The association of the aldehyde dehydrogenases-2 (ALDH2) Glu504Lys polymorphism (also named Glu487Lys, or rs671) and cancers has been investigated. This meta-analysis aims to comprehensively assess the influence of this polymorphism on the overall cancer risk.
Eligible publications were retrieved according to inclusion/exclusion criteria and the data were analyzed using the Review Manager software (V5.2).
A meta-analysis based on 51 case-control studies consisting of 16774 cases and 32060 controls was performed to evaluate the association between the ALDH2 Glu504Lys polymorphism and cancer risk. The comparison of genotypes Lys+ (Lys/Lys and Lys/Glu) with Glu/Glu yielded a significant 20% increased cancer risk (OR = 1.20, 95%CI: 1.03–1.39, P = 0.02, I2 = 92%). Subgroup analysis by cancer type indicated a significantly increased UADT cancer risk (OR = 1.39, 95%CI: 1.11–1.73, P = 0.004, I2 = 94%) in individuals with the Lys+ genotypes. Subgroup analysis by country indicated that individuals from Japan with the Lys+ genotypes had a significant 38% increased cancer risk (OR = 1.38, 95%CI: 1.12–1.71, P = 0.003, I2 = 93%).
Citation: Cai Q, Wu J, Cai Q, Chen E-Z, Jiang Z-Y (2015) Association between Glu504Lys Polymorphism of ALDH2 Gene and Cancer Risk: A Meta-Analysis. PLoS ONE 10(2): e0117173. https://doi.org/10.1371/journal.pone.0117173
Academic Editor: Qing-Yi Wei, Duke Cancer Institute, UNITED STATES
Received: June 25, 2014; Accepted: December 18, 2014; Published: February 13, 2015
Copyright: © 2015 Cai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This work was supported by National Natural Science Foundation (No. 81070367 and No. 81270537). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Based on available epidemiological data, alcohol ingestion is shown to be carcinogenic to humans and causally related with liver, colorectal, female breast and upper aerodigestive tract (UADT) cancers . Approximately 3.6% of all cancer-related cases and 3.5% of all cancer-related deaths worldwide are related to chronic alcohol drinking . Alcohol in humans is oxidized to acetaldehyde, which interferes DNA synthesis and repair and consequently results in tumor development .
Aldehyde dehydrogenase-2 (ALDH2) is expressed in the liver as well as gastrointestinal tract. It belongs to a low-Km mitochondrial ALDH and is the second enzyme to eliminate most of the acetaldehyde generated during alcohol metabolism in vivo . Human ALDH2 gene is located on chromosome 12q24 and the polymorphisms of ALDH2 gene would affect the blood acetaldehyde concentrations after alcohol consumption . The Glu504Lys polymorphism (also named Glu487Lys, or rs671 has been the most commonly studied . The exact position of the variant is 457 of NP_001191818.1 and 504 of NP_000681.2. The glutamate of this polymorphism is corresponding to *1 allele, and lysine corresponding to *2 allele. Such a polymorphism (Glu to Lys, or G to A, or *1 to *2) was reported to have decreased activity of ALDH2 enzyme and cause much higher blood levels of acetaldehyde, which is highly prevalent among East Asians .
Therefore, it is hypothesized that the genetic polymorphism in ALDH2 gene may be strongly correlated with the susceptibility to cancer, and a number of studies have investigated the association between ALDH2 Glu504Lys polymorphism and cancer risk. Most of the studies focused on esophageal cancer, followed by colorectal cancer, head and neck cancer, etc. In a meta-analysis by Yang et al , ALDH2 504Lys allele was found to increase the risk of esophageal cancer at all levels of exposure to ethanol and acetaldehyde after drinking. On contrary, another meta-analysis by Zhao et al  showed reduced risk for colorectal cancer associated with ALDH2 504lys allele carriers. Considering the contradictory results of the previous studies on ALDH2 Glu504Lys polymorphism with different cancers, we conducted the present meta-analysis to evaluate the relation of ALDH2 Glu504Lys polymorphism with the overall cancer risk.
Materials and Methods
Publications were searched via the PubMed bibliographical database with the last update as of 30 April, 2014. The following keywords and MeSH terms were used: [“aldehyde dehydrogenase 2” or “ALDH2”] and [“polymorphism” or “genetic polymorphism” or “mutation” or “variation” or ”variant” or “single nucleotide polymorphism” or “SNP”] and [“cancer” or “malignant tumor” or “malignant neoplasm”]. As a prerequisite, only studies published in English were identified. All eligible studies were retrieved and the full text of the articles was examined to make sure the data of interest were included. In addition, if multiple reports from the same patients were found, only the publication with the most complete data set was included. If more than one ethnic population or cancer type were included in one article, data were extracted separately for each ethnic population or cancer type whenever possible.
Inclusion and exclusion criteria
Studies that we identified were required to meet the following criteria: (1) study on the evaluation of the ALDH2 Glu504Lys polymorphism and cancer risk; (2) case-control study that used either population- or hospital-based designs; (3) study that contained complete information about all genotype frequency. Studies were excluded if they were case-only studies, review articles, or reports without usable data.
