Aldehyde Dehydrogenase 2 Gene Research Articles

Effectiveness of genetic feedback on alcohol metabolism to reduce alcohol consumption in young adults: an open-label randomized controlled trial

BackgroundIt is unclear whether brief interventions using the combined classification of alcohol-metabolizing enzymes aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) together with behavioral changes in alcohol use can reduce excessive alcohol consumption. This study aimed to examine the effects of a brief intervention based on the screening of ALDH2 and ADH1B gene polymorphisms on alcohol consumption in Japanese young adults.MethodsIn this open-label randomized controlled trial, we enrolled adults aged 20–30 years who had excessive drinking behavior (average amount of alcohol consumed: men, ≥ 4 drinks/per day and women, ≥ 2 drinks/per day; 1 drink = 10 g of pure alcohol equivalent). Participants were randomized into intervention or control group using a simple random number table. The intervention group underwent saliva-based genotyping of alcohol-metabolizing enzymes (ALDH2 and ADH1B), which were classified into five types. A 30-min in-person or online educational counseling was conducted approximately 1 month later based on genotyping test results and their own drinking records. The control group received traditional alcohol education. Average daily alcohol consumption was calculated based on the drinking diary, which was recorded at baseline and at 3 and 6 months of follow-up. The primary endpoint was average daily alcohol consumption, and the secondary endpoints were the alcohol-use disorder identification test for consumption (AUDIT-C) score and behavioral modification stages assessed using a transtheoretical model.ResultsParticipants were allocated to the intervention (n = 100) and control (n = 96) groups using simple randomization. Overall, 28 (29.2%) participants in the control group and 21 (21.0%) in the intervention group did not complete the follow-up. Average alcohol consumption decreased significantly from baseline to 3 and 6 months in the intervention group but not in the control group. The reduction from baseline alcohol consumption values and AUDIT-C score at 3 months were greater in the intervention group than in the control group (p < 0.001). In addition, the behavioral modification stages were significantly changed by the intervention (p < 0.001).ConclusionsGenetic testing for alcohol-metabolizing enzymes and health guidance on type-specific excessive drinking may be useful for reducing sustained average alcohol consumption associated with behavioral modification.Trial registrationR000050379, UMIN000044148, Registered on June 1, 2021.

Research Progress on the Correlation between Acetaldehyde Dehydrogenase 2 and Hepatocellular Carcinoma Development.

Hepatocellular carcinoma (HCC) is the predominant pathologic type of primary liver cancer. It is a malignant tumor of liver epithelial cells. There are many ways to treat HCC, but the survival rate for HCC patients remains low. Therefore, understanding the underlying mechanisms by which HCC occurs and develops is critical to explore new therapeutic targets. Aldehyde dehydrogenase 2 (ALDH2) is an important player in the redox reaction of ethanol with endogenous aldehyde products released by lipid peroxidation. Increasing evidence suggests that ALDH2 is a crucial regulator of human tumor development, including HCC. Therefore, clarifying the relationship between ALDH2 and HCC is helpful for formulating rational treatment strategies. This review highlights the regulatory roles of ALDH2 in the development of HCC, elucidates the multiple potential mechanisms by which ALDH2 regulates the development of HCC, and summarizes the progress of research on ALDH2 gene polymorphisms and HCC susceptibility. Meanwhile, we envision viable strategies for targeting ALDH2 in the treatment of HCC SIGNIFICANCE STATEMENT: Numerous studies have aimed to explore novel therapeutic targets for HCC, and ALDH2 has been reported to be a critical regulator of HCC progression. This review discusses the functions, molecular mechanisms, and clinical significance of ALDH2 in the development of HCC and examines the prospects of ALDH2-based therapy for HCC.

