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Association between alcohol dehydrogenase-2 gene polymorphism and esophageal cancer risk: a meta-analysis

Abstract

Background

It has been shown that gene polymorphisms may play an important role in the carcinogenesis of esophageal cancer. This study is to investigate the role of alcohol dehydrogenase 1B (ADH1B) gene Arg47His polymorphism in esophageal cancer susceptibility.

Methods

Case-control studies published between January 2000 and June 2015 were searched to retrieve relevant articles. The pooled odds ratio (OR) and 95 % confidence interval (CI) were employed to calculate the strength of association.

Results

A total of 23 relevant articles were finally selected for the analysis, including 9338 esophageal cancer patients and 14,896 matched controls. Overall, we found that the 47His allele was significant associated with the decreased risk of esophageal cancer when compared with the 47Arg allele in total populations (A vs. G: OR = 0.67, 95 % CI = 0.59–0.76, P < 0.00001). This protective relationship was observed under other genetic models as well (P < 0.00001). Subgroup analysis by ethnicity showed that ADH1B Arg47His variant was associated with the decreased esophageal cancer risk under all the genetic models (P < 0.00001) among Asians, especially in Chinese and Japanese; while in non-Asians, no significant correlation was detected in any genetic models (P > 0.05). Furthermore, Arg/Arg genotype of ADH1B Arg47His variant combined with drinking, smoking and males appeared to show a high risk in patients with esophageal cancer.

Conclusions

Our results suggested that ADH1B gene Arg47His variant was associated with the decreased esophageal cancer risk. Genetic-environmental interaction should be further considered in the future researches.

Background

Esophageal cancer (or oesophageal cancer), a type of cancer arising from the esophagus, is the eighth most common cancer and the sixth leading cause of cancer-related death worldwide [1]. Squamous cell carcinomas (SCC), which is more common in the developing world, and adenocarcinomas (AC), which is more common in the developed world, are two main forms of histologically confirmed esophageal cancer [2, 3]. The clinical symptoms include difficulty in swallowing, enlarged lymph glands around the collarbone, a dry cough, weight loss, and possibly hematemesis [4]. The established risk factors for this disease are environmental factors (alcohol drinking, smoking, infecting bacteria or virus), genetic factors (mutations in enzymes that metabolize alcohol), cultural factors (high-temperature food items such as pork braised in brown sauce and old stocked rice), obesity and gastroesophageal reflux [58]. The incidence of esophageal cancer is threefold higher in men than women [9] and is high in east Asia, southern Africa, and southern Europe while is low in North America and other parts of Europe [10]. The highest reported incidence and mortality rates occur in China, which is almost 20 to 30 times higher than that in the USA [11]. According to cancer statistics, there will be an estimated 16,980 new cases and 15,590 deaths in both sexes in the USA in 2015 [12]. Although many advances in diagnosis and treatment such as endoscopic resection, chemotherapy, and surgery have the potential to substantially reduce mortality and morbidity [13, 14], the prognosis of patients with esophageal cancer remains poor and the 5-year survival rate is still low, ranging from 15 to 25 % [15, 16]. Therefore, identifying new biomarkers for early diagnosis and treatment is vital to decide therapeutic options, improve treatment efficiency, and predict prognosis [17].

Evidences have shown that gene polymorphisms may play an important role in the carcinogenesis of esophageal cancer [18]. Alcohol dehydrogenase gene (ADH), at chromosome 4, is a key cytosolic enzyme for ethanol [19]. It encodes at least seven ADH isoforms (ADH1–ADH7), each with slightly different properties [20], and may be involved in the metabolic pathways of several neurotransmitters [21]. The ADH1B (also known as ADH2) gene is located on human chromosome 4q21-q23. It is the locus responsible for most of the ADH activity on ethanol in the liver [22]. Single nucleotide polymorphisms (SNPs) occurring in this gene may be capable of altering ethanol metabolism, and individuals expressing the ADH1B variants would have different alcohol elimination rates [23]. One of the most studied SNP was Arg47His (rs1229984), a G to A base transition in exon 3 leading to the substitution of arginine (ADH1B*1) to histidine (ADH1B*2) at codon 47th position. ADH1B*2 is common in more than 90 % of Asians and reduced their risk for alcoholism but fewer than 20 % of Caucasians or Africans [24]. This variant was shown to be strongly associated with alcohol dependence, abuse, consumption, and alcohol-induced liver diseases [25, 26].

Several studies have identified the relationship between ADH1B polymorphism and esophageal cancer susceptibility, but the consistent results were not obtained. For example, Ito et al. demonstrated that ADH1B Arg47His variant was associated with esophageal cancer in Japanese and might be used in personalized prevention programs [27], while Ma et al. did not show significant associations between variations in the ADH1B gene and esophageal squamous cell carcinoma (ESCC) risk in Chinese [28]. Although previous meta-analyses were performed to evaluate this association [2931], limited articles were selected, only Asian population was used for analysis, and some repeated participants were included. Furthermore, Asians and Caucasians may have different incidence, distribution, and susceptibilities to esophageal cancer due to different heritage backgrounds [32]. All these factors may influence the reliable of the results. Therefore, we conducted the present meta-analysis to review all the published articles among any ethnicities to obtain a relative reliable result.

