{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T16:13:31Z","timestamp":1776701611722,"version":"3.51.2"},"reference-count":46,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T00:00:00Z","timestamp":1632873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["DMR-109-197"],"award-info":[{"award-number":["DMR-109-197"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["CMU108-MF-83 and CMU109-MF-38"],"award-info":[{"award-number":["CMU108-MF-83 and CMU109-MF-38"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 108-2314-B-182-026, MOST 108-2314-B-182A-108-MY3"],"award-info":[{"award-number":["MOST 108-2314-B-182-026, MOST 108-2314-B-182A-108-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chang Gung Memorial Hospital, Taiwan","award":["BMRPC18, CMRPG3J1253, CMRPG3C1913, CMRPD1H0351, CMRPD1J0111"],"award-info":[{"award-number":["BMRPC18, CMRPG3J1253, CMRPG3C1913, CMRPD1H0351, CMRPD1J0111"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Nasopharyngeal carcinoma (NPC) and alcohol flush syndrome are thought to be strongly influenced by genetic factors and are highly prevalent amongst East Asians. Diminished activity of aldehyde dehydrogenase (ALDH), a major enzyme in the alcohol-metabolizing pathway, causes the flushing syndrome associated with alcoholic consumption. The genetic effect of ALDH isoforms on NPC is unknown. We therefore investigated the association between the genetic polymorphisms of all 19 ALDH isoforms and NPC among 458 patients with NPC and 1672 age- and gender-matched healthy controls in Taiwan. Single-nucleotide polymorphisms (SNPs) located between the 40,000 base pairs upstream and downstream of the 19 ALDH isoform coding regions were collected from two genome-wise association studies conducted in Taiwan and from the Taiwan Biobank. Thirteen SNPs located on ALDH4A1, ALDH18A1, ALDH3B2, ALDH1L2, ALDH1A2, and ALDH2 Glu487Lys (rs671) were associated with NPC susceptibility. Stratification by alcohol status revealed a cumulative risk effect for NPC amongst drinkers and non-drinkers, with odds ratios of 4.89 (95% confidence interval 2.15\u201311.08) and 3.57 (1.97\u20136.47), respectively. A synergistic effect was observed between SNPs and alcohol. This study is the first to report associations between genetic variants in 19 ALDH isoforms, their interaction with alcohol consumption and NPC in an East Asian population.<\/jats:p>","DOI":"10.3390\/genes12101547","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T08:27:44Z","timestamp":1632904064000},"page":"1547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Associations between ALDH Genetic Variants, Alcohol Consumption, and the Risk of Nasopharyngeal Carcinoma in an East Asian Population"],"prefix":"10.3390","volume":"12","author":[{"given":"Wen-Ling","family":"Liao","sequence":"first","affiliation":[{"name":"Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan"},{"name":"Center for Personalized Medicine, China Medical University Hospital, Taichung 40447, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fu-Chun","family":"Chan","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1777-9578","authenticated-orcid":false,"given":"Kai-Ping","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-Wen","family":"Chang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan"},{"name":"Human Genetic Center, Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Che-Hong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1037-4615","authenticated-orcid":false,"given":"Wen-Hui","family":"Su","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Department of Otolaryngology\u2014Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33302, Taiwan"},{"name":"Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Chang Gung Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7840-1504","authenticated-orcid":false,"given":"Hen-Hong","family":"Chang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan"},{"name":"Department of Chinese Medicine, China Medical University Hospital, Taichung 40402, Taiwan"},{"name":"Traditional Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/S0140-6736(19)30956-0","article-title":"Nasopharyngeal carcinoma","volume":"394","author":"Chen","year":"2019","journal-title":"Lancet"},{"key":"ref_3","first-page":"1","article-title":"Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma","volume":"9","author":"Yu","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.ajhg.2009.07.007","article-title":"Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3","volume":"85","author":"Tse","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/ng.601","article-title":"A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci","volume":"42","author":"Bei","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1158\/1055-9965.EPI-15-0144","article-title":"A GWAS Meta-analysis and Replication Study Identifies a Novel Locus within CLPTM1L\/TERT Associated with Nasopharyngeal Carcinoma in Individuals of Chinese