Study based on the acetaldehyde dehydrogenase 2 gene polymorphism and acetaminophen-induced liver injury

Objective: To explore the association between aldehyde dehydrogenase 2 (ALDH2) gene polymorphisms and abnormal liver function-induced by acetaminophen (APAP) drugs. Methods: An ALDH2 gene knockout mouse model was constructed using CRISPR/Cas9 gene editing technology. The obtained heterozygous mice were mated with opposite sex of heterozygotes. Genomic DNA was extracted from the tail of the offspring mouse. The polymerase chain reaction (PCR) method was used to determine the ALDH2 genotype. APAP was further used to induce acute drug-induced liver injury models in wild-type and ALDH2 knockout mice. Blood and liver tissues of mice were collected for liver function index, HE staining, F4/80 immunohistochemistry, and other detections. The intergroup mean was compared using a one-way ANOVA. The LSD- t test was used for pairwise comparison. Results: ALDH2 knockout mice were bred successfully. The genotyping of the offspring was segregated into the wild-type (ALDH2(+/+)), heterozygous mutant (ALDH2(+/-)), and homozygous mutant (ALDH2(-/-)), respectively. Biochemical and histological results after APAP modeling showed that the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBil) was not significantly increased in the blank control group (P < 0.05), while the ALT, AST,ALP, and TBil were all elevated in the APAP experimental group. The levels of ALT (P = 0.004), AST (P = 0.002), and TBil (P = 0.012) were significantly elevated among the mutant group compared to those in the wild-type group, and the expression levels of these indicators were also significantly elevated among the homozygous mutant group compared to those in the heterozygous mutant group (P = 0.003, 0 and 0.006). In addition, the ALP levels were higher in the heterozygous mutation group than those in the homozygous mutant group (P = 0.085) and wild-type group mice, but the difference was only statistically significant compared to wild-type mice (P = 0.002). HE staining results showed that mice in the APAP experimental group had hepatocyte degeneration, necrosis, and increased inflammatory cell infiltration, which was mostly evident in mutant mice. Simultaneously, the F4/80 immunohistochemical staining results showed that brown granules were visible in the liver tissue of APAP experimental group mice, and its expression levels were significantly enhanced compared to the blank control group. Conclusion: APAP-induced liver function abnormalities were associated with the ALDH2 gene polymorphism. The liver injury symptoms were increased in ALDH2 mutant mice following APAP modeling, and the ALDH2 gene defect may alleviate, to some extent, APAP-induced liver function abnormalities.

ALDH2 deficiency exacerbates MCD-diet induced MASLD by modulating bile acid metabolism

Aldehyde dehydrogenase 2 (ALDH2), an acetaldehyde dehydrogenase in mitochondria, is primarily responsible for metabolizing alcohol-derived acetaldehyde and other endogenous aldehydes. Inactivating ALDH2 rs671 polymorphism is found in up to 8 % of the global population and 40 % of the East Asian population. Recent studies have shown that rs671 SNP mutation in the human ALDH2 gene is associated with an increased risk of metabolic dysfunction-associated steatotic liver diseases (MASLD), but the mechanism remains unclear. Here, we identify the role of ALDH2 in MASLD. Firstly, ALDH2 activity was lower in MASLD patients and the methionine-choline deficiency (MCD) diet induced MASLD model. Secondly, activation of ALDH2 activity with Alda-1 (ALDH2 agonist) attenuated MCD-diet induced hepatic triglyceride (TG) accumulation and steatosis, whereas the opposite result was observed with cyanamide (CYA, ALDH2 inhibitor). Furthermore, ALDH2 deficiency exacerbated hepatic steatosis, inflammation, and fibrosis in the MCD-diet induced mice. RNA sequencing (RNA-seq) revealed that oxysterol 7-α hydroxylase (Cyp7b1) and the related metabolic pathway significantly changed in the MCD-diet challenged ALDH2−/− mice. In ALDH2−/− mice, the expression of Cyp7b1 was downregulated and FXR/SHP signaling was inhibited, reducing the alternative bile acid (BA) synthetic pathway. In our in vitro experiments, knockdown of ALDH2 exacerbated TG accumulation in hepatocytes, whereas the opposite result was observed with overexpression of ALDH2. Moreover, chenodeoxycholic acid (CDCA) rescued ALDH2 downregulation induced TG accumulation in hepatocytes. Our study reveals that ALDH2 attenuates hepatocyte steatosis by regulating the alternative BA synthesis pathway, and ALDH2 may serve as a potential target for the treatment of MASLD.

