Effect of ALDH2 polymorphism on cancer risk in Asians: A meta-analysis.

Numerous studies have investigated the association between ALDH2 gene rs671G>A polymorphism and various cancer type in Asians. However, the results remain inconclusive.We conducted a comprehensive meta-analysis including 63 articles with 66 studies containing 25,682 cases and 47,455 controls retrieved by searching PubMed and Embase electronic databases up to March 5, 2018.Pooled results indicated that ALDH2 gene rs671 polymorphism was significantly associated with the overall cancer risk in Asians (homozygous model: odds ratio [OR] = 0.85, 95% confidence interval [CI] = 0.72-0.99, P = .042; heterozygous model: OR = 1.32, 95% CI = 1.14-1.52, P  < .001; recessive model: OR = 0.73, 95% CI = 0.60-0.88, P = .001; dominant model: OR = 1.32, 95% CI = 1.16-1.51, P < .001; and allele comparison model: OR = 1.11, 95% CI = 1.03-1.19, P = .004), especially in esophageal cancer and among the Chinese and the Japanese.Our results suggest that ALDH2 rs671 polymorphism is associated with the overall cancer risk in Asians. Well-designed prospective studies with more information about gene-environment interaction, such as drinking, should be conducted to validate our findings.

Introduction

Cancer has been a major killer worldwide, with an estimation of 18.1 million new cases and 9.6 million deaths occurring in 2018.[ In China, cancer has also been the leading cause of death with the increasing incidence and mortality since 2010. In 2015, 4,292,000 new cancer cases and 2,814,000 cancer deaths were projected to occur in China, that is, about 12,000 new cancer cases and 7500 cancer deaths on average per day.[ Cancer is a multifactorial disease. Besides the internal/inherited factors, the environmental factors have been considered to play an important role in cancer development including tobacco, alcohol, diet, obesity, infectious agents, and radiation.[ Approximately 3.6% of all cancers and 3.5% of all cancer deaths are attributable to alcohol consumption.[ Meanwhile, the effect of alcohol consumption on the risk of cancer is on the rise, and the trend seems to continue.[

Alcohol itself is not carcinogenic, but its metabolite, acetaldehyde, is known to interfere DNA synthesis and repairmen and consequently increase the risk of cancer. Alcohol is mainly metabolized by 2 key NAD-dependent enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Alcohol is 1st conversed into acetaldehyde by ADH. Acetaldehyde is then oxidized to harmless acetate by ALDH.[ Aldehyde dehydrogenase-2 (ALDH2) is the major enzyme to eliminate most of the acetaldehyde.[

The ALDH2 gene, located at chromosome 12q24, is composed of 13 exons with 46,031 base pairs, and its polymorphisms affect the blood acetaldehyde concentrations after alcohol consumption.[ Rs671G>A, the most commonly studied polymorphism, is reported to an amino acid substitution from glutamine to lysine (Glu487Lys).[ The 487Lys allele encodes a catalytically inactive subunit and finally affects the status of the ALDH2 enzyme, with only 6.25% of normal 487Glu activity.[ Such a polymorphism inactivates ALDH2 and leads a high concentration of blood acetaldehyde after drinking alcohol, which could contribute to susceptibility to carcinogenesis.[ Increasing evidence suggests that the rs671 polymorphism may be associated with many types of cancer, such as head and neck cancer, esophageal cancer, liver cancer, breast cancer, colorectal cancer and gastric cancer.[ However, the results remain inconclusive. Hence, we conducted a comprehensive meta-analysis to assess the association of ALDH2 rs671 polymorphism and the overall cancer risk in Asians.

Materials and methods

Search strategy

PubMed and Embase electronic databases were searched to retrieve all the relevant studies up to March 5, 2018. The following search terms were used: “alcohol dehydrogenase 2 or ALDH2” or “polymorphism or variant or variation” or “cancer or tumor or neoplasm or carcinoma.” Additionally, all the eligible studies and reviews were checked to avoid the missing of any relevant studies. However, only the largest or the latest study would be included in our meta-analysis. As this article is a meta-analysis of the previous published studies, hence patients consent and approval of the ethics committee were not required.