Ancestry","volume":"25","author":"Bei","year":"2016","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3317","DOI":"10.1073\/pnas.1523436113","article-title":"Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma","volume":"113","author":"Dai","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.31557\/APJCP.2019.20.11.3505","article-title":"Nasopharyngeal Carcinoma (NPC) Risk Factors: A Systematic Review and Meta-Analysis of the Association with Lifestyle, Diets, Socioeconomic and Sociodemographic in Asian Region","volume":"20","author":"Okekpa","year":"2019","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.oraloncology.2011.03.017","article-title":"Tobacco smoking, alcohol drinking, and the risk of different histological types of nasopharyngeal cancer in a low-risk population","volume":"47","author":"Polesel","year":"2011","journal-title":"Oral Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1002\/ijc.25696","article-title":"Nasopharyngeal carcinoma risk by histologic type in central China: Impact of smoking, alcohol and family history","volume":"129","author":"Ji","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1111\/acer.14184","article-title":"Association Between Alcohol Consumption and Risk of Nasopharyngeal Carcinoma: A Comprehensive Meta-Analysis of Epidemiological Studies","volume":"43","author":"Du","year":"2019","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/01635580802372633","article-title":"Alcohol Consumption and the Risk of Nasopharyngeal Carcinoma: A Systematic Review","volume":"61","author":"Chen","year":"2008","journal-title":"Nutr. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1146\/annurev-pharmtox-010814-124915","article-title":"A Personalized Medicine Approach for Asian Americans with the Aldehyde Dehydrogenase 2*2 Variant","volume":"55","author":"Gross","year":"2015","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Crous-Bou, M., Rennert, G., Cuadras, D., Salazar, R., Cordero, D., Rennert, H.S., Lejbkowicz, F., Kopelovich, L., Lipkin, S.M., and Gruber, S.B. (2013). Polymorphisms in Alcohol Metabolism Genes ADH1B and ALDH2, Alcohol Consumption and Colorectal Cancer. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080158"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s12263-009-0154-1","article-title":"Acetaldehyde as an underestimated risk factor for cancer development: Role of genetics in ethanol metabolism","volume":"5","author":"Seitz","year":"2010","journal-title":"Genes Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7100","DOI":"10.1021\/bi034182w","article-title":"Coenzyme Isomerization is Integral to Catalysis in Aldehyde Dehydrogenase\u2020,\u2021","volume":"42","author":"Hurley","year":"2003","journal-title":"Biochemistry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1002\/ijc.28885","article-title":"The interplay between alcohol consumption, oral hygiene, ALDH2 and ADH1B in the risk of head and neck cancer","volume":"135","author":"Tsai","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Brooks, P.J., Enoch, M.-A., Goldman, D., Li, T.-K., and Yokoyama, A. (2009). The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000050"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4225","DOI":"10.1158\/1078-0432.CCR-15-1800","article-title":"ALDH1A3, the Major Aldehyde Dehydrogenase Isoform in Human Cholangiocarcinoma Cells, Affects Prognosis and Gemcitabine Resistance in Cholangiocarcinoma Patients","volume":"22","author":"Chen","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00428-013-1508-z","article-title":"Cancer stem cell characteristics, ALDH1 expression in the invasive front of nasopharyngeal carcinoma","volume":"464","author":"Luo","year":"2014","journal-title":"Virchows Arch."},{"key":"ref_21","first-page":"1","article-title":"Transcriptome analysis and prognosis of ALDH isoforms in human cancer","volume":"8","author":"Chang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/1479-7364-2-2-138","article-title":"Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family","volume":"2","author":"Vasiliou","year":"2005","journal-title":"Hum. Genom."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Su, W.-H., Shugart, Y.Y., Chang, K.-P., Tsang, N.-M., Tse, K.-P., and Chang, Y.-S. (2013). How Genome-Wide SNP-SNP Interactions Relate to Nasopharyngeal Carcinoma Susceptibility. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0083034"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41525-021-00178-9","article-title":"Genetic profiles of 103,106 individuals in the Taiwan Biobank provide insights into the health and history of Han Chinese","volume":"6","author":"Wei","year":"2021","journal-title":"NPJ Genom. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Howie, B.N., Donnelly, P., and Marchini, J. (2009). A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies. PLoS Genet., 5.","DOI":"10.1371\/journal.pgen.1000529"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrg3706","article-title":"Statistical power and significance testing in large-scale genetic studies","volume":"15","author":"Sham","year":"2014","journal-title":"Nat. Rev. Genet."