Analysis of Correlation Between Coronary Heart Disease and Genetic Polymorphism Detected by Gold Magnetic Nanoparticles Chromatography.

It aimed to explore the correlation of Glu504Lys locus mutation of aldehyde dehydrogenase-2 (ALDH2) with coronary heart disease (CHD) based on gold magnetic nanoparticles (GMNPs) chromatography and amplification refractory mutation system-PCR (ARMS-PCR). 120 CHD patients admitted to the cardiovascular Department of Wenling First People's Hospital affiliated to Wenzhou Medical University from December 2020 to December 2021 were selected as Case group and 80 non-CHD patients admitted during the same period were selected as Ctrl group. The venous blood and indexes of Total Cholesterol (TC), Triglyceride (TG), Low Density Lipoprotein Cholesterol (LDL-C), High Density Lipoprotein Cholesterol (HDL-C), and Fasting Blood Glucose (FBS) were collected. The ARMS-PCR GMNPs chromatography based on ARMS-PCR and immunochromatography assay was adopted to detect gene polymorphism of ALDH2. Correlation between ALDH2 gene polymorphism and risk factors of CHD was analyzed via logistic regression. In contrast to Ctrl group, the genotypes of GG, GA, and AA in Case group were evidently different (P < 0.05), and the frequency of A allelic gene was obviously increased (P < 0.05). Under the dominant model, frequency of GA + AA genotype in Case group was remarkably higher in contrast to Ctrl group (P < 0.05). Under the recessive model, there was no obvious difference in genotype frequency between two groups. In contrast to Ctrl group, TC, LDL-C, and FBS in Case group were notably increased (P < 0.05), while HDL-C was notably decreased (P < 0.05). The distribution frequency of abnormal LDL-C, HDL-C, and FBS in Case group was notably higher in contrast to Ctrl group (P < 0.05). LDL-C and FBS had no obvious effect on the genotypes and frequency distribution of alleles in CHD patients. However, the frequency distribution of genotypes of GA and AA and A allelic gene in patients with abnormal HDL-C was notably lower in contrast to those with normal HDL-C (P < 0.05). Logistic regression analysis showed that abnormal HDC-C with A allelic gene were independent risk factors for CHD (P = 0.001, OR = 1.934). The gene polymorphism of Glu504Lys locus of ALDH2 was closely related to the pathogenesis of CHD, A allelic gene may be a susceptibility gene for CHD, and patients with abnormal HDC-C and carried A allelic gene had relatively higher incidence of CHD.

SLC3A2, as an indirect target gene of ALDH2, exacerbates alcohol-associated liver cancer via the sphingolipid biosynthesis pathway.

Excessive drinking is one of the main causes of liver cancer. In the process of alcohol metabolism, aldehyde dehydrogenase 2 (ALDH2) is the key enzyme of acetaldehyde metabolism. ALDH2 gene deficiency is positively associated with the risk of hepatocellular carcinoma (HCC). However, no studies have shown a connection between ALDH2 and another metabolic regulatory gene, SLC3A2. In this study, we analyzed the expression levels of ALDH2 and SLC3A2 in liver cancer tissues based on the TCGA database. Subsequently, we constructed ALDH2 knockout and SLC3A2 knock-in transgenic mice to check the roles of ALDH2 and SLC3A2 in tumorigenesis in vivo. In addition, we examined the mechanisms of ALDH2 and SLC3A2 in HCC cells using small RNA interference technology. Consistent with previous studies, we also confirmed the functions of ALDH2 in inhibiting hepatocarcinogenesis, while SLC3A2 had the opposite effect. The main finding of this study is that ALDH2 inhibited BSG expression through the TGF-β1 pathway, which indirectly inhibited SLC3A2 expression; subsequently, the sphingolipid metabolism pathway was also inhibited in HCC cells. Therefore, SLC3A2 is a novel target for HCC treatment.

