Clinical significance of ALDH2 rs671 polymorphism in esophageal cancer: evidence from 31 case-control studies

Zhao, Tingting; Wang, Chun; Song, Lili; Gu, Dongying; Xu, Zhi; Zhang, Xunlei; Xu, Yong; Chen, Jinfei

doi:10.2147/ott.s76526

Cited by 25 publications

(35 citation statements)

References 52 publications

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“…non‐flushers were 1.02 (0.53, 1.99) among non‐ or light consumers (<200 g/week), 2.54 (1.64, 3.91) among moderate consumers (200–390 g/week) and 2.90 (1.82, 4.62) among heavy consumers (>390 g/week) . Several previous Chinese studies also showed increased EC risk associated with GA heterozygotes among non‐consumers or consumers of ≤30 g/d …”

Section: Discussionmentioning

confidence: 91%

“…The rs671 GA heterozygotes were linked to an increased EC risk (OR = 2.34; 95% CI: 1.75, 3.13) in a recent meta‐analysis of 31 case–control studies, almost exclusively conducted in China and Japan . The OR (95% CI) of GA heterozygotes for EC was 1.21 (0.95, 1.73) among non‐alcohol consumers, 3.79 (3.04, 4.72) among light consumers (1–350 g/week of alcohol) and 6.50 (5.34, 7.92) among heavy consumers (≥350 g/week of alcohol).…”

Section: Discussionmentioning

confidence: 97%

“…It has been suggested that there is an association between ALDH2 genotype and EC risk which is dependent on alcohol consumption. In a meta‐analysis of 31 case–control studies, the possession of inactive ALDH2 does not increase EC risk unless alcohol is consumed . Numerous case–control studies, almost exclusively conducted in Asian populations, have addressed the association of EC with ALDH2 genotype or self‐reported facial flushing as a surrogate marker of inactive ALDH2 .…”

Section: Introductionmentioning

confidence: 99%

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Association of low‐activity ALDH2 and alcohol consumption with risk of esophageal cancer in Chinese adults: A population‐based cohort study

Guo

Zheng

et al. 2018

Intl Journal of Cancer

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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); p interaction = 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); p interaction = 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.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Association of low‐activity ALDH2 and alcohol consumption with risk of esophageal cancer in Chinese adults: A population‐based cohort study

Guo

Zheng

et al. 2018

Intl Journal of Cancer

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“…In site-specific studies, potential linkages of the ALDH*2 genotype to colorectal, stomach, pancreatic, breast, and head and neck cancers have been suggested. A subset of these sitespecific cancers have been further investigated via meta-analyses [48][49][50]. Nonetheless, weak associations and study limitations prevent sweeping conclusions regarding the role(s) of ALDH2*2 inheritance in cancer risk.…”

Section: Diseases Associated With the Inheritance Of Aldh2*2mentioning

confidence: 99%

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

Gueldner¹,

Sayes²,

Abel³

et al. 2016

J Drug Metab Toxicol

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Ethanol is metabolized by Alcohol Dehydrogenase (ADH) to acetaldehyde and then irreversibly oxidized by Aldehyde Dehydrogenase (ALDH) to nontoxic acetate. In individuals expressing the ALDH2*2 variant enzyme, the rate of conversion from acetaldehyde to acetate is reduced and leads to flushing, nausea, and tachycardia due to increased blood levels of acetaldehyde. The ALDH2*2 variant has a lowered NAD + coenzyme binding affinity, which results in a lowered clearance capacity toward acetaldehyde. This polymorphism is caused by the substitution of glutamate for lysine at position 487 within the catalytic active site of ALDH2, resulting in effects on subunit and quaternary complex activity. ALDH2*2 alleles are dominant over ALDH2*1 and therefore are expected to contribute to the formation of inactive heterotetramers decreased enzymatic activity in both homozygous and heterozygous individuals. Consequently, a higher susceptibility to various diseases such as Alzheimer's, osteoporosis, and acute coronary syndrome has been associated with ALDH2*2 carriers. Additionally, the polymorphism seems to affect the efficacy of Glyceryl Trinitrate (GTN), a drug intended to treat coronary heart disease, in carriers of ALDH2*2 alleles. However, the polymorphism is believed to afford a protective effect against alcoholism as the side effects of acetaldehyde build-up are undesirable. Disulfiram, a drug historically used to treat alcohol dependency, induces the same undesirable physiological effects as the variant enzyme in non-carriers by inhibiting the normal functioning of ALDH2 enzyme.

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“…The genetic background of residents from high- and low-incidence areas for both GCA and ESCC may be different. Previous reports including our GWAS studies show that alcohol drinking interacted with ALDH2 (rs671) on ESCC susceptibility 7,32,33 . Owing to the similar underlying molecular mechanism involved in both GCA and ESCC, the researchers found that the rs671 variation might interact with alcohol consumptions on GCA susceptibility.…”

Section: Discussionmentioning

confidence: 54%

Association of genotypes of rs671 within <i>ALDH2</i> with risk for gastric cardia adenocarcinoma in the Chinese Han population in high- and low-incidence areas

Zhang

Song

Zhao

et al. 2017

Cancer Biology &Amp; Medicine

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Objective: This study aimed to determine if gastric cardia adenocarcinoma (GCA) risk was associated with the lys (A or *2) allele at the rs671 (glu504lys) polymorphism within the aldehyde dehydrogenase 2 (ALDH2) gene in a Chinese Han population. We also aimed to investigateALDH2 genotypic distributions between subjects from high- and low-incidence areas for both GCA and esophageal squamous cell carcinoma (ESCC). Methods: We designed a case-control study including 2,686 patients with GCA and 3,675 control subjects from high- and low-incidence areas for both GCA and ESCC in China. TaqMan allele discrimination assay was used to genotype the rs671 polymorphism.χ2 test and binary logistic regression analysis were used to estimate the odds ratios for the development of GCA, and multivariate ordinal logistic regression was used to analyzeALDH2 genotypic distributions among different groups. Results: Compared withALDH2*1/*1 homozygotes,ALDH2*1/*2 andALDH2*2/*2 carriers did not increase the risk for GCA in the Chinese Han population (P>0.05). Interestingly, the ratio of homozygous or heterozygousALDH2 *2 carriers in high-incidence areas for both GCA and ESCC was lower than that in low-incidence areas (P<0.001). Conclusions: Genotypes of rs671 atALDH2 may not increase GCA susceptibility in Chinese Han populations. In addition, theALDH2 genotypic distribution differs between Chinese Han populations from high- and low-incidence areas for both GCA and ESCC. Our findings may shed light on the possible genetic mechanism for the dramatic geographic differences of GCA occurrence in China.

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Clinical significance of ALDH2 rs671 polymorphism in esophageal cancer: evidence from 31 case-control studies

Cited by 25 publications

References 52 publications

Association of low‐activity ALDH2 and alcohol consumption with risk of esophageal cancer in Chinese adults: A population‐based cohort study

Association of low‐activity ALDH2 and alcohol consumption with risk of esophageal cancer in Chinese adults: A population‐based cohort study

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

Association of genotypes of rs671 within <i>ALDH2</i> with risk for gastric cardia adenocarcinoma in the Chinese Han population in high- and low-incidence areas

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