},{"key":"ref_28","first-page":"24","article-title":"Overexpression of the human aldehyde dehydrogenase class I results in in-creased resistance to 4-hydroperoxycyclophosphamide","volume":"3","author":"Moreb","year":"1996","journal-title":"Cancer Gene Ther."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yang, C., Wang, X., Liao, X., Han, C., Yu, T., Qin, W., Zhu, G., Su, H., Yu, L., and Liu, X. (2017). Aldehyde dehydrogenase 1 (ALDH1) isoform expression and potential clinical implications in hepatocellular carcinoma. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182208"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.3892\/ijo.2013.1837","article-title":"Aldehyde dehydrogenasehigh gastric cancer stem cells are resistant to chemotherapy","volume":"42","author":"Nishikawa","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11018","DOI":"10.18632\/oncotarget.6920","article-title":"Aldehyde dehydrogenase 1A1 in stem cells and cancer","volume":"7","author":"Tomita","year":"2016","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1002\/humu.20477","article-title":"Impact of theAlcohol-Dehydrogenase(ADH)1CandADH1Bpolymorphisms on drinking behavior in nonalcoholic Japanese","volume":"28","author":"Matsuo","year":"2007","journal-title":"Hum. Mutat."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"921","DOI":"10.7150\/ijbs.42300","article-title":"Aldehyde Dehydrogenase, Liver Disease and Cancer","volume":"16","author":"Wang","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"BSR20181915","DOI":"10.1042\/BSR20181915","article-title":"Association of ADH1B Arg47His polymorphism with the risk of cancer: A meta-analysis","volume":"39","author":"Tan","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_35","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":"Yang","year":"2010","journal-title":"World J. Gastroenterol."},{"key":"ref_36","first-page":"1","article-title":"Role of aldehyde dehydrogenases, alcohol dehydrogenase 1B genotype, alcohol consumption, and their combination in breast cancer in East-Asian women","volume":"10","author":"Park","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/978-3-319-98788-0_10","article-title":"ALDH1L1 and ALDH1L2 Folate Regulatory Enzymes in Cancer","volume":"1032","author":"Krupenko","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.3389\/fgene.2019.01013","article-title":"The Role of Single-Nucleotide Polymorphisms in the Function of Candidate Tumor Suppressor ALDH1L1","volume":"10","author":"Krupenko","year":"2019","journal-title":"Front. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4927","DOI":"10.7314\/APJCP.2015.16.12.4927","article-title":"Evaluation of Risk Factors for Nasopharyngeal Carcinoma in a High-risk Area of India, the Northeastern Region","volume":"16","author":"Lourembam","year":"2015","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6715","DOI":"10.1007\/s13277-014-1897-x","article-title":"Dysfunction of mitochondria due to environmental carcinogens in nasopharyngeal carcinoma in the ethnic group of Northeast Indian population","volume":"35","author":"Ghosh","year":"2014","journal-title":"Tumor Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.1007\/s13277-014-2942-5","article-title":"Contribution of susceptibility locus at HLA class I region and environmental factors to occurrence of nasopharyngeal cancer in Northeast India","volume":"36","author":"Lakhanpal","year":"2014","journal-title":"Tumor Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40880-016-0174-3","article-title":"Associations of lifestyle and diet with the risk of nasopharyngeal carcinoma in Singapore: A case\u2013control study","volume":"36","author":"Yong","year":"2017","journal-title":"Chin. J. Cancer"},{"key":"ref_43","first-page":"3335","article-title":"Contribution of Matrix Metallopeptidase-1 Genotypes, Smoking, Alcohol Drinking and Areca Chewing to Nasopharyngeal Carcinoma Sus-ceptibility","volume":"36","author":"Tsai","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1158\/1055-9965.EPI-20-1702","article-title":"The Evolving Epidemiology of Nasopharyngeal Carcinoma","volume":"30","author":"Chang","year":"2021","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1158\/1055-9965.EPI-04-0680","article-title":"Evaluation of Risk Factors for Nasopharyngeal Carcinoma in High-Risk Nasopharyngeal Carcinoma Families in Taiwan","volume":"14","author":"Yang","year":"2005","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1093\/aje\/kwx018","article-title":"Active and Passive Smoking and Risk of Nasopharyngeal Carcinoma: A Population-Based Case-Control Study in Southern China","volume":"185","author":"Chang","year":"2017","journal-title":"Am. J. Epidemiol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/10\/1547\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:07:07Z","timestamp":1760166427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/10\/1547"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,29]]},"references-count":46,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["genes12101547"],"URL":"https:\/\/doi.org\/10.3390\/genes12101547","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,29]]}}}