Aldehyde dehydrogenase 2 rs671 genetic polymorphisms are associated with chemotherapy-induced nausea and vomiting

To investigate the correlation between aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphisms and chemotherapy-induced nausea and vomiting (CINV). A total of 90 Chinese patients with malignant tumors receiving chemotherapy for the first time were recruited in this study. The occurrence of CINV was observed within 120 h after treatment with docetaxel and cis-platinum chemotherapy (DP regimen). The data of the patients (including age, gender, tumor stage, habitual alcohol consumption, motion sickness, morning sickness, and average sleep time prior to chemotherapy) were collected through a questionnaire. ALDH2 rs671 polymorphisms of the patients were analyzed using a multiple single nucleotide polymorphism genotyping, and the Hardy-Weinberg equation was used for genetic linkage analysis. The correlations between the factors including ALDH2 rs671 polymorphisms and the occurrence of CINV were analyzed. The incidence of CINV was 48.9% among the patients receiving their first chemotherapy with DP regimen. Univariate analysis indicated that the genetic polymorphisms of ALDH2 rs671 were significantly correlated with the occurrence of CINV (P < 0.05). Multivariate logistic analysis indicated that ALDH2 rs671 mutation (OR: 3.019, 95% CI: 1.056-8.628, P < 0.05) and average sleep time prior to chemotherapy no longer than 6 h (OR: 2.807, 95% CI: 1.033-7.628, P < 0.05) were risk factors for CINV in patients with malignant tumors receiving the first chemotherapy with DP regimen. ALDH2 gene mutation at rs671 is a risk factor contributing to the occurrence of CINV, and understanding of the underlying mechanism may help to more effectively control the occurrence of CINV.

Patients with Non-Alcoholic Fatty Liver Disease and Alcohol Dehydrogenase 1B/Aldehyde Dehydrogenase 2 Mutant Gene Have Higher Values of Serum Alanine Transaminase.

Patients with non-alcoholic fatty liver disease (NAFLD) share similar pathophysiologies to those of patients with alcohol liver disease. Alcoholic metabolic enzyme-related genes (alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2)) may be associated with pathophysiology in NAFLD patients. In this study, the association between ADH1B/ALDH2 gene polymorphism and serum metabolic factors, body statures, and hepatic steatosis/fibrosis status was evaluated in patients with NAFLD. Using biochemistry data, abdominal ultrasonography, fibrosis evaluation (Kpa), and steatosis evaluation (CAP), ADH1B gene SNP rs1229984 and ALDH2 gene SNP rs671 polymorphism were analyzed in sixty-six patients from 1 January 2022 to 31 December 2022. The percentage of the mutant type (GA + AA) was 87.9% (58/66) in the ADH1B allele and 45.5% (30/66) in the ALDH2 allele. Patients with the mutant-type ADH1B/ALDH2 allele had higher values of alanine aminotransferase (ALT) than the wild type (β = 0.273, p = 0.04). No association was observed between body mass index, serum metabolic factors (sugar and lipid profile), CAP, kPa, and ADH1B/ALDH2. A high proportion of the mutant-type ADH1B allele (87.9%) and ALDH2 allele (45.5%) was observed in patients with NAFLD. No association was observed between ADH1B/ALDH2 allele, BMI, and hepatic steatosis/fibrosis. Patients with the mutant-type ADH1B/ALDH2 allele had higher values of ALT than those with the wild type.

ALDH2 as a potential stem cell-related biomarker in lung adenocarcinoma: Comprehensive multi-omics analysis

Lung adenocarcinoma (LUAD) is the most prevalent lung cancer and one of the leading causes of death. Previous research found a link between LUAD and Aldehyde Dehydrogenase 2 (ALDH2), a member of aldehyde dehydrogenase gene (ALDH) superfamily. In this study, we identified additional useful prognostic markers for early LUAD identification and targeting LUAD therapy by analyzing the expression level, epigenetic mechanism, and signaling activities of ALDH2 in LUAD patients. The obtained results demonstrated that ALDH2 gene and protein expression significantly downregulated in LUAD patient samples. Furthermore, The American Joint Committee on Cancer (AJCC) reported that diminished ALDH2 expression was closely linked to worse overall survival (OS) in different stages of LUAD. Considerably, ALDH2 showed aberrant DNA methylation status in LUAD cancer. ALDH2 was found to be downregulated in the proteomic expression profile of several cell biology signaling pathways, particularly stem cell-related pathways. Finally, the relationship of ALDH2 activity with stem cell-related factors and immune system were reported. In conclusion, the downregulation of ALDH2, abnormal DNA methylation, and the consequent deficit of stemness signaling pathways are relevant prognostic and therapeutic markers in LUAD.