Two investigators (QC and JW) independently extracted the following information from all selected articles: first author, year of publication, country of origin, population ethnicity, study design (population- or hospital-based), cancer type, genotyping information (number of genotypes, genotype distribution in cases and controls). Ethnic backgrounds were categorized as Asian, African or Mixed (composed of different ethnic groups). Cancers of oral cavity, oropharynx, hypopharynx, larynx, esophagus and stomach were defined as upper aerodigestive tract (UADT) cancer .
Before estimating the relationship between the ALDH2 Glu504Lys polymorphism and cancer risk, we tested whether the genotype frequencies of the controls were in Hardy-Weinberg equilibrium (HWE) using a χ2 test (P>0.05) .
The strength of the association between the ALDH2 Glu504Lys polymorphism and cancer risk was measured by odds ratios (ORs) with their 95% confidence intervals (95%CI). The statistical significance of pooled ORs was assessed by the Z-test. Heterogeneity was assessed by the I2 statistic, which was documented for the percentage of the observed between-study variability due to heterogeneity rather than chance with the ranges of 0 to 100% [I2 = 0–25%, no heterogeneity; I2 = 25–50%, moderate heterogeneity; I2 = 50–75%, large heterogeneity; I2 = 75–100%, extreme heterogeneity] . When the Q test was significant (P<0.05) or I2>50%, indicating the presence of heterogeneity, a random-effects model (the DerSimonian & Laird method) was used ; otherwise, the fixed-effects model (the Mantel-Haenszel method) was used . Sensitivity analysis was performed by excluding the studies that the genotype distribution in controls was not in HWE or which did not provide the three genotypes in controls to evaluate the stability of the results. Statistical analysis was conducted using the software Review Manager (V5.2) for Mac Os X.
Publication bias was evaluated by using the fail-safe number (Nfs) with the significance set at 0.05 for each meta-comparison. If the calculated Nfs value was smaller than the number of observed studies, the result might run the risk of having publication bias. We calculated the Nfs0.05 according to the formula Nfs0.05 = (ΣZ/1.64)2-k, where k is the number of included articles .
Studies and population
Initially, we identified 164 related articles. The titles and abstracts of all articles were reviewed and 75 articles were excluded; full texts were also reviewed and 38 articles were further excluded. Finally, 51 case-control studies with a total of 16774 cases and 32060 controls were included in this meta-analysis. A diagram schematizing the selection process is presented in Fig. 1. Cancers were confirmed pathologically or histologically in most articles. Because the studies of Miyasaka et al  and Li et al  each included separate analysis of two cancer types and population, we treated them separately. As shown in Table 1, there are 53 case-control studies from 51 publications in the meta-analysis. The genotype distribution in the controls of all studies was in agreement with the HWE except for 11 studies, in 8 studies allele distributions were not in HWE [16–23] and in 3 studies the PHWE values were not available [24–26]. The detailed characteristics of the studies are shown in the S1 Table.
In the genotypic model, the comparison of Lys+ with Glu/Glu genotype generated a significant 20% increased cancer risk (OR = 1.20, 95%CI: 1.03–1.39, P = 0.02, I2 = 92%; Table 2, Fig. 2). However, in the allelic model, comparison of Lys with Glu allele generated a non-significant 3% increased cancer risk (OR = 1.03, 95%CI: 0.94–1.13, P = 0.52, I2 = 86%; Table 2). Among the 53 case-control studies, 51 studies of Asians, 1 study of Africans , 1 study of mixed population . When we restricted analyses to Asians, no change in OR occurred for either models (data not shown).
In the genotypic model, the comparison of Lys+ with Glu/Glu genotype generated a significant 20% increased cancer risk (OR = 1.20, 95%CI: 1.03–1.39, P = 0.02, I2 = 92%).
In this meta-analysis, five cancer types were addressed: 32 studies focused on UADT cancer [17,19–21,23,24,27–51], 9 studies on colorectal cancer [16,18,52–58], 5 studies on hepatocellular carcinoma [22,26,59–61], 3 studies on breast cancer [62–64], 2 studies on lung cancer [25,65], and 2 studies on pancreatic cancer [16,66]. A significantly increased risk of UADT cancer (OR = 1.39, 95%CI: 1.11–1.73, P = 0.004, I2 = 94%; Table 2) was observed in individuals with the Lys+ genotypes. Furthermore, according to the position of the tumor located, we performed position-specific analyses in the UADT cancer subgroup. The results indicated that individuals with the variant allele (504Lys) significantly increased 52% risk of esophageal cancer (OR = 1.52, 95%CI: 1.12–2.08, P = 0.008, I2 = 96%; Fig. 3), 22% risk of head and neck cancer (OR = 1.22, 95%CI: 1.07–1.39, P = 0.003, I2 = 0%; Fig. 3) and 18% risk of gastric cancer (OR = 1.18, 95%CI: 1.03–1.35, P = 0.02, I2 = 0%; Fig. 3). However, the magnitude of association in genotypic models was weakened for digestive track cancers: colorectal cancer (OR = 0.90, 95%CI: 0.75–1.08, P = 0.26, I2 = 56%; Table 2), hepatocellular cancer (OR = 0.99, 95%CI: 0.74–1.32, P = 0.95, I2 = 51%; Table 2), pancreatic cancer (OR = 1.14, 95%CI: 0.92–1.42, P = 0.24, I2 = 0%; Table 2) and breast cancer (OR = 0.97, 95%CI: 0.82–1.14, P = 0.70, I2 = 0%; Table 2), lung cancer (OR = 1.03, 95%CI: 0.77–1.37, P = 0.85, I2 = 63%; Table 2).
