Clinical significance of ALDH2 rs671 polymorphism in esophageal cancer: evidence from 31 case-control studies.
ABSTRACT: BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2), a critical enzyme for the detoxification of alcohol, is associated with many types of cancers. To verify the relationship of ALDH2 rs671 G>A polymorphism and esophageal cancer (EC), we performed a meta-analysis of a total of 31 published data including 8,510 patients and 16,197 controls. METHODS: The pooled odds ratio (OR) and the 95% confidence interval (CI) were calculated using a fixed or random-effects model. Heterogeneity (PH ), publication bias, and sensitivity analysis were also determined. RESULTS: Although a protective effort was found in the rs671 homozygote comparison (AA/GG: OR=0.69; 95% CI=0.48-0.98), the heterozygote comparison was apparently associated with the risk of EC, particularly in the Chinese population ( AG/GG: OR=1.39; 95% CI=1.03-1.87). Alcohol consumption remarkably increased this risk, especially in the AG genotype. Drinking men with the AG genotype appeared to show a higher risk ( AG/GG: OR=4.39; 95% CI=1.24-6.55) than drinking women. CONCLUSION: The present meta-analysis provided advanced information regarding the association of the ALDH2 A>G polymorphism and EC. Taken together, insights from this study suggested an enhanced effect on the development of EC through a genetic-environmental interaction.
Project description:In last decades, many scholars have studied the relationship between aldehyde dehydrogenase 2 (ALDH2) rs671 and ischemic stroke (IS), however, the results obtained from these studies were inconclusive. The purpose of this study was to investigate the association between rs671 and the risk of IS by systematically review.Two researchers independently screened relevant published literatures, derived data and estimated the risk of bias of the research in Pubmed, Embase, Ovid, China National Knowledge Infrastructure (CNKI), Cochrane Library and China Biomedical Literature Database throughout March 29, 2020. All statistical analyses were performed with the Stata 12.0 software. The data of the study was analyzed using fixed and random effects models. The results were expressed by odds ratio (OR) and 95% confidence interval (95%CI).A total of 10 articles were included this study. The total number of samples for all studies was 5265, including 2762 cases and 2503 controls. Statistical results indicated statistical differences between ALDH2 rs671 polymorphism and IS under dominant model (AA vs. AG?+?GG) and allelic model (A vs G), ORs (95% CI) were 1.66 (1.27-2.17) (P?=?.00) and 1.34 (1.05-1.71) (P?=?.02), respectively. But there was no statistical difference under recessive model (AA?+?AG vs GG), OR (95% CI) was 1.40 (0.99-1.97), P?=?.06.ALDH2 rs671 polymorphism was related to IS risk for Chinese population and the A allele of rs671 may be a risk factor of IS.
Project description:Existing evidence remains inconclusive as to how the association between inactive ALDH2 and esophageal cancer (EC) depends on alcohol consumption. The study is based on the China Kadoorie Biobank cohort, with 10 years follow-up of 0.5 million adults aged 30-79 years. ALDH2 activity was assessed by both self-reported flushing response and Glu504Lys (rs671 G?>?A) polymorphism. Among both male and female participants who consumed alcohol less than weekly (n?=?69,519; 211 EC cases), low active or inactive ALDH2 was not associated with increased EC risk [HRs (95% CIs): GA vs. GG 0.75 (0.54, 1.04); AA vs. GG 1.01 (0.46, 2.20)]. Among male weekly alcohol consumers, both flushing response [n?=?59,380; 501 EC cases; HRs (95% CIs): "soon after drinking" vs. "no" flushing response 1.45 (1.05, 2.01)] and rs671 [n?=?10,692; 94 EC cases; GA vs. GG 3.31 (1.94, 5.67)] were associated with EC risk. The increased EC risk associated with "soon" response or rs671 GA was apparent in men consuming alcohol ?30g/d. Among male daily consumers, the HRs (95% CIs) for EC associated with 15g/d of alcohol were 1.28 (1.15, 1.44) for "soon" response [vs. other responses: 1.12 (1.09, 1.15); pinteraction ?=?0.047; n?=?36,401, 425 EC cases] and 1.41 (1.08, 1.82) for rs671 GA [vs. GG: 1.16 (1.06, 1.27); pinteraction ?=?0.493; n?=?6,607, 80 EC cases]. Self-reported flushing response had low sensitivity (56.8%) and high specificity (88.4%) in identifying rs671 A allele among male weekly alcohol consumers. In conclusion, low-activity ALDH2 was associated with increased EC risk among male heavy alcohol consumers. More accurate measurement of alcohol-related EC risk allows better achievement of precision prevention.