ALDH2 deficiency increases susceptibility to binge alcohol-induced gut leakiness, endotoxemia, and acute liver injury in mice through the gut-liver axis

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme responsible for metabolizing toxic acetaldehyde to acetate and acts as a protective or defensive protein against various disease states associated with alcohol use disorder (AUD), including alcohol-related liver disease (ARLD). We hypothesized that Aldh2-knockout (KO) mice are more susceptible to binge alcohol-mediated liver injury than wild-type (WT) mice through increased oxidative stress, gut leakiness and endotoxemia. Therefore, this study aimed to investigate the protective role of ALDH2 in binge alcohol-induced gut permeability, endotoxemia, and acute inflammatory liver injury by exposing Aldh2-KO or WT mice to a single oral dose of binge alcohol 3.5, 4.0, or 5.0 g/kg. Our findings showed for the first time that ALDH2 deficiency in Aldh2-KO mice increases their sensitivity to binge alcohol-induced oxidative and nitrative stress, enterocyte apoptosis, and nitration of gut tight junction (TJ) and adherent junction (AJ) proteins, leading to their degradation. These resulted in gut leakiness and endotoxemia in Aldh2-KO mice after exposure to a single dose of ethanol even at 3.5 g/kg, while no changes were observed in the corresponding WT mice. The elevated serum endotoxin (lipopolysaccharide, LPS) and bacterial translocation contributed to systemic inflammation, hepatocyte apoptosis, and subsequently acute liver injury through the gut-liver axis. Treatment with Daidzin, an ALDH2 inhibitor, exacerbated ethanol-induced cell permeability and reduced TJ/AJ proteins in T84 human colon cells. These changes were reversed by Alda-1, an ALDH2 activator. Furthermore, CRISPR/Cas9-mediated knockout of ALDH2 in T84 cells increased alcohol-mediated cell damage and paracellular permeability. All these findings demonstrate the critical role of ALDH2 in alcohol-induced epithelial barrier dysfunction and suggest that ALDH2 deficiency or gene mutation in humans is a risk factor for alcohol-mediated gut and liver injury, and that ALDH2 could be an important therapeutic target against alcohol-associated tissue or organ damage.

ALDH2 gene polymorphism is associated with fitness in the elderly Japanese population

PurposeThe aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which is exclusive to the Asian population, is related to many diseases. A high reactive oxygen species production in mitochondria, and low muscle strength in athletes and non-athletes, has been observed, as our previous study demonstrated. The purpose of this research was to investigate the influence of ALDH2 rs671 on the loss of muscle strength with aging and replicate our previous study in non-athletes.MethodsHealthy Japanese individuals (n = 1804) aged 23–94 years were genotyped using DNA extracted from saliva. Muscle strength was assessed using grip strength and chair stand test (CST). The interaction between age and genotypes was analyzed by two-way analysis of covariance (ANCOVA) adjusted for sex, body mass index (BMI), and exercise habit.ResultsIndividuals aged ≧55 with the AA genotype had a lower performance than those with the GG + GA genotype in the grip strength test (28.1 ± 9.1 kg vs. 29.1 ± 8.3 kg, p = 0.021). There was an interaction between age and genotype, where individuals with ≧55 years old AA genotype had a higher loss of strength compared to GG + GA genotypes in the CST (0.025). No interaction in other models and no sex differences were found.ConclusionThis study replicated previous results of the relationship between the AA genotype with lower muscle strength and as a novelty showed that this genotype is associated with a higher age-related loss of strength.

Aldehyde dehydrogenase 2 polymorphism is associated with chemotherapy-related cognitive impairment in patients with breast cancer who receive chemotherapy.

