Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population
Abstract
Although alcohol intake as well as hepatitis viruses has been associated with hepatocellular carcinoma (HCC), gene-alcohol interactions on HCC risk remain to be elucidated. We conducted a case-control study to examine whether polymorphisms of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) modified the HCC risk depending on the amount of alcohol intake. ADH2 and ALDH2 genotyping was performed by a duplex polymerase chain reaction with confronting two-pair primers in 209 newly diagnosed HCC cases and 2 different controls [275 hospital controls and 381 patients with chronic liver disease (CLD)]. Multiple logistic regression analyses revealed that heavy drinkers consuming >or=3 "go"s/day of sake (69 g of ethanol/day) showed an increased risk of HCC based on comparison of HCC cases with hospital controls [adjusted odds ratio (OR) = 13.5; 95% confidence interval (CI) 3.3-54.3] or CLD patients (adjusted OR = 7.0; 95% CI 2.5-19.2), whereas the overall risk was not elevated among light to moderate drinkers consuming <3 "go"s/day. Interestingly, light to moderate drinking was associated with an increased risk among those with ALDH2*1/*2 (adjusted OR = 4.5 or 2.0), but not among those with ALDH2*1/*1 (adjusted OR = 0.8 or 1.0; p interaction = 0.03 or 0.13). However, this gene-alcohol interaction was not observed for heavy drinking. Among light to moderate drinkers, people with the combination of ALDH2*1/*2 and ADH2*2/*2 revealed the highest risk of HCC. These findings indicate that the ALDH2 polymorphism may modify HCC risk among light to moderate drinkers.
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ALDH2*2 allele is associated with a high incidence of liver cancer in heavy drinkers.
“The ALDH2 mutant genotype, ALDH2*2 allele (also known as ALDH2(E487K) or ALDH2 rs671 polymorphism), has been found to be associated with a high incidence of liver cancer in heavy drinkers [118,119,120].”
From Pathophysiological Aspects of Alcohol Metabolism in the Liver (2021) · cites this paper as [119]
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MethodSelf-citationOrigin and Spread of the ALDH2 Glu504Lys Allele
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“Although polymorphisms in the ALDH2 gene are known to contribute to alcohol-induced facial flushing, variation in this response to alcohol and susceptibility to alcoholism due to alterations in ALDH2 activity caused by genetic variation have only recently been recognized as having both a positive and negative effect o…”
BackgroundYe, X., Wang, X., Shang, L., Zhu, G., Su, H., Han, C., Qin, W., Li, G., & Peng, T. (2018) · Cancer Management and Research · doi:10.2147/cmar.s162105 · Cited by 21 · see citing works
“These findings are consistent with those of previous studies 43,44,46,47 that genotypes, including mutant alleles, have more or less a direct or indirect impact on HCC development due to the ALDH2 gene alone or combined with other factors.”
Willner, I. R., & Reuben, A. (2005) · Current Opinion in Internal Medicine · doi:10.1097/01.mog.0000160044.87933.87 · Cited by 21 · see citing works
Alcohol-Metabolizing Enzymes, Liver Diseases and Cancer
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“Since only two studies [11, 12] investigated the association between ADH2 polymorphism–alcohol interaction and HCC risk, the pooled”
BackgroundHeme oxygenase 1 protects ethanol-administered liver tissue in Aldh2 knockout mice
Matsumoto, A., Thompson, D., Chen, Y., Vasiliou, V., Kawamoto, T., & Ichiba, M. (2016) · Alcohol · doi:10.1016/j.alcohol.2016.02.004 · Cited by 16 · see citing works
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“This has been explained as people carrying the ALDH2*1/*2 genotype metabolized alcohol in the middle level, which lead to the accumulation of acetaldehyde in the body (Sakamoto et al., 2006; Seitz and Stickel, 2006).”
BackgroundAssociation of ADH1B Arg47His polymorphism with the risk of cancer: a meta-analysis
Tan, B., & Ning, N. (2019) · Bioscience Reports · doi:10.1042/bsr20181915 · Cited by 15 · see citing works
Huang, P.-H., Hu, C.-C., Chien, C.-H., Chen, L.-W., Chien, R.-N., Lin, Y.-S., Chao, M., Lin, C.-L., & Yeh, C.-T. (2019) · Journal of Cancer · doi:10.7150/jca.33221 · Cited by 15 · see citing works
“The mutant genotype of ALDH2 may have direct or indirect impacts to be implicated in the development of HCC, whether or not it is combined with viral hepatitis or alcohol ingestion [23, 24].”