Methods

Identification of relevant studies

Electronic databases of PubMed, Web of Science, Medline, Embase, CNKI (China National Knowledge Internet), and Wanfang were comprehensively searched to retrieve relevant articles published between January 2000 and June 2015. The MeSH terms were as follows: “esophageal cancer or oesophageal cancer or esophageal squamous cell carcinomas or esophageal adenocarcinomas,” “alcohol dehydrogenase or ADH1B or ADH2,” and “polymorphism or variant or mutation” as well as their combinations. The equivalent Chinese characters were used in Chinese database. We also manually searched the references of included studies in order to obtain more related articles. Our analysis only considered studies that were written in English and Chinese.

Inclusion and exclusion criteria

The eligible articles must meet the following criteria. The inclusion criteria were as follows: (1) case-control studies evaluating the correlation of ADH1B Arg47His polymorphism in esophageal cancer occurrence; (2) patents with esophageal cancer should be diagnosed clinically and confirmed histologically, the controls should be age-, ethnicity-matched participants without malignancy and digestive and chronic diseases; (3) the genotype information were available to extract; and (4) the genotypes of controls were consistent with Hardy-Weinberg equilibrium (HWE). The exclusion criteria were as follows: (1) duplicate articles from the same authors or laboratories or conducted among the same populations; (2) conference reports or reviews; (3) without control group; and (4) data could not be extracted.

Data extraction

Two of our authors independently assessed the quality of selected studies. Each item of a single study should be achieved a final consensus. The extracted information was as follow: the name of first author, published year, country, ethnicity, mean age, sample size, genotype method, alleles and genotypes distribution, source of cases and controls, and HWE of genotypes in controls.

Statistical analysis

The pooled odds ratio (OR) with its 95 % confidence interval (CI) were employed to estimate the association between ADH1B Arg47His variant and esophageal carcinoma susceptibility. The Z test was used to determine the significance of ORs, and P value was less than 0.05 considered as statistically significance. The allelic model (His vs. Arg), the homologous model (His/His vs. Arg/Arg), the heterogeneous model (Arg/His vs. Arg/Arg), the dominant model (His/His+Arg/His vs. Arg/Arg) and the recessive model (His/His vs. Arg/His+Arg/Arg) were examined. The Q test and the I 2 test were used to assess the degree and proportion of between-study heterogeneity, respectively. The fixed-effect model was used when the P value of the Q test was more than 0.10 and the I 2 of the I 2 test was less than 50 %; otherwise, the random-effect model was used. All statistical analyses were conducted in Review Manager 5.2 (the Cochrane Collaboration, Oxford, England). All the tests were two-sided.

Results

Characteristics of included studies

We firstly identified 105 articles. After the inclusion and exclusion criteria filtering, a total of 23 relevant articles were finally screened out, including 9338 esophageal cancer patients and 14,896 matched controls. Figure 1 presented the selection process. Of the 23 articles, two were written in Chinese [33, 34] and 21 were in English [3555]. The participants of Hashibe et al.’s study were from five countries (Romania, Poland, Russia, Slovakia, and Czech Republic) [38], while other studies were from seven countries (Japan, Thailand, Iran, Kashmir, Sudan, Dutch and China), respectively. There were two sources of controls: population-based controls and hospital-based controls. The ADH1B Arg47His variant was measured in eight methods. Table 1 listed the main characteristics of included studies. Table 2 displayed the alleles and genotypes information of ADH1B Arg47His variant in each included studies.

Fig. 1
figure1

Flow diagram of the selection process

Table 1 Main characteristics of included studies in this meta-analysis
Table 2 Distribution of alleles and genotypes in each included studies

Overall association between ADH1B Arg47His polymorphism and esophageal cancer risk

A significant heterogeneity among all the included studies was observed (P < 0.01 and I 2 > 50 %), and the random-effect model was used. Table 3 listed the results of the association between the ADH1B Arg47His polymorphism and esophageal cancer susceptibility. Overall, we found that the frequency of 47His allele was higher than the 47Arg allele in both cases and controls, and the statistical analysis demonstrated that the 47His allele was significant associated with the decreased risk of esophageal cancer in total populations (His vs. Arg: OR = 0.67, 95 % CI = 0.59–0.76, P < 0.00001) as shown in Fig. 2. This significant protective relationship was also identified under other genetic models (P < 0.00001). Subgroup analysis by ethnicity showed that this polymorphism revealed an ethnic difference and geographic variance. In Asians, ADH1B 47His variant was shown to be associated with the decreased esophageal cancer risk under all the genetic models (P < 0.00001); while in non-Asians, no significant correlation was detected in any genetic models (P > 0.05). Figure 3 showed the result of the His carriers of the His/His and Arg/His genotypes compared with the Arg/Arg genotype in both groups. Furthermore, we also considered the role of this genetic variant in esophageal cancer among different countries. There were 12 articles in China (5485 patients and 6982 controls), five in Japan (2319 patients and 5213 controls), and six in other countries. Our result demonstrated that ADH1B Arg47His variant was a protective factor for cancer risk in Chinese and Japanese populations as shown in Fig. 4.