Chemotherapy-related cognitive impairment (CRCI) is a common but easily overlooked condition that markedly affects the quality of life (QOL) of patients with breast cancer. The rs671 is a common gene polymorphism of aldehyde dehydrogenase 2 (ALDH2) in Asia that is involved in aldehyde metabolism and may be closely related to CRCI. However, no study has yet summarised the association between ALDH2 and CRCI. This study enrolled one hundred and twenty-four patients diagnosed with breast cancer according to the pathology results, genotyped for ALDH2 single-nucleotide polymorphisms (SNP) to explore these. The mini-mental state exam (MMSE), verbal fluency test (VFT), and digit span test (DST) results were compared in these patients before and after chemotherapy (CT). We found that patients with ALDH2 gene genotypes of rs671_GG, rs886205_GG, rs4648328_CC, and rs4767944_TT polymorphisms were more likely to suffer from cognitive impairment during chemotherapy. A trend toward statistical significance was observed for rs671_GG of DST (z=2.769, p=0.006), VFT (t=4.624, P<0.001); rs886205_GG of DST (z=3.663, P<0.001); rs4648328_CC of DST (z=2.850, p=0.004), VFT (t=3.477, p=0.001); and rs4767944_TT of DST (z=2.967, p=0.003), VFT (t=2.776, p=0.008). The cognitive indicators of these patients significantly decreased after chemotherapy (p < 0.05). The difference in ALDH2 rs671 was most obvious. Our results showed what kinds of ALDH2 genotyped patients that are more likely to develop CRCI. In the future, it may be possible to infer the risk of CRCI by detecting the single-nucleotide locus of ALDH2 that is conducive to strengthening clinical interventions for these patients and improving their QOL. More importantly, this study has important implications for Asian women with breast cancer as ALDH2 rs671 is a common polymorphism in Asians.

Aldehyde dehydrogenase 2 and arrhythmogenesis.

Cardiac arrhythmia is a common cardiovascular disease that leads to considerable economic burdens and significant global public health challenges. Despite the remarkable progress made in recent decades, antiarrhythmic therapy remains suboptimal. Aldehyde dehydrogenase 2 (ALDH2), a critical detoxifying enzyme, catalyzes toxic aldehydes and protects individuals from damage caused by oxidative stress. Accumulating evidence has demonstrated that ALDH2 activation has potential antiarrhythmic benefits. The correlation between ALDH2 deficiency and arrhythmogenesis has been widely recognized. In this review, we summarize recent research on the potential role of ALDH2 activation and antiarrhythmic protection, as well as the role played by the ALDH2∗2 polymorphism (rs671) in promoting arrhythmic risk. Additionally, we discuss important new findings illustrating the use of ALDH2 activators, which may prove to be promising antiarrhythmic therapy agents.

ALDH2 Polymorphism rs671 *1/*2 Genotype is a Risk Factor for the Development of Alcoholic Liver Cirrhosis in Hakka Alcoholics.

BackgroundAlcoholics are prone to alcoholic cirrhosis (ALC). Aldehyde dehydrogenase 2 (ALDH2) is involved in alcohol metabolism. Herein, the relationship between ALDH2 genotypes and ALC was analyzed among Hakka alcoholics in southern China.MethodsA total of 213 alcoholics and 214 non-alcoholics were included in the study. The ALDH2 gene rs671 polymorphism was analyzed, life history, disease history, and auxiliary examination results of these participants were collected.ResultsThe alcoholics had higher level of total serum protein, and serum globulin, lower level of serum albumin, serum albumin/globulin ratio, serum prealbumin, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) than non-alcoholics. In the 213 alcoholics, 180 developed ALC. There were 206 non-ALC persons in the 214 non-alcoholics. The proportion of the ALDH2 rs671 G/G homozygous (*1/*1) was significantly lower in ALC patients (83.3%) than that of other groups (100.0% in non-ALC in alcoholics, 95.6% in non-ALC in non-alcoholics), while the proportion of the G/A heterozygous (*1/*2) was significantly higher in ALC patients (16.7%) than that of other groups (0% in non-ALC in alcoholics, 4.4% in non-ALC in non-alcoholics). Logistic regression analysis indicated that participants with low level of NLR (adjusted OR 5.543, 95% CI 2.964–10.368, P<0.001), LMR (adjusted OR 9.256, 95% CI 4.740–18.076, P<0.001), and PLR (adjusted OR 6.047, 95% CI 3.372–10.845, P<0.001), and ALDH2 G/A genotype (adjusted OR 6.323, 95% CI 2.477–16.140, P<0.001) had a significantly higher risk of ALC.ConclusionALDH2 polymorphism rs671 *1/*2 genotype is a potential risk factor for the development of ALC among Hakka alcoholics.