Individuals with the variant allele (504Lys) had 52% increased risk of esophageal cancer (OR = 1.52, 95%CI: 1.12–2.08, P = 0.008), 22% risk of head and neck cancer (OR = 1.22, 95%CI: 1.07–1.39, P = 0.003) and 18% risk of gastric cancer (OR = 1.18, 95%CI: 1.03–1.35, P = 0.02).
Of the 53 case-control studies, 27 studies were performed in Japan [16,20,24,26,27,30,36,37,40,41,44,45,47,48,50,51,54–59,61,63,65,66], 18 studies were performed in China [18,19,21,22,28,29,31,32,35,38,39,42,43,46,49,52,53,60], 8 studies were performed in other countries [17,23,25,33,34,62,64]. We found individuals from Japan with the Lys+ genotypes had a significant 38% increased cancer risk (OR = 1.38, 95%CI: 1.12–1.71, P = 0.003, I2 = 93%; Table 2). However, we did not observe any significant associations among China (Lys vs. Glu: OR = 0.97, 95%CI: 0.84–1.12, P = 0.66, I2 = 83%; Lys+ vs. Glu/Glu: OR = 1.02, 95%CI: 0.83–1.26, P = 0.85, I2 = 87%; Table 2) or other countries (Lys vs. Glu: OR = 0.99, 95%CI: 0.87–1.13, P = 0.93, I2 = 33%; Lys+ vs. Glu/Glu: OR = 0.99, 95%CI: 0.86–1.13, P = 0.85, I2 = 0%; Table 2).
In the view of study design, of which 21 were population-based [16–18,21,22,25,28,29,32,35,38,39,43,44,47,51,53,54,60], 30 were hospital-based [19,20,23,24,26,27,30,31,33,34,36,40,42,45,46,48–50,52,55–59,61–66] and 2 studies were conducted on both population-based and hospital-based control group [37,41]. The magnitude of association in population-based studies was significantly weakened for genotypic model (OR = 1.08, 95%CI: 0.90–1.29, P = 0.39, I2 = 83%; Table 2). Meanwhile, the magnitude of association in hospital-based studies was not significantly changed (Lys vs. Glu: OR = 1.02, 95%CI: 0.91–1.14, P = 0.72, I2 = 84%; Lys+ vs. Glu/Glu: OR = 1.23, 95%CI: 1.02–1.49, P = 0.03, I2 = 91%; Table 2).
In order to control for the difference of sample size, we chose the size of 300 in both case and control groups as the cut-off, 17 studies were conducted with subjects >300 [20,25,27–29,31,33,35–37,42,52,54,62–65]. However, no significant association was found in either model (Table 2).
Test of heterogeneity
In the pooled analysis, we have found heterogeneities in allelic model comparison (Lys vs Glu: Pheterogeneity <0.00001, I2 = 86%) and genetic model comparison (Lys+ vs Glu/Glu: Pheterogeneity<0.00001, I2 = 92%). A random effects model was performed in these analyses. Then we performed subgroup analysis based on cancer type, country, study design and sample size and assessed the source of heterogeneity for genetic model comparison (Lys+ vs Glu/Glu). As a result, cancer type (χ2 = 10.05, df = 4, P = 0.04) and country (χ2 = 7.18, df = 2, P = 0.03) but not study design (χ2 = 1.86, df = 2, P = 0.39) or sample size (χ2 = 0.09, df = 1, P = 0.76) were the significant sources of heterogeneity.
Sensitivity analysis and Publication bias
Influence analysis was conducted by repeating the meta-analysis while excluding the studies that were not in HWE or the PHWE values were not available. The estimated pooled odds ratio did not change, suggesting that the results are stable. Furthermore, when we conducted cancer-specific and size-specific sensitivity analyses, we found the magnitude of association in genotypic models was significantly strengthened in subgroup of colorectal cancer (OR = 0.85, 95%CI: 0.74–0.94, P = 0.02, I2 = 23%; data not shown) and subjects <300 (OR = 1.23, 95%CI: 1.03–1.47, P = 0.02, I2 = 80%; data not shown). Moreover, the estimated pooled odds ratio in other subgroups did not change, which suggested that the results of stratified analyses were also stable.
Lastly, to assess publication bias, we calculated the fail-safe number (Nfs) at a significance level of 0.05 for each comparison. The Nfs0.05 values for the comparison of Lys versus Glu (Nfs0.05 = 2767), Lys+ versus Glu/Glu (Nfs0.05 = 4998) were greater than the number of studies included in the meta-analysis.