Project description:Alcohol drinking is a major risk factor for esophageal cancer (EC) and the metabolism of ethanol has been suggested to play an important role in esophageal carcinogenesis. Epidemiologic studies, including genomewide association studies (GWAS), have identified single nucleotide polymorphisms (SNPs) in alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) to be associated with EC. Using a population-based case-control study with 858 EC cases and 1,081 controls conducted in Jiangsu Province, China, we aimed to provide further information on the association of ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms with EC in a Chinese population. Results showed that ADH1B (rs1229984) was associated with EC with odds ratios (ORs) of 1.34 [95% confidence interval (CI): 1.08-1.66] for G-allele carriers compared to A/A homozygotes. No heterogeneity was detected on this association across different strata of alcohol drinking and tobacco smoking. Statistical interaction between ALDH2 (rs671) and alcohol drinking on EC susceptibility in both additive and multiplicative scales was observed. Compared to G/G homozygotes, A-allele carriers were positively associated with EC among moderate/heavy drinkers (OR = 1.64, 95% CI: 1.12-2.40) and inversely associated with EC among never/light drinks (OR = 0.75, 95% CI: 0.54-1.03). In addition, statistical interaction between ALDH2 and ADH1B polymorphisms on EC susceptibility among never/light drinkers was indicated. We did not observe association of ADH1C polymorphism with EC. In conclusion, our findings indicated that ADH1B (rs1229984) was associated with EC independent of alcohol drinking and tobacco smoking status and alcohol drinking interacted with ALDH2 (rs671) on EC susceptibility in this high-risk Chinese population.
Project description:To date, the relationship between the aldehyde dehydrogenases-2 (ALDH2) rs671 G>A (Glu504Lys) polymorphism and gastric cancer (GC) risk has not been thoroughly elucidated. To derive a more precise estimation of the effect of the ALDH2 rs671 G>A polymorphism on GC, we conducted this meta-analysis. We searched for qualified studies in the Embase, PubMed, Wang Fan and China National Knowledge Infrastructure databases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association. A total of 6,421 GC patients and 8,832 control subjects were included in the present study. The pooled results indicated no significant relationship between the ALDH2 rs671 G>A polymorphism and GC susceptibility in all genetic models. A stratified analysis by country showed that the ALDH2 rs671 G>A polymorphism might be a risk factor for GC in Japan (Allele model: Punadjusted = 0.034; Dominant model: Punadjusted = 0.040); however, the result was nonsignificant when the Bonferroni correction and false discovery rate (FDR) were applied. In subgroup analyses by drinking status in the dominant model, our study revealed that the ALDH2 rs671 G>A polymorphism significantly increased the risk of GC for drinkers (dominant model: P < 0.001). No relationship between the ALDH2 rs671 G>A polymorphism and GC risk was observed in any other subgroup. Our present study indicated no association between the ALDH2 rs671 G>A polymorphism and GC risk in Eastern Asian populations. However, the ALDH2 rs671 G>A polymorphism can significantly increase GC risk for drinkers.
Project description:Acetaldehyde dehydrogenase 2 (ALDH2) and cytochrome P450 2E1 (CYP2E1) have been associated with hepatocellular carcinoma (HCC) susceptibility and prognosis. The polymorphisms ALDH2 rs671 and CYP2E1 rs2031920 are reportedly correlated with the prevalence of HCC in other countries. The aim of this study was to investigate associations between ALDH2 and CYP2E1, and HCC susceptibility in a population of Guangxi, southern China, an area with a high incidence of HCC.The study cohort included 300 HCC cases, 292 healthy controls for HCC susceptibility analysis, and another 20 HCC cases and 10 healthy controls for ascertainment. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method.The study results demonstrated that mutant genotypes of ALDH2 (G/A and A/A) led to significant differences in HCC susceptibility, as compared with the wild genotype (G/G) with the same C1/C1 genotype in non-drinking individuals (adjusted P=0.010, OR=0.20, 95% CI=0.06-0.68). The mutant genotypes of CYP2E1 (C1/C2 and C2/C2) brought about significant differences in HCC susceptibility, as compared with the wild genotype (C1/C1) and the same G/G genotype (adjusted P=0.025, OR=0.42, 95% CI=0.20-0.90). Drinking plays a role in HCC susceptibility in the same G/G genotype individuals (adjusted P=0.004, OR=0.32, 95% CI=0.15-0.69), but had no impact when combined with CYP2E1 for analysis (all P>0.05).These results suggest that the mutant genotypes of ALDH2 and CYP2E1 may be protective factors for HCC susceptibility in Guangxi province, China.
