Meta-analysis of the ADH1B and ALDH2 Polymorphisms and the Risk of Colorectal Cancer in East Asians

Guo, Xufeng; Wang, Jun; Yu, Shijie; Song, Jia; Ji, Mengyao; Zhang, Jixiang; Cao, Zhuo; Wang, Jing; Dong, Weiguo

doi:10.2169/internalmedicine.52.1202

Cited by 19 publications

(21 citation statements)

References 21 publications

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“…Oxidative stress increases the risk of various types of pathophysiology, such as HT, Alzheimer's disease, myocardial infarction, coronary spastic angina, colorectal cancer, diabetic retinopathy, and bone marrow failure in Fanconi anemia patients among East Asians [28][29][30][31][32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Associations between aldehyde dehydrogenase 2 (ALDH2) genetic polymorphisms, drinking status, and hypertension risk in Japanese adult male workers: a case–control study

Ota

Hisada

et al. 2015

Environ Health Prev Med

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Objectives We sought to identify associations between aldehyde dehydrogenase 2 (ALDH2), alcohol consumption, and hypertension in Japanese men. Methods The study participants were 1,225 male Japanese workers. We collected lifestyle information, body measurements, blood biochemical parameters, blood pressure measurements, and ALDH2 genotyping data during medical examinations conducted between March 2004 and January 2005 at a work facility and an affiliated company. Lifestyle data on alcohol intake and smoking were collected using self-administered questionnaires at the same time as when the aforementioned measurements were obtained. Results The genotype frequencies of ALDH2 genetic polymorphisms were 62.6, 32.7, and 4.7 % for

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Section: Discussionmentioning

confidence: 99%

Associations between aldehyde dehydrogenase 2 (ALDH2) genetic polymorphisms, drinking status, and hypertension risk in Japanese adult male workers: a case–control study

Ota

Hisada

et al. 2015

Environ Health Prev Med

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“…People with the ALDH2*2 polymorphism are reported to be at a greater risk of developing esophageal and other digestive tract cancers (12)(13)(14)38), attributable to ACE-induced DNA damage and genome instability (39,40). Aldh2 E487K KI mice did not exhibit obvious damage in the esophagus or stomach after 2 mo of daily ethanol challenge, judged by histology evaluation.…”

Section: Increased Hepatocarcinogenesis By Aldh2(e487k)mentioning

confidence: 97%

“…As a result, Fanconi anemia patients with the ALDH2*2 allele exhibit accelerated disease progression (11). ALDH2*2 can also increase the risk for gastrointestinal cancers, such as gastric carcinoma (12), esophageal cancer (13), and colon cancer (14). Despite the liver being the major organ of ethanol detoxification, the relationship between ALDH2*2 and the risk for liver cancer remains unclear (15,16).…”

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confidence: 99%

ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis

Jin

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the liver removes toxic aldehydes including acetaldehyde, an intermediate of ethanol metabolism. Nearly 40% of East Asians inherit an inactive ALDH2*2 variant, which has a lysine-for-glutamate substitution at position 487 (E487K), and show a characteristic alcohol flush reaction after drinking and a higher risk for gastrointestinal cancers. Here we report the characterization of knockin mice in which the ALDH2(E487K) mutation is inserted into the endogenous murine Aldh2 locus. These mutants recapitulate essentially all human phenotypes including impaired clearance of acetaldehyde, increased sensitivity to acute or chronic alcohol-induced toxicity, and reduced ALDH2 expression due to a dominant-negative effect of the mutation. When treated with a chemical carcinogen, these mutants exhibit increased DNA damage response in hepatocytes, pronounced liver injury, and accelerated development of hepatocellular carcinoma (HCC). Importantly, ALDH2 protein levels are also significantly lower in patient HCC than in peritumor or normal liver tissues. Our results reveal that ALDH2 functions as a tumor suppressor by maintaining genomic stability in the liver, and the common human ALDH2 variant would present a significant risk factor for hepatocarcinogenesis. Our study suggests that the ALDH2*2 allele-alcohol interaction may be an even greater human public health hazard than previously appreciated. ALDH2*2 polymorphism | Asian flush | alcohol metabolism | mouse model | liver cancer M itochondrial aldehyde dehydrogenase 2 (ALDH2) is essential for alcohol detoxification. It is the second enzyme in the major oxidative pathway of alcohol metabolism, removing acetaldehyde (ACE), a toxic intermediate product from ethanol metabolism (1). More than 500 million people worldwide, mostly in East Asia, have a G-to-A point mutation in their ALDH2 gene (2, 3). This mutation results in a glutamic acid-to-lysine substitution at residue 487 (E487K) of the human ALDH2 protein (designated ALDH2*2). ALDH2*2 has significantly reduced ability to metabolize ACE (4, 5). Importantly, its activity is partially dominant-negative over that of the wild-type ALDH2*1, due to the structural alterations introduced by the mutation to the ALDH2 homotetramer complex (6). As a result, individuals with a heterozygous ALDH2*2/2*1 genotype have less than half the wild-type activity, and ALDH2*2/2*2 homozygotes have very low residual activity (7). Accumulated ACE can cause an alcohol flush reaction, commonly found in Asians with this variant after alcohol consumption (also called "Asian glow").ACE binds to cellular proteins and DNA, leading to DNA damage and organ injury (8). Specifically, endogenous aldehydes are detrimental to hematopoietic stem cells that are defective in Fanconi anemia DNA repair (9, 10). As a result, Fanconi anemia patients with the ALDH2*2 allele exhibit accelerated disease progression (11). ALDH2*2 can also increase the risk for gastrointestinal cancers, such as gastric carcinoma (12), esophagea...

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“…All these features are limitations of previous conventional observational studies . Mendelian randomisation has already been used successfully in both cardiovascular and cancer epidemiology to clarify the causal effects of alcohol on disease.…”

Section: Introductionmentioning

confidence: 99%

Alcohol consumption and prostate cancer incidence and progression: A Mendelian randomisation study

Brunner

Davies

Martin

et al. 2016

Intl Journal of Cancer

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Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol‐metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study‐specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol‐metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer‐specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta‐analysed using fixed‐effect and random‐effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed‐effect meta‐analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low‐grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression.

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Meta-analysis of the ADH1B and ALDH2 Polymorphisms and the Risk of Colorectal Cancer in East Asians

Cited by 19 publications

References 21 publications

Associations between aldehyde dehydrogenase 2 (ALDH2) genetic polymorphisms, drinking status, and hypertension risk in Japanese adult male workers: a case–control study

Associations between aldehyde dehydrogenase 2 (ALDH2) genetic polymorphisms, drinking status, and hypertension risk in Japanese adult male workers: a case–control study

ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis

Alcohol consumption and prostate cancer incidence and progression: A Mendelian randomisation study

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