To our knowledge, this is the first meta-analysis to evaluate the association between the Glu504Lys polymorphism of ALDH2 gene and the overall cancer risk. Our study suggests that individuals with the variant allele (504Lys) appear to be associated with an increased risk of cancer. Due to the prevalent of ALDH2 polymorphism in approximately half of East Asians but absent in Europeans and Africans  and possibility of population admixture that may potentially elevate type I error rate of association studies and lead to inconsistent results , we further excluded mixed populations and restricted analyses to Asians. However, no substantial change was observed, which confirmed the positive result of initial overall analyses. Genome-wide association (GWA) studies had also been previously conducted on the association of ALDH2 gene with cancer risks. McKay et al  reported the increased UADT cancer risk with the minor allele of rs4767364 in Europeans, which is similar to the UADT cancer risk effect observed for heterozygote rs671 carriers in Asians. Their results implicated the variant at 12q24 in UADT cancer susceptibility. With an elaborative genome-wide gene-environment interaction analysis, Wu et al  found that the most significant interaction region was for variants at 12q24 harboring ALDH2 and a joint analysis showed that alcohol drinkers carrying both risk alleles of ALDH2 and ADH1B had the highest risk of ESCC. Furthermore, Ioannidis et al  provided an overview of GWA-identified genetic associations with solid tumors since 2007 and showed the association between esophageal cancer and genetic variant rs671 with a median odds ratio (OR) of 1.67 (interquartile range = 1.58–1.76). The results from these GWA studies and our meta-analysis collectively suggest the importance of ALDH2 polymorphism carrying the susceptibility of cancer risks.
In the subgroup analysis by cancer type, significantly increased risk of UADT cancer with ALDH2 polymorphism was observed but no significant association was found among studies of other cancers (i.e., colorectal cancer, hepatocellular cancer, breast cancer, lung cancer and pancreatic cancer). In the UADT cancer subgroup, we further performed position-specific analyses and the results showed that individuals with the variant allele (504Lys) significantly increased 52% risk of esophageal cancer, 22% risk of head and neck cancer and 18% risk of gastric cancer. Some previous meta-analysis had reported the similarly elevated risks [72–74]. Furthermore, when we excluded the studies that were not in HWE or the PHWE values were not available, interestingly, we found the effect of variant allele (504Lys) on colorectal cancer was contrary to that on UADT cancer. Recently, Zhao et al  had reported a similar result and put forward a possible explanation that the unpleasant symptoms resulting from high blood acetaldehyde levels after alcohol consumption may prevent the individuals with the variant allele (504Lys) from consuming alcohol and may keep them from developing alcoholism thus they have much lower chance to expose to the carcinogen acetaldehyde. However, as we could not perform subgroup analysis according to drinkers and non-drinkers to clarify the alcohol-genotype interaction, it is not possible to know whether the role of Lys+ genotypes is protective or not.
In the general population, the variant 504Lys allele is prevalent in Northeast Asian individuals (approximately 45% of Japanese, 31% of Chinese, 29% of Koreans and 10% of Thais) . After stratified by country, significantly increased overall cancer risk was found in Japanese. However, no significant association was found in Chinese and populations from other countries. It may be uncommon for the same polymorphism playing different roles in cancer susceptibility in the same ethnic population. Oze et al  had collected four studies and showed that the Glu504Lys polymorphism had strong effect modification with alcohol drinking and alcohol drinking would increase the risk of esophageal cancer in the Japanese population. Meanwhile, a similar meta-analysis conducted in Chinese Han population had reached a similar conclusion . However, data from the present study indicated that no association of this polymorphism with the overall cancer risk in Chinese. In addition, we had searched for the studies from other parts of Asia, such as South Asia, West Asia, Middle Asia, etc, but no data was available so far.
Heterogeneity is a potential problem when interpreting the results of a meta-analysis, and identifying the sources of heterogeneity is one of the most important goals of meta-analysis. In the present study, significant between-study heterogeneity in the pooled analyses of all included studies was found in both allelic and genetic models. To find the sources of heterogeneity, we performed subgroup analyses stratified by cancer type, country, study design and sample size. Our results indicated that the sources of heterogeneity were from cancer type and country, suggesting that the results of cancer-specific and country-specific analysis were reliable. Furthermore, if the distribution of genotypes in the control groups were not in HWE, the results of the genetic association studies might be spurious. Hence, we performed sensitivity analysis by excluding the studies that were not in HWE or the PHWE values were not available. Except the cancer-specific analysis of colorectal cancer group and size-specific analysis of subject <300 group, the results were persistent and robust, suggesting that this factor had little effect on the overall estimates.
Despite the clear strength of our study including large sample sizes, some limitations of this meta-analysis should be mentioned. First, since the negative findings are usually difficult to get published or only published in some non-English journals, the ones that reported in other languages may bias the present results. Second, the present study was based on unadjusted ORs, and the confounding factors such as age may still bring some bias. Third, as the lack of sufficient original data, we could not conduct subgroup analysis according to drinking status that may influence the cancer risk. Forth, besides ALDH, activity of alcohol dehydrogenase (ADH) that is responsible for oxidation of ethanol to acetaldehyde can also play an important in the accumulation of acetaldehyde ; therefore, further study is needed to assess the independent and combined effect of ADH and ALDH polymorphisms.
