Association between Glu504Lys Polymorphism of ALDH2 Gene and Cancer Risk: A Meta-Analysis

Cai, Qiang; Wu, Jian; Cai, Qing; Chen, Erzhen; Jiang, Zhaoyan

doi:10.1371/journal.pone.0117173

Cited by 30 publications

(39 citation statements)

References 73 publications

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“…Considering the effects of randomization of the alleles of the ALDH2 genotype, the confounders can be considered to have been automatically adjusted in this analysis. Although the G allele was found to be predictive of increased alcohol intake, a protective effect in GG homozygotes compared to A allele carriers against cancer development has also been observed in previous studies [17, 20–23]. These findings have demonstrated that the systematic effect of acetaldehyde is greater than the direct effect of alcohol on the human body as a carcinogen.…”

Section: Discussionmentioning

confidence: 53%

Effects of alcohol consumption, ALDH2 rs671 polymorphism, and Helicobacter pylori infection on the gastric cancer risk in a Korean population

et al. 2016

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The effect of alcohol consumption on the risk of gastric cancer (GC) has not yet been fully elucidated, and an aldehyde dehydrogenase 2 (ALDH2) polymorphism, rs671, is a genetic variant that influences alcohol consumption in East Asians. Additionally, the discrepancy between the Helicobacter pylori (H. pylori) infection prevalence and GC incidence across Asian countries has not been explained. This study evaluated the effects of alcohol consumption and genetic susceptibility to defective acetaldehyde metabolism on the GC risk and their interactions with H. pylori infection. This study included 450 Korean GC cases and 1,050 controls recruited at the National Cancer Center. Data for 795 patients and 4,893 controls were used for further confirmation of the effect of rs671. Increased GC risks were evident for rs671 A allele carriers (odds ratio (OR), 1.23; 95% confidence interval (CI), 1.08-1.41) and H. pylori-infected individuals (OR, 7.07; 95% CI, 4.60-10.86), but no dose-response association with alcohol consumption was observed. Furthermore, the interactions between these factors were not significant. This study has demonstrated that alcohol consumption and rs671 should be considered simultaneously when assessing the GC risk. Additionally, alcohol-related factors were not found to interact with H. pylori infection, and further studies evaluating other environmental factors are required to explain the Asian enigma.

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Section: Discussionmentioning

confidence: 53%

Effects of alcohol consumption, ALDH2 rs671 polymorphism, and Helicobacter pylori infection on the gastric cancer risk in a Korean population

et al. 2016

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“…Alternatively, mutations or polymorphisms in ALDH genes, several of which have been described, could confer a hyper-responsiveness to glutamate levels that then drive the stemness phenotype. 49,50 For example, the glutamate to lysine single nucleotide polymorphism (Glu504Lys) was reported to have decreased activity of the ALDH enzyme and caused much higher blood levels of acetaldehyde; in a meta-analysis this showed an increased risk for cancer, especially esophageal cancer. 50 …”

Section: Discussionmentioning

confidence: 99%

Head and Neck Squamous Cell Carcinoma Metabolism Draws on Glutaminolysis, and Stemness Is Specifically Regulated by Glutaminolysis via Aldehyde Dehydrogenase

Kamarajan

Rajendiran²,

Kinchen

et al. 2017

J. Proteome Res.

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Cancer cells use alternate energetic pathways; however, cancer stem cell (CSC) metabolic energetic pathways are unknown. The purpose of this study was to define the metabolic characteristics of head and neck cancer at different points of its pathogenesis with a focus on its CSC compartment. UPLC-MS/MS-profiling and GC-MS-validation studies of human head and neck cancer tissue, saliva, and plasma were used in conjunction with in vitro and in vivo models to carry out this investigation. We identified metabolite biomarker panels that distinguish head and neck cancer from healthy controls, and confirmed involvement of glutamate and glutaminolysis. Glutaminase, which catalyzes glutamate formation from glutamine, and aldehyde dehydrogenase (ALDH), a stemness marker, were highly expressed in primary and metastatic head and neck cancer tissues, tumorspheres, and CSC versus controls. Exogenous glutamine induced stemness via glutaminase, whereas inhibiting glutaminase suppressed stemness in vitro and tumorigenesis in vivo. Head and neck CSC (CD44hi/ALDHhi) exhibited higher glutaminase, glutamate, and sphere levels than CD44lo/ALDHlo cells. Glutaminase drove transcriptional and translational ALDH expression, and glutamine directed even CD44lo/ALDHlo cells toward stemness. Glutaminolysis regulates tumorigenesis and CSC metabolism via ALDH. These findings indicate that glutamate is an important marker of cancer metabolism whose regulation via glutaminase works in concert with ALDH to mediate cancer stemness. Future analyses of glutaminolytic-ALDH driven mechanisms underlying tumorigenic transitions may help in the development of targeted therapies for head and neck cancer and its CSC compartment.

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“…Since 2007, numerous epidemiological studies have investigated the link between inheritance of the ALDH2*2 allele and cancer susceptibility in the context of alcohol consumption. A 2015 meta-analysis of ALDH2*2 and all cancers, revealed roughly 20% increased cancer risk in ALDH2*2 homozygous individuals [48]. In site-specific studies, potential linkages of the ALDH*2 genotype to colorectal, stomach, pancreatic, breast, and head and neck cancers have been suggested.…”

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

confidence: 99%

“…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%

“…The presence of an ALDH2*2 allele by itself is not causally associated with hypertension, rather consumption of alcohol in combination in individuals with the low activity variant which leads to an increase in acetaldehyde concentrations and in aids in the rapid diffusion of aldehydes across cellular membranes is causally associated with adverse physiological issues [1]. Those who express the wild type enzyme are less likely to develop disease from complications stemming from a decreased metabolic rate [28,42,48,50,51,69]. ALDH2*2 and disease unrelated to alcohol consumption: Ischemia occurs when blood flow to a certain tissue system is decreased, which can ultimately damage the tissue.…”

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

confidence: 99%

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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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Association between Glu504Lys Polymorphism of ALDH2 Gene and Cancer Risk: A Meta-Analysis

Cited by 30 publications

References 73 publications

Effects of alcohol consumption, ALDH2 rs671 polymorphism, and Helicobacter pylori infection on the gastric cancer risk in a Korean population

Effects of alcohol consumption, ALDH2 rs671 polymorphism, and Helicobacter pylori infection on the gastric cancer risk in a Korean population

Head and Neck Squamous Cell Carcinoma Metabolism Draws on Glutaminolysis, and Stemness Is Specifically Regulated by Glutaminolysis via Aldehyde Dehydrogenase

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

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