Table 3 Meta-analysis of the overall association between ADH1B Arg47His polymorphism and esophageal cancer risk
Fig. 2
figure2

Meta-analysis of ADH1B Arg47His polymorphism and esophageal cancer risk in a random-effect model under the allelic models (His vs. Arg)

Fig. 3
figure3

Subgroup analysis by ethnicity of ADH1B Arg47His polymorphism and esophageal cancer susceptibility under the dominant model (His/His+Arg/His vs. Arg/Arg)

Fig. 4
figure4

Association between ADH1B Arg47His polymorphism and esophageal cancer under the dominant model based on countries

Combined effect of ADH1B Arg47His variant and alcohol drinking, tobacco smoking, and gender difference on esophageal cancer risk

Fifteen studies estimated the combined effect of ADH1B Arg47His polymorphism and alcohol drinking on esophageal cancer risk. However, the relevant data could be extracted only from 12 studies, including 3545 patients and 6909 controls. Based on these data, we could only assess the combined effect on esophageal cancer susceptibility under the Arg/Arg versus His/His+Arg/His model. We divided the subjects into two groups: non-drinking group (1134 cases and 3526 controls) and drinking group (2411 cases and 3383 controls). Our results found that Arg/Arg genotype compared with the His carrier of His/His and Arg/His genotypes was significantly associated with the increased higher risk of esophageal cancer in the drinking group (OR = 3.15, 95 % CI = 2.66–3.74, P < 0.00001) and lower in the non-drinking group (OR = 1.71, 95 % CI = 1.23–2.38, P = 0.001) as shown in Fig. 5.

Fig. 5
figure5

Forest plot of the combined effect of ADH1B Arg47His polymorphism and alcohol drinking condition and esophageal cancer risk under the Arg/Arg versus Arg/His+His/His model (a non-drinkers; b drinkers)

Four articles considered the combined effect of ADH1B Arg47His polymorphism and tobacco smoking on esophageal cancer susceptibility, containing 2382 patients and 4792 controls. Our result demonstrated that the Arg/Arg genotype was associated with esophageal cancer occurrence in both non-smokers (OR = 2.40, 95 % CI = 1.44–3.98, P = 0.0007) and smokers (OR = 3.35, 95 % CI = 2.22–5.05, P < 0.00001) in the random-effect model as shown in Fig. 6, and this relationship was a bit stronger in smokers than that in non-smokers.

Fig. 6
figure6

Meta-analysis of the combined effect of ADH1B Arg47His polymorphism and smoking status and esophageal cancer risk under the Arg/Arg versus Arg/His+His/His model

Six articles were selected for gender variance (five for males and two for females). Our result showed that the Arg/Arg genotype of ADH1B Arg47His variant increased the esophageal cancer risk in male patients (OR = 3.44, 95 % CI = 2.42–4.89, P < 0.0001), while not in female patients (OR = 1.62, 95 % CI = 0.90–2.91, P = 0.11) as shown in Fig. 7.

Fig. 7
figure7

Forest plot of the combined effect of ADH1B Arg47His polymorphism and gender variance and esophageal cancer risk under the Arg/Arg versus Arg/His+His/His model (a males; b females)

Sensitivity analysis and publication bias

We deleted a single included study at a time to verify whether our results were influenced by each study. The result showed that even though the between-study heterogeneity was reduced, the pooled ORs were not significantly changed, indicating that there was no publication bias in the present meta-analysis. The funnel plot among the total population under the dominant model further reveal no publication bias as shown in Fig. 8.

Fig. 8
figure8

Funnel plot of the publication bias in this meta-analysis under the dominant model in total population (His/His+Arg/His vs. Arg/Arg)

Discussion

In this meta-analysis, we totally screened out 23 relevant articles. Our results showed that the ADH1B Arg47His variant was correlated with the decreased occurrence of esophageal cancer under all the genetic models among total population. Subgroup analysis by ethnicity demonstrated that this variant was associated with the decreased cancer risk in Asian populations as well, especially in Chinese and Japanese. However, in non-Asian population, no significant relationship was observed. Furthermore, we found that the combined effect of Arg/Arg genotype in ADH1B Arg47His variant and alcohol drinking, tobacco smoking, and male patients revealed a higher risk on esophageal cancer risk when compared with the His carrier of His/His and Arg/His genotypes, respectively. Our results were consistent with previous meta-analyses which showed that ADH1B*47Arg could significantly increase the risk of ESCC in Asians, especially when coupled with alcohol drinking [2931].

