":"crossref","first-page":"267","DOI":"10.15288\/jsa.1996.57.267","article-title":"Investigator-observed alcohol-induced flushing but not self-report of flushing is a valid predictor of ALDH2 genotype","volume":"57","author":"TL Wall","year":"1996","journal-title":"J Stud Alcohol"},{"key":"pone.0255276.ref035","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1111\/j.1530-0277.1992.tb01907.x","article-title":"Subjective feelings of alcohol intoxication in Asians with genetic variations of ALDH2 alleles","volume":"16","author":"TL Wall","year":"1992","journal-title":"Alcohol Clin Exp Res"},{"key":"pone.0255276.ref036","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1097\/FPC.0000000000000096","article-title":"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","volume":"24","author":"GS Peng","year":"2014","journal-title":"Pharmacogenet Genomics"},{"key":"pone.0255276.ref037","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1093\/carcin\/23.11.1851","article-title":"Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma","volume":"23","author":"A Yokoyama","year":"2002","journal-title":"Carcinogenesis"},{"key":"pone.0255276.ref038","first-page":"65","volume-title":"Kokumin Eiyo no Genjo, 2001 (The National Nutrition Survey in Japan, 2001)","author":"Ministry of Health, Labour and Welfare","year":"2003"},{"key":"pone.0255276.ref039","first-page":"49","volume-title":"Kokumin Eisei no Doko, 2003 (Journal of Health and Welfare Statistics, 2003)","author":"Health and Welfare Statistics Association","year":"2003"},{"key":"pone.0255276.ref040","doi-asserted-by":"crossref","first-page":"622","DOI":"10.3390\/ijerph14060622","article-title":"How Social Reactions to Alcohol-Related Facial Flushing Are Affected by Gender, Relationship, and Drinking Purposes: Implications for Education to Reduce Aerodigestive Cancer Risks","volume":"14","author":"IM Newman","year":"2017","journal-title":"Int J Environ Res Public Health"}],"container-title":["PLOS 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