Inclusion and exclusion criteria

The studies included in our meta-analysis must meet the following criteria: evaluating the association between the ALDH2 rs671 polymorphism and cancer risk in Asians; case–control design; written in English and Chinese; and sufficient information for estimation of odds ratios (ORs) and their 95% confidence intervals (CIs). The exclusion criteria were as follows: case only studies; duplicate articles; and reviews, meta-analyses, and comments. Studies with genotype frequencies in the controls departure from Hardy–Weinberg equilibrium (HWE) were also excluded, unless further evidence indicated that another polymorphism was in HWE.

Data extraction

Two investigators assessed and extracted the information from all the eligible publications independently. The following information was collected: the surname of authors, year of publication, country of origin, cancer type, source of control, and alleles and genotypes distribution. In case of any disagreement, the issue was resolved by discussion with a third investigator until consensus was reached.

Statistical analysis

Goodness-of-fit Chi-squared test was employed to evaluate HWE in the control subjects of each study. P < .05 was considered significant and indicated the study departed from HWE. Crude ORs and their corresponding 95% CIs were applied to assess the strength of association between the ALDH2 rs671 polymorphism and the overall cancer risk in Asians under the five genetic models: homozygous model (AA vs GG), heterozygous model (GA vs GG), recessive model (AA vs GA + GG), dominant model (GA + AA vs GG), and allele comparison model (A vs G). Stratification analyses were also conducted to assess the association regarding country, cancer type, and source of control. Q value was performed to test the heterogeneity among studies. If no significant heterogeneity was observed with P-value more than .10, a fixed-effects model (the Mantel–Haenszel method) was adopted. Otherwise, the random-effects model (the DerSimonian and Laird method) was applied.[ Moreover, we used Egger linear regression to detect the symmetry of funnel plots and the potential publication bias.[ All the statistical analyses were performed with STATA 12.0 (STATA Corporation, College Station, TX). All the P-values were 2-sided, and P < .05 was considered statistically significant.

Results

Eligible studies

A total of 381 relevant articles were retrieved from PubMed and Embase electronic databases using search terms described in the materials and methods part. After title and abstract screening, 286 articles were excluded for not dealing with the association between the ALDH2 rs671 polymorphism and any cancer risk in Asians. Only 95 articles remained for further assessment, among which, 21 were excluded for being irrelevant; 9 without sufficient information; 6 overlapped with others and 1 departed from HWE.[ On the contrary, 5 additional articles were found manually. Ultimately, 63 articles with 66 studies comprising 25,682 cases and 47,455 controls were subject to the final meta-analysis,[ and the characteristics of all the original studies are shown in Table 1. The studies were conducted on various types of cancer, such as esophageal cancer (21 studies), oral cancer (6), hepatocellular cancer (7), colorectal cancer (10), breast cancer (3), head and neck cancer (3), lung cancer (2), pancreatic cancer (2), gastric cancer (8), bladder cancer (1) and upper aerodigestive tract cancer (UADT) (3). Among them, 31 were conducted in China, 29 in Japan, 5 in Korea, and 1 in Thailand. Out of the 66 studies selected, 42 were hospital based (HB) and 24 were population based (PB).

Table 1

Characteristics of studies included in ALDH2 rs671 polymorphism and cancer risk.