In conclusion, this meta-analysis indicated that the Glu504Lys polymorphism of ALDH2 gene is a candidate for susceptibility to overall cancers, especially in esophageal cancer and among Japanese population. Moreover, due to the limitations mentioned above, well-designed studies taking into consideration of gene-gene and gene-environment interactions should be performed to confirm such associations.
S1 Table. Detailed information of studies included in ALDH2 Glu504Lys polymorphism and cancer risk.
S1 Checklist. Meta-analysis on Genetic Association Studies Checklist (PLOS ONE).
S2 Checklist. PRISMA 2009 Checklist.
Conceived and designed the experiments: ZYJ EZC. Performed the experiments: Qiang Cai JW. Analyzed the data: Qu Cai JW. Contributed reagents/materials/analysis tools: Qiang Cai Qu Cai. Wrote the paper: Qiang Cai ZYJ.
- 1. Scoccianti C, Straif K, Romieu I (2013) Recent evidence on alcohol and cancer epidemiology. Future Oncol 9: 1315–1322. pmid:23980679
- 2. Varela-Rey M, Woodhoo A, Martinez-Chantar ML, Mato JM, Lu SC (2013) Alcohol, DNA methylation, and cancer. Alcohol Res 35: 25–35.
- 3. Seitz HK, Meier P (2007) The role of acetaldehyde in upper digestive tract cancer in alcoholics. Transl Res 149: 293–297. pmid:17543846
- 4. Liu P, Wang X, Hu CH, Hu TH (2012) Bioinformatics analysis with graph-based clustering to detect gastric cancer-related pathways. Genet Mol Res 11: 3497–3504. pmid:23079843
- 5. Eriksson CJ (2001) The role of acetaldehyde in the actions of alcohol (update 2000). Alcohol Clin Exp Res 25: 15S–32S. pmid:11391045
- 6. Eng MY, Luczak SE, Wall TL (2007) ALDH2, ADH1B, and ADH1C genotypes in Asians: a literature review. Alcohol Res Health 30: 22–27. pmid:17718397
- 7. Jo SA, Kim EK, Park MH, Han C, Park HY, et al. (2007) A Glu487Lys polymorphism in the gene for mitochondrial aldehyde dehydrogenase 2 is associated with myocardial infarction in elderly Korean men. Clin Chim Acta 382: 43–47. pmid:17459359
- 8. Yang SJ, Yokoyama A, Yokoyama T, Huang YC, Wu SY, et al. (2010) Relationship between genetic polymorphisms of ALDH2 and ADH1B and esophageal cancer risk: a meta-analysis. World J Gastroenterol 16: 4210–4220. pmid:20806441
- 9. Zhao H, Liu KJ, Lei ZD, Lei SL, Tian YQ (2014) Meta-analysis of the aldehyde dehydrogenases-2 (ALDH2) Glu487Lys polymorphism and colorectal cancer risk. PLoS One 9: e88656. pmid:24558407
- 10. Terry MB, Gammon MD, Zhang FF, Vaughan TL, Chow WH, et al. (2007) Alcohol dehydrogenase 3 and risk of esophageal and gastric adenocarcinomas. Cancer Causes Control 18: 1039–1046. pmid:17665311
- 11. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634. pmid:9310563
- 12. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327: 557–560. pmid:12958120
- 13. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–188.
- 14. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22: 719–748.
- 15. Xue P, Niu WQ, Jiang ZY, Zheng MH, Fei J (2012) A meta-analysis of apolipoprotein E gene epsilon2/epsilon3/epsilon4 polymorphism for gallbladder stone disease. PLoS One 7: e45849. pmid:23049877
- 16. Miyasaka K, Hosoya H, Tanaka Y, Uegaki S, Kino K, et al. (2010) Association of aldehyde dehydrogenase 2 gene polymorphism with pancreatic cancer but not colon cancer. Geriatr Gerontol Int 10 Suppl 1: S120–126. pmid:20590827
- 17. Li DP, Dandara C, Walther G, Parker MI (2008) Genetic polymorphisms of alcohol metabolising enzymes: their role in susceptibility to oesophageal cancer. Clin Chem Lab Med 46: 323–328. pmid:18254707
- 18. Chiang CP, Jao SW, Lee SP, Chen PC, Chung CC, et al. (2012) 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 46: 37–49. pmid:21940137
- 19. Li QD, Li H, Wang MS, Diao TY, Zhou ZY, et al. (2011) Multi-susceptibility genes associated with the risk of the development stages of esophageal squamous cell cancer in Feicheng County. BMC Gastroenterol 11: 74. pmid:21672255
- 20. Tanaka F, Yamamoto K, Suzuki S, Inoue H, Tsurumaru M, et al. (2010) Strong interaction between the effects of alcohol consumption and smoking on oesophageal squamous cell carcinoma among individuals with ADH1B and/or ALDH2 risk alleles. Gut 59: 1457–1464. pmid:20833657