Esophageal cancer is considered as a serious malignancy worldwide for its extremely aggressive nature and poor survival rate [56]. It is a multistep, multifactorial disease, and the incidence is varied due to the geographical diversities; thus, the therapeutic management might be different as well. Genetic variations might be involved in esophageal cancer development and predict the prognosis [57]. Studies have shown that ADH gene might play a role in carcinogenesis. ADH constitutes a large family of enzymes and is a metabolic barrier against self-administer ethanol [58]. ADH isoenzyme is responsible for the reversible oxidation of alcohols to acetaldehyde, which is in turn oxidized to aldehyde by aldehyde dehydrogenases (ALD) [59]. ADH1B and ALDH2 are the major enzymes involved in the alcohol-metabolizing pathways in humans. ADH1B is one member of ADH family and is expressed in the liver and presented in gastrointestinal tract. This gene is mainly contributed for ethanol to carcinogenic metabolite conversion during the elimination phage [60]. In addition, ADH1B expression could result in high blood acetaldehyde levels, which can easily give rise to DNA damage, and finally cause the cancer occurrence [61]. Genetic polymorphisms of ADH1B could modulate exposure levels to ethanol. ADH1B can include three alleles (ADH2*1, ADH2*2, and ADH2*3). Among which, the Arg47His variant (ADH2*2) was the most studied. The activity of ADH1B was increased by 40-fold in ADH1B His/His individuals [62], resulting in the fast accumulation of acetaldehyde.

SNPs of ADH1B gene (the major alcohol-metabolizing enzyme gene) may modify the effects of alcohol on metabolic and clinical phenotypes [63]. Blood ethanol concentrations of ADH1B*2/*2 group were shown higher than those of ADH1B*1/*2 group [64]. ADH1B allele was associated with a reduction in alcohol consumption [65] and might be an important protective factor for alcoholic liver cirrhosis, especially for Asians [66]. ADH2*2 predicted less drinking and was a protective effect against heavy drinking in Jewish samples [67]. Heavy alcohol consumption and heavy smoking were shown to be associated with the increased risk of esophageal cancer particularly in individuals with the flushing response [68].

Previous studies have found that ADH1B Arg47His polymorphism was associated with the pathogenesis of cancers such as colorectal cancer [69] and head and neck cancer [70], while no positive correlation was found in hepatocellular carcinoma [71] and gastric cancer [72]. Several studies have identified the association between ADH1B polymorphism and esophagus cancer susceptibility. Chen et al. have observed that individuals with ADH1BArg/Arg genotype had a 3.99-fold risk of developing esophageal cancer compared with those with ADH1B His/His genotype [73]. Li et al. have demonstrated that ADH2*1 was associated with the increased risk of oesophageal cancer, possibly due to the tolerance of the carriers of these alleles to alcohol consumption compared to those with high-activity alleles ADH2*2 which are associated with higher production of the unpleasant acetaldehyde intermediate [74]. Oze et al. found that the magnitude of effect of ADH1B polymorphisms was greater in subjects who were heavy drinkers, heavy smokers, and had esophageal cancer [75]. Consumption of tobacco and alcohol, coupled with ADH1B genotypes, determines a substantial magnitude of tumorigenetic effect on earlier age ESCC diagnosis [76].

Several limitations were presented in this meta-analysis. Firstly, most of the included studies were conducted in the Asian population, while other ethnicities should be considered in the future. Secondly, the stages of patients with esophageal cancer could not be extracted from the included studies, which might limit the application of our results. Thirdly, the combined effect of ADH1B Arg47His variant and age group also should be focused on. Lastly, other polymorphisms in ADH1B gene or other ADH genes which might alter the metabolism of alcohol should be included.

Conclusions

In conclusion, our results suggested that ADH1B Arg47His polymorphism might be a protective factor on esophageal cancer susceptibility in Asians. The Arg/Arg genotypes combined with alcohol drinking, tobacco smoking, and males might be strongly increased the risk of esophageal cancer. However, further studies with more ethnicities should be taken into account in future researches.

Abbreviations

AC, adenocarcinomas; ADH, alcohol dehydrogenase gene; ADH1B, alcohol dehydrogenase 1B; ALD, aldehyde dehydrogenases; CI, confidence interval; OR, odds ratio; SCC, squamous cell carcinomas; SNPs, single nucleotide polymorphisms

References

  1. 1.