BackgroundImportance of an Aldehyde Dehydrogenase 2 Polymorphism in Preventive Medicine
Matsumoto, A. (2018) · Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene) · doi:10.1265/jjh.73.9 · Cited by 14 · see citing works
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“42,43 ADH1B, mapped to 4q23, is about 15 kb in length, and contains nine exons, and can catalyze the rate of ethanol metabolization into acetaldehyde.”
BackgroundChen, Y., Liu, H., Yu, Z., Yang, Y., Huang, Q., Deng, C., Rao, H., & Wu, H. (2022) · International Journal of General Medicine · doi:10.2147/ijgm.s356761 · Cited by 10 · see citing works
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“Epidemiological evidence has also suggested a tie between ALDH2 polymorphisms and alcoholic liver diseases (Kitagawa et al., 2000; Li et al., 2006; Sakamoto et al., 2006; Li et al., 2009; Quillen et al., 2014) and activating or overexpressing ALDH2 has been demonstrated to be protective in models of alcohol-induced li…”
BackgroundCritical review on the use and abuse of alcohol. When the dose makes the difference
Sarno, R. D., Brigida, A. L., Caprio, G. G., Ciardiello, D., Dallio, M., Sangineto, M., Fagoonee, S., Abenavoli, L., Luzza, F., Gravina, A. G., et al. (2020) · Minerva Medica · doi:10.23736/s0026-4806.20.06584-2 · Cited by 9 · see citing works
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“Sakamoto et al.30 also showed that relatively high doses of alcohol were related with HCC.”
BackgroundTrépo, E., Zucman‐Rossi, J., & Nault, J. (2026) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-026-01175-y · Cited by 6 · see citing works
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Hot and Cold HCC: Uncoupling Viral Oncogenesis and Therapy
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“Previous studies showed that the roles of the ADH2 and ALDH2 genotypes on immunity were controversial (Kaliappan et al., 2008; Matsuo et al., 2006; Sakamoto et al., 2006).”
BackgroundInteraction Between Aflatoxin B1 and Other Risk Factors in Hepatocarcinogenesis
Kew, M. C. (2009) · Springer eBooks · doi:10.1007/978-3-642-00725-5_7 · Cited by 3 · see citing works
“Acetaldehyde also decreases the methylation of cytosine, impairs DNA repair, and affects sister chromatid exchange, all of which may contribute to its carcinogenic potential (Lieber and DeCarli 1970; Sakamoto et al. 2006 ).”
BackgroundEpidemiology of Hepatocellular Carcinoma
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Alcohol Consumption and Cervical Carcinogenesis: Time to Draw Conclusions
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- Authors
- Sakamoto, T., Hara, M., Higaki, Y., Ichiba, M., Horita, M., Mizuta, T., Eguchi, Y., Yasutake, T., Ozaki, I., Yamamoto, K., Onohara, S., Kawazoe, S., Shigematsu, H., Koizumi, S., & Tanaka, K.
- Affiliations
- Saga University (JP)
- Corresponding author
- Sakamoto, Tatsuhiko
- ORCID
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2005-09-26
- Volume
- 118
- Issue
- 6
- Pages
- 1501-1507
- ISSN
- 0020-7136 (ISSN-L)
- OpenAlex
- W2019937184
- Cited by
- 88
- References
- 35
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 6 · 2020: 3 · 2019: 9 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 7 · 2014: 2 · 2012: 4
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- hepatocellular carcinoma, alcohol consumption, ALDH2 polymorphism, heavy drinking, light to moderate drinking, sake, chronic liver disease, alcohol dehydrogenase, aldehyde dehydrogenase, Japanese population
- MeSH terms
- Aldehyde Dehydrogenase, Mitochondrial, Adult, Aged, Alcohol Dehydrogenase, Alcohol Drinking, Aldehyde Dehydrogenase, Female, Gene Frequency, Genotype, Carcinoma, Hepatocellular, Humans, Japan, Liver Neoplasms, Male, Middle Aged, Polymorphism, Genetic, Surveys and Questionnaires, Risk Factors, Odds Ratio, Case-Control Studies, Asian People
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