- 21. Ding JH, Li SP, Cao HX, Wu JZ, Gao CM, et al. (2009) Polymorphisms of alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 and esophageal cancer risk in Southeast Chinese males. World J Gastroenterol 15: 2395–2400. pmid:19452585
- 22. Ding J, Li S, Wu J, Gao C, Zhou J, et al. (2008) Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes, alcohol drinking and the risk of primary hepatocellular carcinoma in a Chinese population. Asian Pac J Cancer Prev 9: 31–35. pmid:18439068
- 23. Boonyaphiphat P, Thongsuksai P, Sriplung H, Puttawibul P (2002) Lifestyle habits and genetic susceptibility and the risk of esophageal cancer in the Thai population. Cancer Lett 186: 193–199. pmid:12213289
- 24. Oikawa T, Iijima K, Koike T, Uno K, Horii T, et al. (2010) Deficient aldehyde dehydrogenase 2 is associated with increased risk for esophageal squamous cell carcinoma in the presence of gastric hypochlorhydria. Scand J Gastroenterol 45: 1338–1344. pmid:20521872
- 25. Eom SY, Zhang YW, Kim SH, Choe KH, Lee KY, et al. (2009) Influence of NQO1, ALDH2, and CYP2E1 genetic polymorphisms, smoking, and alcohol drinking on the risk of lung cancer in Koreans. Cancer Causes Control 20: 137–145. pmid:18798003
- 26. Munaka M, Kohshi K, Kawamoto T, Takasawa S, Nagata N, et al. (2003) Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and the risk of hepatocellular carcinoma. J Cancer Res Clin Oncol 129: 355–360. pmid:12759747
- 27. Matsuo K, Oze I, Hosono S, Ito H, Watanabe M, et al. (2013) The aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphism interacts with alcohol drinking in the risk of stomach cancer. Carcinogenesis 34: 1510–1515. pmid:23455379
- 28. Gao Y, He Y, Xu J, Xu L, Du J, et al. (2013) Genetic variants at 4q21, 4q23 and 12q24 are associated with esophageal squamous cell carcinoma risk in a Chinese population. Hum Genet 132: 649–656. pmid:23430454
- 29. Wu M, Chang SC, Kampman E, Yang J, Wang XS, et al. (2013) Single nucleotide polymorphisms of ADH1B, ADH1C and ALDH2 genes and esophageal cancer: a population-based case-control study in China. Int J Cancer 132: 1868–1877. pmid:22930414
- 30. Matsuo K, Rossi M, Negri E, Oze I, Hosono S, et al. (2012) Folate, alcohol, and aldehyde dehydrogenase 2 polymorphism and the risk of oral and pharyngeal cancer in Japanese. Eur J Cancer Prev 21: 193–198. pmid:21946912
- 31. Gu H, Gong D, Ding G, Zhang W, Liu C, et al. (2012) A variant allele of ADH1B and ALDH2, is associated with the risk of esophageal cancer. Exp Ther Med 4: 135–140. pmid:23060937
- 32. Wang Y, Ji R, Wei X, Gu L, Chen L, et al. (2011) Esophageal squamous cell carcinoma and ALDH2 and ADH1B polymorphisms in Chinese females. Asian Pac J Cancer Prev 12: 2065–2068. pmid:22292652
- 33. Shin CM, Kim N, Cho SI, Kim JS, Jung HC, et al. (2011) Association between alcohol intake and risk for gastric cancer with regard to ALDH2 genotype in the Korean population. Int J Epidemiol 40: 1047–1055. pmid:21507992
- 34. Ji YB, Tae K, Ahn TH, Lee SH, Kim KR, et al. (2011) ADH1B and ALDH2 polymorphisms and their associations with increased risk of squamous cell carcinoma of the head and neck in the Korean population. Oral Oncol 47: 583–587. pmid:21576033
- 35. Cao HX, Li SP, Wu JZ, Gao CM, Su P, et al. (2010) Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes, alcohol drinking and the risk for stomach cancer in Chinese males. Asian Pac J Cancer Prev 11: 1073–1077. pmid:21133627
- 36. Oze I, Matsuo K, Hosono S, Ito H, Kawase T, et al. (2010) Comparison between self-reported facial flushing after alcohol consumption and ALDH2 Glu504Lys polymorphism for risk of upper aerodigestive tract cancer in a Japanese population. Cancer Sci 101: 1875–1880. pmid:20518787
- 37. Cui R, Kamatani Y, Takahashi A, Usami M, Hosono N, et al. (2009) Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk. Gastroenterology 137: 1768–1775. pmid:19698717
- 38. Yang SJ, Wang HY, Li XQ, Du HZ, Zheng CJ, et al. (2007) Genetic polymorphisms of ADH2 and ALDH2 association with esophageal cancer risk in southwest China. World J Gastroenterol 13: 5760–5764. pmid:17963305
- 39. Guo YM, Wang Q, Liu YZ, Chen HM, Qi Z, et al. (2008) Genetic polymorphisms in cytochrome P4502E1, alcohol and aldehyde dehydrogenases and the risk of esophageal squamous cell carcinoma in Gansu Chinese males. World J Gastroenterol 14: 1444–1449. pmid:18322963