    Schweigert M, Dubecz A, Stein HJ. Oesophageal cancer—an overview. Nat Rev Gastroenterol Hepatol. 2013;10:230–44.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Napier KJ, Scheerer M, Misra S. Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol. 2014;6:112.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Stewart BW, Wild CP. World cancer report 2014. Geneva: International Agency for Research on Cancer; 2014.

  4. 4.

    Kornblum N. Esophageal Cancer[M], Geriatric Gastroenterology. New York: Springer; 2012. p. 571-579.

  5. 5.

    Arnal MJD, Arenas ÁF, Arbeloa ÁL. Esophageal cancer: risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol. 2015;21:7933.

    Google Scholar 

  6. 6.

    Gao Y-B, Chen Z-L, Li J-G, Hu X-D, Shi X-J, Sun Z-M, Zhang F, Zhao Z-R, Li Z-T, Liu Z-Y. Genetic landscape of esophageal squamous cell carcinoma. Nat Genet. 2014.

  7. 7.

    Tang W, Chen Z, Lin K, Su M, Au W. Development of esophageal cancer in Chaoshan region, China: association with environmental, genetic and cultural factors. Int J Hyg Environ Health. 2015;218:12–8.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Whiteman DC, Sadeghi S, Pandeya N, Smithers BM, Gotley DC, Bain CJ, Webb PM, Green AC. Combined effects of obesity, acid reflux and smoking on the risk of adenocarcinomas of the oesophagus. Gut. 2008;57:173–80.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Giri S, Pathak R, Aryal MR, Karmacharya P, Bhatt VR, Martin MG. Incidence trend of esophageal squamous cell carcinoma: an analysis of Surveillance Epidemiology, and End Results (SEER) database. Cancer Causes Control. 2015;26:159–61.

    Article  PubMed  Google Scholar 

  11. 11.

    Andrici J, Eslick GD. Epidemiology and Risk Factors for Esophageal Cancer[M], Esophageal Cancer. Heidelberg: Springer International Publishing; 2015. p. 1-23.

  12. 12.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.

    Article  PubMed  Google Scholar 

  13. 13.

    Merkow RP, Bilimoria KY, Keswani RN, Chung J, Sherman KL, Knab LM, Posner MC, Bentrem DJ. Treatment trends, risk of lymph node metastasis, and outcomes for localized esophageal cancer. J Natl Cancer Inst. 2014;106:dju133.

    Article  PubMed  Google Scholar 

  14. 14.

    Lao-Sirieix P, Fitzgerald RC. Screening for oesophageal cancer. Nat Rev Clin Oncol. 2012;9:278–87.

    Article  PubMed  Google Scholar 

  15. 15.

    Kaz AM, Grady WM. Epigenetic biomarkers in esophageal cancer. Cancer Lett. 2014;342:193–9.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet. 2013;381:400–12.

    Article  PubMed  Google Scholar 

  17. 17.

    Whiteman DC. Esophageal cancer: priorities for prevention. Curr Epidemiol Rep. 2014;1:138–48.

    Article  Google Scholar 

  18. 18.

    Chattopadhyay I. A brief overview of genetics of esophageal squamous cell carcinoma. J Cell Sci Molecul Biol. 2014;1:103.

    Google Scholar 

  19. 19.

    Zuo L, Wang K, Zhang X-Y, Pan X, Wang G, Tan Y, Zhong C, Krystal JH, Zhang H, Luo X. Association between common alcohol dehydrogenase gene (ADH) variants and schizophrenia and autism. Hum Genet. 2013;132:735–43.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Luo X, Kranzler HR, Zuo L, Zhang H, Wang S, Gelernter J. ADH7 variation modulates extraversion and conscientiousness in substance-dependent subjects. Am J Med Genet B Neuropsychiatr Genet. 2008;147:179–86.

    Article  Google Scholar 

  21. 21.

    Svensson S, Some M, Lundsjö A, Helander A, Cronholm T, Höög JO. Activities of human alcohol dehydrogenases in the metabolic pathways of ethanol and serotonin. Eur J Biochem. 1999;262:324–9.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Strommer J. The plant ADH gene family. Plant J. 2011;66:128–42.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Yoshida A. Genetics of human alcohol-metabolizing enzymes. Prog Nucleic Acid Res Mol Biol. 1991;40:225–67.

    Google Scholar 

  24. 24.

    Bosron WF, Li TK. Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism. Hepatology. 1986;6:502–10.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Bierut LJ, Goate AM, Breslau N, Johnson EO, Bertelsen S, Fox L, Agrawal A, Bucholz KK, Grucza R, Hesselbrock V. ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry. Mol Psychiatry. 2012;17:445–50.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Li D, Zhao H, Gelernter J. Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and alcohol-induced medical diseases. Biol Psychiatry. 2011;70:504–12.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ito H, Oze I, Hosono S, Watanabe M, Tanaka H, Matsuo K. The risk prediction for esophageal cancer by drinking, smoking, and the polymorphisms of ALDH2 and ADH1B. Cancer Res. 2015;75:4618.