Project description:Gout is a common disease resulting from hyperuricemia. Recently, a genome-wide association study identified an association between gout and a single nucleotide polymorphism (SNP) rs2188380, located on an intergenic region between MYL2 and CUX2 on chromosome 12. However, other genes around rs2188380 could possibly be gout susceptibility genes. Therefore, we performed a fine-mapping study of the MYL2-CUX2 region. From 8,595 SNPs in the MYL2-CUX2 region, 9 tag SNPs were selected, and genotyping of 1,048 male gout patients and 1,334 male controls was performed by TaqMan method. Eight SNPs showed significant associations with gout after Bonferroni correction. rs671 (Glu504Lys) of ALDH2 had the most significant association with gout (P = 1.7 × 10(-18), odds ratio = 0.53). After adjustment for rs671, the other 8 SNPs no longer showed a significant association with gout, while the significant association of rs671 remained. rs671 has been reportedly associated with alcohol drinking behavior, and it is well-known that alcohol drinking elevates serum uric acid levels. These data suggest that rs671, a common functional SNP of ALDH2, is a genuine gout-associated SNP in the MYL2-CUX2 locus and that "A" allele (Lys) of rs671 plays a protective role in the development of gout.
Project description:Introduction: Recently, molecular epidemiological studies have suggested that aldehyde dehydrogenase 2 (ALDH2) rs671 G>A polymorphism may be a risk factor for ischemic stroke (IS). However, the results reported have not been consistent. Methods: We conducted the meta-analysis to explore the precise association between ALDH2 rs671 G>A polymorphism and IS risk. Five online databases were searched and the relative studies were reviewed from inception to October 1, 2018. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated in each genetic model of the general and subgroup. Furthermore, the heterogeneity, accumulative analyses, sensitivity analyses and publication bias were calculated simultaneously. Results: Overall, nine case-control studies involving 6,129 subjects were included in this meta-analysis. All studies were focused on the Chinese population and some significant associations were found between ALDH2 rs671 G>A polymorphism and IS risk (A vs G: OR=1.29, 95% CI=1.01-1.65, P=0.04, I2=78.2%; AA vs GG: OR=1.86, 95% CI=1.27-2.21, P<0.01, I2=11.3%; AA vs GG + GA: OR=1.67, 95% CI=1.27-2.19, P<0.01, I2=0%). Some significant and similar results were also observed in the subgroup analysis. Conclusion: Our meta-analysis indicates that the ALDH2 rs671 G>A polymorphism may play an important role in the occurrence of IS by reducing the activity of ALDH2 and interfering with the metabolic processes involving acetaldehyde.