Meta-analysis results

Between-study heterogeneity was found for all the 5 genetic models. Therefore, we used random-effects model to calculate the ORs and their 95% CIs. A significant association between ALDH2 rs671 polymorphism and overall cancer risk in Asians was observed under all the 5 genetic models (Table 2): homozygous model (AA vs GG): OR = 0.85, 95% CI = 0.72 to 0.99, P = .042; heterozygous model (GA vs GG): OR = 1.32, 95% CI = 1.14 to 1.52, P < .001; recessive model (AA vs GA + GG): OR = 0.73, 95% CI = 0.60 to 0.88, P = .001 (Fig. 1); dominant model (GA + AA vs GG): OR = 1.32, 95% CI = 1.16 to 1.51, P < .001; and allele comparison model (A vs G): OR = 1.11, 95% CI = 1.03 to 1.19, P = .004 (Fig. 2). In the stratification analyses by country, the similar results were found in Japanese. However, ALDH2 rs671 polymorphism was associated with the increased cancer risk in Chinese: heterozygous model (GA vs GG): OR = 1.21, 95% CI = 1.02 to 1.44, P = .029; dominant model (GA + AA vs GG): OR = 1.35, 95% CI = 1.11 to 1.64, P = .003; and allele comparison model (A vs G): OR = 1.12, 95% CI = 1.01 to 1.25, P = .030; and with the decreased cancer risk in Korean: homozygous model (AA vs GG): OR = 0.57, 95% CI = 0.35 to 0.91, P = .018; recessive model (AA vs GA + GG): OR = 0.55, 95% CI = 0.34 to 0.88, P = .013. In terms of the stratification analyses by cancer type, there was significant association between ALDH2 rs671 polymorphism and esophageal cancer: heterozygous model (GA vs GG): OR = 1.79, 95% CI = 1.28 to 2.49, P = .001; recessive model (AA vs GA + GG): OR = 0.53, 95% CI = 0.35 to 0.81, P = .004; dominant model (GA + AA vs GG): OR = 1.69, 95% CI = 1.25 to 2.29, P = .001; and allele comparison model (A vs G): OR = 1.28, 95% CI = 1.08 to 1.50, P = .003], oral cancer, head and neck cancer, and UADT. Meanwhile, in the stratification analyses by source of control, a significant association was only found in HB: homozygous model (AA vs GG): OR = 0.76, 95% CI = 0.62 to 0.94, P = .011; heterozygous model (GA vs GG): OR = 1.59, 95% CI = 1.32 to 1.92, P < .001; recessive model (AA vs GA + GG): OR = 0.58, 95% CI = 0.45 to 0.76, P < .001; dominant model (GA + AA vs GG): OR = 1.55, 95% CI = 1.32 to 1.82, P < .001; and allele comparison model (A vs G): OR = 1.19, 95% CI = 1.09 to 1.29, P < .001.

Table 2

Stratified analyses of the ALDH2 rs671 polymorphism and cancer risk.

Figure 1

Forest plot of the association between ALDH2 rs671 polymorphism and overall cancer risk in Asians in the recessive model.

Figure 2

Forest plot of the association between ALDH2 rs671 polymorphism and overall cancer risk in Asians in the allele comparison model.

Heterogeneity and sensitivity analyses

Heterogeneities were detected among all the studies investigating the association between ALDH2 rs671 polymorphism and the overall cancer risk in Asians (homozygous model, P < .001; heterozygous model, P < .001; recessive model, P < .001; dominant model, P < .001; and allele comparison model, P < 0.001). Therefore, we used the random-effects model to calculate the pooled ORs and their 95% CIs. Moreover, the leave-one-out sensitivity analyses indicated that no single study was able to change the results of our final meta-analysis.

Publication bias

The funnel plot and Egger linear regression analysis were used to evaluate the publication bias, and no evidence of publication bias was observed (homozygous model, P = .405; heterozygous model, P = .683; recessive model, P = .219; dominant model, P = .841; and allele comparison model, P = .569).

Discussion

ALDH2 gene, located at chromosome 12q24, is composed of 13 exons with 46,031 base pairs. ALDH2 is one of the major enzymes which plays a key role in alcohol metabolism. Alcohol is 1st conversed into acetaldehyde by ADH, and acetaldehyde is then oxidized to harmless acetate by ALDH.[ Therefore, the blood acetaldehyde concentrations after alcohol consumption are mainly dependent on the enzyme activity of ALDH2. However, acetaldehyde could interfere DNA synthesis and repair and consequently results in more than 200 diseases, including alcohol-related cancer.[ Many studies have investigated the role of ALDH2 gene polymorphisms and their relationship with acetaldehyde elimination. Among them, ALDH2 rs671G>A polymorphism was found dramatically reducing the activity of ALDH2 enzyme and maintaining the high blood acetaldehyde concentrations after alcohol consumption.[ Drinking the same amount of alcohol, the blood acetaldehyde concentrations in individuals with ALDH2 GA and AA genotype were 6 and 19 folds higher than that with ALDH2 GG genotype, respectively.[ The accumulation and continuous exposure of acetaldehyde may contribute to the development of cancer.