    Article  Google Scholar 

  28. 28.

    Ma W-J, Lv G-D, Zheng S-T, Huang C-G, Liu Q, Wang X, Lin R-Y, Sheyhidin I, Lu X-M. DNA polymorphism and risk of esophageal squamous cell carcinoma in a population of North Xinjiang, China. World J Gastroenterol. 2010;16:641.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Zhang L, Jiang Y, Wu Q, Li Q, Chen D, Xu L, Zhang C, Zhang M, Ye L. Gene–environment interactions on the risk of esophageal cancer among Asian populations with the G48A polymorphism in the alcohol dehydrogenase-2 gene: a meta-analysis. Tumor Biol. 2014;35:4705–17.

    CAS  Article  Google Scholar 

  30. 30.

    Zhang G, Mai R, Huang B. ADH1B Arg47His polymorphism is associated with esophageal cancer risk in high-incidence Asian population: evidence from a meta-analysis. PLoS One. 2010;5.

  31. 31.

    Yang S-J, Yokoyama A, Yokoyama T, Huang Y-C, Wu S-Y, Shao Y, Niu J, Wang J, Liu Y, Zhou X-Q. Relationship between genetic polymorphisms of ALDH2 and ADH1B and esophageal cancer risk: a meta-analysis. World J Gastroenterol. 2010;16:4210.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Zhang H-Z, Jin G-F, Shen H-B. Epidemiologic differences in esophageal cancer between Asian and Western populations. Chin J Cancer. 2012;31:281.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Hou A, Tong X, Miao Z. Correlation of alcohol dehydrogenase and aldehyde dehydrogenase polymorphisms, and alcohol drinking in esophageal cancer. China J Pharm Econ. 2014;223–224.

  34. 34.

    Chen H. A match case–control study on esophageal cancer susceptibility with lifestyle habits and genetic polymorphisms of ALDH2 and ADH2. Sichuan University; Master’s degree; 2005.

  35. 35.

    Cui R, Kamatani Y, Takahashi A, Usami M, Hosono N, Kawaguchi T, Tsunoda T, Kamatani N, Kubo M, Nakamura Y. Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk. Gastroenterology. 2009;137:1768–75.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Lee CH, Lee JM, Wu DC, Goan YG, Chou SH, Wu I, Kao EL, Chan TF, Huang MC, Chen PS. Carcinogenetic impact of ADH1B and ALDH2 genes on squamous cell carcinoma risk of the esophagus with regard to the consumption of alcohol, tobacco and betel quid. Int J Cancer. 2008;122:1347–56.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Tanaka F, Yamamoto K, Suzuki S, Inoue H, Tsurumaru M, Kajiyama Y, Kato H, Igaki H, Furuta K, Fujita H. 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. 2010;59:1457–64.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Hashibe M, Boffetta P, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Mates D, Janout V, Fabiánová E, Bencko V, Moullan N. Evidence for an important role of alcohol-and aldehyde-metabolizing genes in cancers of the upper aerodigestive tract. Cancer Epidemiol Biomarkers Prev. 2006;15:696–703.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Wu M, Chang SC, Kampman E, Yang J, Wang XS, Gu XP, Han RQ, Liu AM, Wallar G, Zhou JY. Single nucleotide polymorphisms of ADH1B, ADH1C and ALDH2 genes and esophageal cancer: A population-based case–control study in China. Int J Cancer. 2013;132:1868–77.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Wang Y, Ji R, Wei X, Gu L, Chen L, Rong Y, Wang R, Zhang Z, Liu B, Xia S. Esophageal squamous cell carcinoma and ALDH2 and ADH1B polymorphisms in Chinese females. Asian Pac J Cancer Prev. 2011;12:2065–8.

    PubMed  Google Scholar 

  41. 41.

    Guo Y-M, Wang Q, Liu Y-Z, Chen H-M, Qi Z, Guo Q-H. Genetic polymorphisms in cytochrome P4502E1, alcohol and aldehyde dehydrogenases and the risk of esophageal squamous cell carcinoma in Gansu Chinese males. World J Gastroenterol. 2008;14:1444.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Gu H, Gong D, Ding G, Zhang W, Liu C, Jiang P, Chen S, Chen Y. A variant allele of ADH1B and ALDH2, is associated with the risk of esophageal cancer. Exp Ther Med. 2012;4:135–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Akbari MR, Malekzadeh R, Shakeri R, Nasrollahzadeh D, Foumani M, Sun Y, Pourshams A, Sadjadi A, Jafari E, Sotoudeh M. Candidate gene association study of esophageal squamous cell carcinoma in a high-risk region in Iran. Cancer Res. 2009;69:7994–8000.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Babiker H. Genetic polymorphisms in alcohol and xenobiotic metabolizing enzymes as risk factors of oesophageal cancer in Sudan. 2015. UOFK.