Single nucleotide polymorphism genotyping of ALDH2 gene based on asymmetric PCR and fluorescent probe-mediated melting curves

Detection of single nucleotide polymorphisms (SNPs) is of great value in precision medicine. The polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene is caused by a G1510A transition, resulting in the substitution of glutamic acid by lysine at position 487. People of different ALDH2 genotypes show different susceptibility to cancer, metabolic diseases, etc. SNP analysis based on fluorescent probe-mediated melting curves is a relatively efficient and cost-effective method. Genomic DNA extracted from 100 whole blood samples was subjected to polymorphisms mutational analysis using asymmetric PCR and probe-mediated melting curves. Then a certain number of samples from each genotype were randomly selected for direct sequencing verification. The new assay can be performed in 2 h without post-PCR processing such as gel electrophoresis and validated by direct sequencing in a blind study with 100% concordance. Moreover, comparing the detection of polymorphisms of ALDH2 with the clinics, and an overall agreement of 100% (100/100) was demonstrated. Our study has shown a high level of concordance between DNA sequencing, which is suitable for the detection of clinical specimens. Based on the concept of probe-mediated melting curves, we further developed this platform as a universal strategy for the detection of polymorphisms related to folate metabolism.

Can gene therapy be used to prevent cancer? Gene therapy for aldehyde dehydrogenase 2 deficiency.

Approximately 8% of the world population and 35 to 45% of East Asians are carriers of the hereditary disorder, aldehyde dehydrogenase 2 (ALDH2) deficiency. ALDH2 plays a central role in the liver to metabolize ethanol. With the common E487K variant, there is a deficiency of ALDH2 function; when ethanol is consumed, there is a systemic accumulation of acetaldehyde, an intermediate product in ethanol metabolism. In ALDH2 deficient individuals, ethanol consumption acutely causes the “Alcohol Flushing Syndrome” with facial flushing, tachycardia, nausea and headaches. With chronic alcohol consumption, ALDH2 deficiency is associated with a variety of disorders, including a remarkably high risk for aerodigestive tract cancers. Acetaldehyde is a known carcinogen. The epidemiologic data relating to the association of ALDH2 deficiency and cancer risk are striking: ALDH2 homozygotes that are moderate to heavy consumers of ethanol have a 7- to 12-fold increased risk for esophageal cancer, making ALDH2 deficiency the most common hereditary disorder associated with an increased cancer risk. In this review, we summarize the genetics and biochemistry of ALDH2, the epidemiology of cancer risk associated with ALDH2 deficiency, the metabolic consequences of ethanol consumption associated with ALDH2 deficiency and gene therapy strategies to correct ALDH2 deficiency and its associated cancer risk. With the goal of reducing the risk of aerodigestive tract cancers, in the context that ALDH2 is a hereditary disorder and ALDH2 functions primarily in the liver, ALDH2 deficiency is an ideal target for the application of adeno-associated virus-mediated liver directed gene therapy to prevent cancer.

Aldehyde Dehydrogenase Mutation Exacerbated High-Fat-Diet-Induced Nonalcoholic Fatty Liver Disease with Gut Microbiota Remodeling in Male Mice.