- 40. Hiraki A, Matsuo K, Wakai K, Suzuki T, Hasegawa Y, et al. (2007) Gene-gene and gene-environment interactions between alcohol drinking habit and polymorphisms in alcohol-metabolizing enzyme genes and the risk of head and neck cancer in Japan. Cancer Sci 98: 1087–1091. pmid:17489985
- 41. Hashimoto T, Uchida K, Okayama N, Imate Y, Suehiro Y, et al. (2006) ALDH2 1510 G/A (Glu487Lys) polymorphism interaction with age in head and neck squamous cell carcinoma. Tumour Biol 27: 334–338. pmid:17033202
- 42. Chen YJ, Chen C, Wu DC, Lee CH, Wu CI, et al. (2006) Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisms on esophageal cancer risks. Int J Cancer 119: 2827–2831. pmid:17036331
- 43. Cai L, You NC, Lu H, Mu LN, Lu QY, et al. (2006) Dietary selenium intake, aldehyde dehydrogenase-2 and X-ray repair cross-complementing 1 genetic polymorphisms, and the risk of esophageal squamous cell carcinoma. Cancer 106: 2345–2354. pmid:16639733
- 44. Asakage T, Yokoyama A, Haneda T, Yamazaki M, Muto M, et al. (2007) Genetic polymorphisms of alcohol and aldehyde dehydrogenases, and drinking, smoking and diet in Japanese men with oral and pharyngeal squamous cell carcinoma. Carcinogenesis 28: 865–874. pmid:17071628
- 45. Yang CX, Matsuo K, Ito H, Hirose K, Wakai K, et al. (2005) Esophageal cancer risk by ALDH2 and ADH2 polymorphisms and alcohol consumption: exploration of gene-environment and gene-gene interactions. Asian Pac J Cancer Prev 6: 256–262. pmid:16235983
- 46. Wu CF, Wu DC, Hsu HK, Kao EL, Lee JM, et al. (2005) Relationship between genetic polymorphisms of alcohol and aldehyde dehydrogenases and esophageal squamous cell carcinoma risk in males. World J Gastroenterol 11: 5103–5108. pmid:16127737
- 47. Yokoyama A, Kato H, Yokoyama T, Tsujinaka T, Muto M, et al. (2002) 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. Carcinogenesis 23: 1851–1859. pmid:12419833
- 48. Matsuo K, Hamajima N, Shinoda M, Hatooka S, Inoue M, et al. (2001) Gene-environment interaction between an aldehyde dehydrogenase-2 (ALDH2) polymorphism and alcohol consumption for the risk of esophageal cancer. Carcinogenesis 22: 913–916. pmid:11375898
- 49. Chao YC, Wang LS, Hsieh TY, Chu CW, Chang FY, et al. (2000) Chinese alcoholic patients with esophageal cancer are genetically different from alcoholics with acute pancreatitis and liver cirrhosis. Am J Gastroenterol 95: 2958–2964. pmid:11051375
- 50. Katoh T, Kaneko S, Kohshi K, Munaka M, Kitagawa K, et al. (1999) Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and oral cavity cancer. Int J Cancer 83: 606–609. pmid:10521794
- 51. Hori H, Kawano T, Endo M, Yuasa Y (1997) Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and human esophageal squamous cell carcinoma susceptibility. J Clin Gastroenterol 25: 568–575. pmid:9451664
- 52. Yang H, Zhou Y, Zhou Z, Liu J, Yuan X, et al. (2009) A novel polymorphism rs1329149 of CYP2E1 and a known polymorphism rs671 of ALDH2 of alcohol metabolizing enzymes are associated with colorectal cancer in a southwestern Chinese population. Cancer Epidemiol Biomarkers Prev 18: 2522–2527. pmid:19706845
- 53. Gao CM, Takezaki T, Wu JZ, Zhang XM, Cao HX, et al. (2008) Polymorphisms of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 and colorectal cancer risk in Chinese males. World J Gastroenterol 14: 5078–5083. pmid:18763293
- 54. Yin G, Kono S, Toyomura K, Moore MA, Nagano J, et al. (2007) Alcohol dehydrogenase and aldehyde dehydrogenase polymorphisms and colorectal cancer: the Fukuoka Colorectal Cancer Study. Cancer Sci 98: 1248–1253. pmid:17517051
- 55. Otani T, Iwasaki M, Hanaoka T, Kobayashi M, Ishihara J, et al. (2005) Folate, vitamin B6, vitamin B12, and vitamin B2 intake, genetic polymorphisms of related enzymes, and risk of colorectal cancer in a hospital-based case-control study in Japan. Nutr Cancer 53: 42–50. pmid:16351505
- 56. Matsuo K, Wakai K, Hirose K, Ito H, Saito T, et al. (2006) A gene-gene interaction between ALDH2 Glu487Lys and ADH2 His47Arg polymorphisms regarding the risk of colorectal cancer in Japan. Carcinogenesis 27: 1018–1023. pmid:16332725