    Google Scholar 

  45. 45.

    Ye B, Ji C-Y, Zhao Y, Li W, Feng J, Zhang X. Single nucleotide polymorphism at alcohol dehydrogenase-1B is associated with risk of esophageal squamous cell carcinoma. Cancer Cell Int. 2014;14:1–7.

    Article  Google Scholar 

  46. 46.

    Gao Y, He Y, Xu J, Xu L, Du J, Zhu C, Gu H, Ma H, Hu Z, Jin G. Genetic variants at 4q21, 4q23 and 12q24 are associated with esophageal squamous cell carcinoma risk in a Chinese population. Hum Genet. 2013;132:649–56.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Dura P, Berkers T, van Veen EM, Salomon J, te Morsche RH, Roelofs HM, Kristinsson JO, Wobbes T, Witteman BJ, Tan AC. Polymorphisms in alcohol-metabolizing enzymes and esophageal carcinoma susceptibility: a Dutch Caucasian case–control study. J Hum Genet. 2013;58:742–8.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Iqbal B, Dar NAG. Comparison of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 polymorphism in esophageal cancer cases vs controls in Kashmir. 2011.

    Google Scholar 

  49. 49.

    J-h D, S-p L, H-x C, Wu J-z, Gao C-m, Y-t L, J-n Z, Chang J, Yao G-h. Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes, alcohol drinking and the risk for esophageal cancer in a Chinese population. J Hum Genet. 2010;55:97–102.

    Article  Google Scholar 

  50. 50.

    Yang S-J, Wang H-Y, Li X-Q, Du H-Z, Zheng C-J, Chen H-G, Mu X-Y, Yang C-X. Genetic polymorphisms of ADH2 and ALDH2 association with esophageal cancer risk in southwest China. World J Gastroenterol. 2007;13:5760–4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Yang C, Matsuo K, Ito H, Hirose K, Wakai K, Saito T, Shinoda M, Hatooka S, Mizutani K, Tajima K. Esophageal cancer risk by ALDH2 and ADH2 polymorphisms and alcohol consumption: exploration of gene-environment and gene-gene interactions. Asian Pac J Cancer Prev. 2005;6:256.

    PubMed  Google Scholar 

  52. 52.

    Chao Y-C, Wang L-S, Hsieh T-Y, Chu C-W, Chang F-Y, Chu H-C. Chinese alcoholic patients with esophageal cancer are genetically different from alcoholics with acute pancreatitis and liver cirrhosis. Am J Gastroenterol. 2000;95:2958–64.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Boonyaphiphat P, Thongsuksai P, Sriplung H, Puttawibul P. Lifestyle habits and genetic susceptibility and the risk of esophageal cancer in the Thai population. Cancer Lett. 2002;186:193–9.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Yokoyama T, Yokoyama A, Kato H, Tsujinaka T, Muto M, Omori T, Haneda T, Kumagai Y, Igaki H, Yokoyama M. Alcohol flushing, alcohol and aldehyde dehydrogenase genotypes, and risk for esophageal squamous cell carcinoma in Japanese men. Cancer Epidemiol Biomarkers Prev. 2003;12:1227–33.

    CAS  PubMed  Google Scholar 

  55. 55.

    Yokoyama A, Muramatsu T, Omori T, Yokoyama T, Matsushita S, Higuchi S, Maruyama K, Ishii H. Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics. Carcinogenesis. 2001;22:433–9.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Zhang Y. Epidemiology of esophageal cancer. World J Gastroenterol. 2013;19:5598.

    Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Cheung WY, Liu G. Genetic variations in esophageal cancer risk and prognosis. Gastroenterol Clin North Am. 2009;38:75–91.

    Article  PubMed  Google Scholar 

  58. 58.

    Jelski W, Orywal K, Laniewska M, Szmitkowski M. The diagnostic value of alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) measurement in the sera of gastric cancer patients. Clin Exp Med. 2010;10:215–9.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    De Smidt O, Du Preez JC, Albertyn J. The alcohol dehydrogenases of Saccharomyces cerevisiae: a comprehensive review. FEMS Yeast Res. 2008;8:967–78.

    Article  PubMed  Google Scholar 

  60. 60.

    Lao-Sirieix P, Caldas C, Fitzgerald RC. Genetic predisposition to gastro-oesophageal cancer. Curr Opin Genet Dev. 2010;20:210–7.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Singh NP, Khan A. Acetaldehyde: genotoxicity and cytotoxicity in human lymphocytes. Mut Res DNA Repair. 1995;337:9–17.

    CAS  Article  Google Scholar 

  62. 62.

    Lee S-L, Höög J-O, Yin S-J. Functionality of allelic variations in human alcohol dehydrogenase gene family: assessment of a functional window for protection against alcoholism. Pharmacogenet Genomics. 2004;14:725–32.