Project description:A previous genome-wide association study identified two novel esophageal squamous cell carcinoma (ESCC) susceptibility genes, ADH1B and ALDH2. We investigated the characteristics of ESCC, and the relationship between metachronous esophageal and/or pharyngeal squamous cell carcinoma (SCC) and the ADH1B & ALDH2 risk alleles. One hundred and seventeen superficial ESCC patients who underwent treatment with endoscopic submucosal dissection (ESD) were followed up using endoscopy for ?12 months. First, we performed a replication analysis to confirm the relationship between ESCC and the ADH1B & ALDH2 risk alleles using 117 superficial ESCC cases and 1125 healthy controls. Next, we investigated the incidence and genetic/environmental factors associated with metachronous SCC development after ESD. We also analyzed the potential risk factors for metachronous SCC development using Cox's proportional hazards model. rs1229984 GG located on ADH1B and rs671 GA located on ALDH2 were significantly associated with ESCC progression (P = 7.93 × 10(-4) and P = 1.04 × 10(-5) ). Patients with rs1229984 GG, those with rs671 GA, smokers, heavy alcohol drinkers (44 g/day ethanol), and presence of multiple Lugol-voiding lesions (LVLs) developed metachronous SCC more frequently (P = 3.20 × 10(-3) , 7.00 × 10(-4) , 4.00 × 10(-4) , 2.15 × 10(-2) , and 4.41 × 10(-3) , respectively), with hazard ratios were 2.84 (95% confidence interval [CI] = 1.43-5.63), 4.57 (95% CI = 1.80-15.42), 4.84 (95% CI = 1.89-16.41), and 2.34 (95% CI = 1.12-5.31), respectively. Multiple logistic regression analysis revealed that rs1229984 GG, rs671 GA, and smoking status were independently associated with the risk of developing metachronous SCCs after ESD. Moreover, we found cumulative effects of these two genetic factors (rs1229984 GG and rs671 GA) and one environmental factor (tobacco smoking) which appear to increase metachrous SCCs after ESD of ESCC risk approximately nearly 12-fold. Our findings elucidated the crucial role of multiple genetic variations in ADH1B and ALDH2 as biomarkers of metachronous ESCC.
Project description:The effects of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 genotypes on the alcohol-blood pressure association are unclear. We examined the association of ADH2 or ALDH2 genotypes with blood pressure in older Chinese men. Based on the Guangzhou Biobank Cohort Study (GBCS), 4792 men with valid ADH2, ALDH2 genotypes were included, and genotyping of rs1229984 ADH2 and rs671 ALDH2 (AA, AG/GA or GG) was performed using a Sequenom Mass-Array platform. Information on socio-demographics and lifestyle factors, including alcohol use, was obtained from a questionnaire, and blood pressure was measured. Among alcohol drinkers, systolic and diastolic blood pressure (SBP and DBP) and mean arterial pressure (MAP) were highest for men with the GG ADH2 genotype (136.6, 77.9 and 97.5?mm?Hg, respectively), followed by those with the (AA/AG ADH2+GG ALDH2) genotype (133.4, 77.6 and 96.2?mm?Hg, respectively) and then the (AA/AG ADH2+AA/AG ALDH2) genotype (SBP=132.6, DBP=76.6 and MAP=95.2?mm?Hg) (P for trend ranged 0.025-0.035). After adjustment for potential confounders, as well as frequency or amount of alcohol use, men with the GG ADH2 genotype were more likely to have hypertension (odds ratio (OR)=1.62, 95% confidence interval 1.15-2.28) as were men with the (AA/AG ADH2+AA/AG ALDH2) genotype (OR=1.40, 95% confidence interval 1.01-1.96) compared with men with the (AA/AG ADH2+GG ALDH2) genotype). ADH2 or ALDH2 genotypes were unrelated to hypertension among those who never drink alcohol. ADH2 genotype influences blood pressure and risk of hypertension among male alcohol drinkers, suggesting that the hypertensive effect of alcohol is due to ethanol rather than acetaldehyde.
Project description:Alcoholic beverages are causally related to esophageal cancer. The genetic polymorphisms of the alcohol-metabolizing enzymes ADH1B rs1229984 and ALDH2 rs671 may modulate individual differences in alcohol-oxidizing capability. A case-control study was conducted to evaluate the genetic effects of these two functional single nucleotide polymorphisms (SNPs) on the development of esophageal cancer. A total of 380 esophageal squamous cell carcinoma cases and 380 controls were recruited. Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Variant alleles of the functional polymorphism ADH1B rs1229984 SNP were associated with an increased risk of esophageal cancer [adjusted odds ratio (OR)=2.39, 95% confidence interval (CI)=1.42-4.03 for ADH1B rs1229984 GG vs. AA]. There was a borderline-significantly decreased risk between the ALDH2 rs671 genotype and esophageal cancer (adjusted OR=0.47, 95% CI=0.22-1.00 for ALDH2 rs671 AA vs. GG). Stratified analyses indicated that both of these effects were more evident among male, younger subjects and smokers. In conclusion, the functional polymorphisms ADH1B rs1229984 and ALDH2 rs671 may contribute to susceptibility to esophageal cancer, particularly among male, younger subjects and smokers.