- 57. Kuriki K, Hamajima N, Chiba H, Kanemitsu Y, Hirai T, et al. (2005) Relation of the CD36 gene A52C polymorphism to the risk of colorectal cancer among Japanese, with reference to with the aldehyde dehydrogenase 2 gene Glu487Lys polymorphism and drinking habit. Asian Pac J Cancer Prev 6: 62–68. pmid:15780035
- 58. Matsuo K, Hamajima N, Hirai T, Kato T, Koike K, et al. (2002) Aldehyde dehydrogenase 2 (ALDH2) genotype affects rectal cancer susceptibility due to alcohol consumption. J Epidemiol 12: 70–76. pmid:12033531
- 59. Sakamoto T, Hara M, Higaki Y, Ichiba M, Horita M, et al. (2006) Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population. Int J Cancer 118: 1501–1507. pmid:16187278
- 60. Yu SZ, Huang XE, Koide T, Cheng G, Chen GC, et al. (2002) Hepatitis B and C viruses infection, lifestyle and genetic polymorphisms as risk factors for hepatocellular carcinoma in Haimen, China. Jpn J Cancer Res 93: 1287–1292. pmid:12495467
- 61. Takeshita T, Yang X, Inoue Y, Sato S, Morimoto K (2000) Relationship between alcohol drinking, ADH2 and ALDH2 genotypes, and risk for hepatocellular carcinoma in Japanese. Cancer Lett 149: 69–76. pmid:10737710
- 62. Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Khuhaprema T, et al. (2010) Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case-control study in Thai women. Breast Cancer Res Treat 123: 885–893. pmid:20180013
- 63. Kawase T, Matsuo K, Hiraki A, Suzuki T, Watanabe M, et al. (2009) Interaction of the effects of alcohol drinking and polymorphisms in alcohol-metabolizing enzymes on the risk of female breast cancer in Japan. J Epidemiol 19: 244–250. pmid:19667493
- 64. Choi JY, Abel J, Neuhaus T, Ko Y, Harth V, et al. (2003) Role of alcohol and genetic polymorphisms of CYP2E1 and ALDH2 in breast cancer development. Pharmacogenetics 13: 67–72. pmid:12563175
- 65. Park JY, Matsuo K, Suzuki T, Ito H, Hosono S, et al. (2010) Impact of smoking on lung cancer risk is stronger in those with the homozygous aldehyde dehydrogenase 2 null allele in a Japanese population. Carcinogenesis 31: 660–665. pmid:20093384
- 66. Kanda J, Matsuo K, Suzuki T, Kawase T, Hiraki A, et al. (2009) Impact of alcohol consumption with polymorphisms in alcohol-metabolizing enzymes on pancreatic cancer risk in Japanese. Cancer Sci 100: 296–302. pmid:19068087
- 67. McKay JD, Truong T, Gaborieau V, Chabrier A, Chuang SC, et al. (2011) A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium. PLoS Genet 7: e1001333. pmid:21437268
- 68. Wu C, Kraft P, Zhai K, Chang J, Wang Z, et al. (2012) Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions. Nat Genet 44: 1090–1097. pmid:22960999
- 69. Ioannidis JP, Castaldi P, Evangelou E (2010) A compendium of genome-wide associations for cancer: critical synopsis and reappraisal. J Natl Cancer Inst 102: 846–858. pmid:20505153
- 70. Goedde HW, Agarwal DP, Fritze G, Meier-Tackmann D, Singh S, et al. (1992) Distribution of ADH2 and ALDH2 genotypes in different populations. Hum Genet 88: 344–346. pmid:1733836
- 71. Deng HW, Chen WM, Recker RR (2001) Population admixture: detection by Hardy-Weinberg test and its quantitative effects on linkage-disequilibrium methods for localizing genes underlying complex traits. Genetics 157: 885–897. pmid:11157005
- 72. Hiyama T, Yoshihara M, Tanaka S, Chayama K (2007) Genetic polymorphisms and esophageal cancer risk. Int J Cancer 121: 1643–1658.
- 73. Hiyama T, Yoshihara M, Tanaka S, Chayama K (2008) Genetic polymorphisms and head and neck cancer risk (Review). Int J Oncol 32: 945–973. pmid:18425322
- 74. Wang HL, Zhou PY, Liu P, Zhang Y (2014) ALDH2 and ADH1 Genetic Polymorphisms May Contribute to the Risk of Gastric Cancer: A Meta-Analysis. PLoS One 9: e88779. pmid:24633362
- 75. Gu JY, Li LW (2014) ALDH2 Glu504Lys polymorphism and susceptibility to coronary artery disease and myocardial infarction in East Asians: a meta-analysis. Arch Med Res 45: 76–83. pmid:24606814
- 76. Oze I, Matsuo K, Wakai K, Nagata C, Mizoue T, et al. (2011) Alcohol drinking and esophageal cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol 41: 677–692. pmid:21430021
- 77. Zhang GH, Mai RQ, Huang B (2010) Meta-analysis of ADH1B and ALDH2 polymorphisms and esophageal cancer risk in China. World J Gastroenterol 16: 6020–6025. pmid:21157980