    CAS  Article  Google Scholar 

  63. 63.

    Kiage JN, James LO, Kabagambe EK. Genetic modification of the effects of alcohol on metabolic and clinical phenotypes: a review. Curr Nutr Rep. 2014;3:213–22.

    CAS  Article  Google Scholar 

  64. 64.

    Kang G, Bae KY, Kim SW, Kim J, Shin HY, Kim JM, Shin IS, Yoon JS, Kim JK. Effect of the allelic variant of alcohol dehydrogenase ADH1B* 2 on ethanol metabolism. Alcohol Clin Exp Res. 2014;38:1502–9.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Ferrari P, McKay J, Jenab M, Brennan P, Canzian F, Vogel U, Tjønneland A, Overvad K, Tolstrup JS, Boutron-Ruault M. Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphisms, alcohol intake and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study. Eur J Clin Nutr. 2012;66:1303–8.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    He L, Deng T, Luo H-S. Genetic polymorphism in alcohol dehydrogenase 2 (ADH2) gene and alcoholic liver cirrhosis risk. Int J Clin Exp. 2015;8:7786.

    CAS  Google Scholar 

  67. 67.

    Hasin D, Aharonovich E, Liu X, Mamman Z, Matseoane K, Carr L, Li T-K. Alcohol and ADH2 in Israel: Ashkenazis, Sephardics, and recent Russian immigrants. Am J Psychiatry. 2014.

  68. 68.

    Ishiguro S, Sasazuki S, Inoue M, Kurahashi N, Iwasaki M, Tsugane S, Group JS. Effect of alcohol consumption, cigarette smoking and flushing response on esophageal cancer risk: a population-based cohort study (JPHC study). Cancer Lett. 2009;275:240–6.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Crous-Bou M, Rennert G, Cuadras D, Salazar R, Cordero D, Rennert HS, Lejbkowicz F, Kopelovich L, Lipkin SM, Gruber SB. Polymorphisms in alcohol metabolism genes ADH1B and ALDH2, alcohol consumption and colorectal cancer. 2013.

    Google Scholar 

  70. 70.

    Ji YB, Tae K, Ahn TH, Lee SH, Kim KR, Park CW, Park BL, Shin HD. 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. 2011;47:583–7.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Liu S, Cui Y, Yang B, Chai P, Su Z, Zhang Q, Zheng D, Li R, Yu G. Relationship between ADH2 Arg47His variation and hepatocellular carcinoma susceptibility: a meta analysis. Int J Clin Exp. 2015;8:9543.

    Google Scholar 

  72. 72.

    Wang H-L, Zhou P-Y, Liu P, Zhang Y. ALDH2 and ADH1 genetic polymorphisms may contribute to the risk of gastric cancer: a meta-analysis. PLoS One. 2014;9.

  73. 73.

    Chen YJ, Chen C, Wu DC, Lee CH, Wu CI, Lee JM, Goan YG, Huang SP, Lin CC, Li TC. Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisms on esophageal cancer risks. Int J Cancer. 2006;119:2827–31.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Li D-P, Dandara C, Walther G, Parker MI. Genetic polymorphisms of alcohol metabolising enzymes: their role in susceptibility to oesophageal cancer. Clin Chem Lab Med. 2008;46:323–8.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Oze I, Matsuo K, Suzuki T, Kawase T, Watanabe M, Hiraki A, Ito H, Hosono S, Ozawa T, Hatooka S. Impact of multiple alcohol dehydrogenase gene polymorphisms on risk of upper aerodigestive tract cancers in a Japanese population. Cancer Epidemiol Biomarkers Prev. 2009;18:3097–102.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Lee CH, Wu DC, Wu I, Goan YG, Lee JM, Chou SH, Chan TF, Huang HL, Hung YH, Huang MC. Genetic modulation of ADH1B and ALDH2 polymorphisms with regard to alcohol and tobacco consumption for younger aged esophageal squamous cell carcinoma diagnosis. Int J Cancer. 2009;125:1134–42.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

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No funding supported this study.

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The data will not be shared because not all authors agreed with this.

Authors’ contributions

NM, SYN, and TX designed and conducted the experiments. BH and CL surveyed the literature and developed the text of the manuscript. XYS helped in the statistical analysis. NM, BH, and TX refined the write-up. All authors read and approved the final manuscript.

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The authors declare that they have no competing interests.

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Correspondence to Tao Xiong.

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Mao, N., Nie, S., Hong, B. et al. Association between alcohol dehydrogenase-2 gene polymorphism and esophageal cancer risk: a meta-analysis. World J Surg Onc 14, 191 (2016). https://doi.org/10.1186/s12957-016-0937-y

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Keywords

  • Esophageal cancer
  • Alcohol dehydrogenase 1B
  • Polymorphism
  • Meta-analysis