To the best of our knowledge, this is the 1st meta-analysis to investigate the association between ALDH2 rs671 polymorphism and the overall cancer risk in Asians. In the present meta-analysis, 63 articles with 66 studies containing 25,682 cases and 47,455 controls were retrieved. A significant association between ALDH2 rs671 polymorphism and the overall cancer risk in Asians was observed. Further stratification analyses indicated that a significant association was also found in esophageal cancer, oral cancer, head and neck cancer, and UADT, while the evidence for other cancers is less, as colorectal cancer and hepatocellular cancer. All of the studies investigated colorectal cancer and hepatocellular cancer have a small sample size that resulted in insufficient statistical power.[ In a latest meta-analysis, Cai et al explored whether the polymorphism was associated with the overall cancer risk in all the ethnicity, and retrieved only 51 studies (49 studies in Asians) with a total of 16,774 cases and 32,060 controls before 2014.[ In turn, in our meta-analysis, at least 15 studies were published evaluating the association between ALDH2 rs671 polymorphism and cancer risk in Asians. Moreover, Cai et al evaluated the association only under 2 genetic models, the dominant model (GA + AA vs GG) and the allele comparison model (A vs G), and ALDH2 rs671 polymorphism was observed to be associated with the increased overall cancer risk under the dominant model instead of the allele comparison model.

In the general population, the prevalence of the variant 487Lys allele varies in different Asian populations, with about 45% of Japanese, 31% of Chinese, and 29% of Koreans.[ In the stratification analyses by country, Cai et al also found that ALDH2 rs671 polymorphism was associated with the increased cancer risk in Japanese under the dominant model rather than the allele comparison model.[ However, the results could not be repeated in the Chinese population. In our meta-analysis, ALDH2 rs671 polymorphism was associated with the increased overall cancer risk in Asians, especially in Japanese and Chinese, not only under the dominant model but also the allele comparison model. Cai et al included only 18 studies with 6193 cases and 8581 controls in Chinese populations in 2014. While, 31 studies with 13,284 cases and 20,449 controls in Chinese populations were retrieved in our meta-analysis. Moreover, unlike this previous article, the studies with genotype frequencies in the controls departure from HWE were not included, unless further evidence indicated that another polymorphism was in HWE. To data, ours is the largest meta-analysis with the strongest statistical power among the existing studies of the same kind.

In our meta-analysis, we found that ALDH2 rs671 polymorphism was associated with an increased overall cancer risk in Asians, especially with esophageal cancer and among the Chinese and the Japanese. Interestingly, individuals with ALDH2 rs671 AA genotype were associated with a reduced risk of esophageal cancer and among the Japanese (Table 2). Such associations were also found in the previous esophageal cancer-specific meta-analysis.[ The AA individuals tend to avoid alcohol intake due to the development of a severe reaction after small amounts of alcohol drinking, which then leads to be associated with a reduced risk of esophageal cancer and among the Japanese.[ However, among the alcohol consumption group, the AA individuals still suffer highly increased esophageal cancer risk (OR = 3.87, 95% CI = 1.67–8.96) compared to the GG individuals.[

Several possible limitations should be acknowledged in our present meta-analysis. First, in the stratification analysis of cancer type and country, the sample sizes of the oral cancer and the head and neck cancer, as well as the sample sizes with the Korean, are relatively small, which might diminish statistical power to evaluate the association. Second, due to the lack of the original information, our meta-analysis was based on unadjusted ORs for other confounding factors, for example, alcohol consumption, which might affect our findings. Third, heterogeneity was observed among the 5 genetic models, and the random-effects model was applied to estimate the association, which might present unstable results. Lastly, we just chose the studies written in English and Chinese, which might overlook the publications in other languages.

In conclusion, our meta-analysis indicated that ALDH2 rs671G>A polymorphism may be associated with the overall cancer risk in Asians, especially in esophageal cancer and among the Chinese and the Japanese. Well-designed prospective studies with more information about gene–environment interaction, such as drinking, should be conducted to validate our findings.

Author contributions

Data curation: Wei Zuo, Zhenyu Zhan.

Methodology: Wei Bai.

Project administration: Zhenyu Zhan.

Software: Wei Zuo, Wei Bai.

Validation: Lin Ma.

Writing – original draft: Shanggan Zeng.

Writing – review & editing: Shanggan Zeng.