Simple SummaryALDH2, mitochondrial aldehyde dehydrogenase 2, is a critical enzyme involved in ethanol clearance in acetaldehyde metabolism. The prevalence of the ALDH2*2 variant is 45% in the Taiwanese population. ALDH2 reportedly has protective properties on myocardial damage, stroke, and diabetic retina damage. However, the effects of ALDH2 in modulation of metabolic syndromes remain unclear. The study evaluated the roles of ALDH2 in a high-fat-diet-induced metabolic syndrome in mice. We explored the effects of ALDH2 gene on NAFLD and potential association with gut microbiota.Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a critical enzyme involved in ethanol clearance in acetaldehyde metabolism and plays a key role in protecting the liver. The ALDH2*2 mutation causes a significant decrease in acetaldehyde scavenging capacity, leading to the accumulation of acetaldehyde after consuming alcohol. The prevalence of the ALDH2*2 variant is in 45% of Taiwanese individuals. ALDH2 reportedly has protective properties on myocardial damage, stroke, and diabetic retina damage. However, the effects of ALDH2 in the modulation of metabolic syndromes remain unclear. This study evaluates the roles of ALDH2 in a high-fat-diet-induced metabolic syndrome in mice. Male (M) and female (F) wild-type (WT) and ALDH2 knock-in C57BL/6J mice (4–5 weeks old) were fed a high-fat diet for 16 weeks. Results showed that the body and white-adipose-tissue weights were significantly increased in ALDH2-M compared to those in the other groups. We observed markedly elevated serum levels of alanine transaminase and glucose. Oral glucose-tolerance test and homeostasis-model assessment of insulin resistance (HOMA-IR) values were significantly higher in ALDH2-M mice than those in WT-M mice, with no observable differences in female mice. Abundant steatosis and inflammatory cells were observed in ALDH2-M, with significantly decreased expression of hepatic genes IRS2, GLUT4, and PGC-1α compared to that in WT-M. ALDH2 gene mutation also affected the β-diversity of gut microbiota in ALDH2-M resulting in the decreased abundance of Actinobacteria and an increase in Deferribacteres. Our results suggest that potential changes in gut microbiota may be associated with the defective ALDH2 exacerbation of high-fat-diet-induced liver diseases in male mice. However, female mice were not affected, and sex hormones may be an important factor that requires further investigation.

Association of Aldehyde Dehydrogenase 2 Gene Polymorphism with Myocardial Infarction.

ObjectiveThis study explored the correlation between myocardial infarction (MI) and the Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene in the Qingyuan area.MethodsThe Glu504Lys polymorphism of the ALDH2 gene was analyzed using the polymerase chain reaction and deoxyribonucleic acid microarray analysis for 468 patients diagnosed with MI for the first time and 132 healthy subjects.ResultsThere was a significant difference in the distribution of the ALDH2 genotype between the MI group and the control group (P = 0.0492), but there was no significant difference in allele frequency between the two groups (P = 0.1363). The clinical data showed that there were statistically significant differences (P < 0.05) in the two groups’ gender and age distributions, rates of diabetes and hypertension, levels of alcohol and tobacco use, serological levels of heart markers, blood lipids and glucose. The subgroup analysis of ALDH2 genotypes found that alcohol consumption, high levels of myoglobin, and low levels of high-density lipoprotein cholesterol were significantly associated with a higher incidence of MI (P < 0.05). After adjusting for gender, hypertension, diabetes, and other related influencing factors, logistic regression analysis showed that the ALDH2 genotype GA/AA was an independent risk factor for MI (P < 0.05, OR = 1.479, 95% CI = 1.003–2.179).ConclusionThe presence of risk alleles with the genetic effect (ALDH2 genotype GA/AA) is an independent risk factor for MI.

Aldehyde Dehydrogenase 2 (ALDH2) Expression Predicts a Poor Prognosis in Acute Myeloid Leukemia

Introduction: The aldehyde dehydrogenase 2 (ALDH2) gene encodes for an enzyme of the aldehyde dehydrogenase family involved in oxidative alcohol metabolism and protection from hypoxic stress. Using a comparative proteomic approach based on in vivo biotinylation, we have recently identified a marked overexpression of ALDH2 in a rat model of acute myeloid leukemia (AML). In solid tumors, ALDH2 has been described to reduce sensitivity to anthracyclines, a mainstay in the treatment of AML. Here, we analyzed the prognostic impact of ALDH2 expression levels in AML.Methods: Using oligonucleotide microarrays, we analyzed ALDH2 gene expression in pretherapeutic bone marrow or blood samples from 492 AML patients who received intensive chemotherapy within the AMLCG-1999 trial (GSE37642). Results were validated in an additional cohort of 270 intensively treated younger AML patients from the HOVON group (GSE6891).Results: When dichotomized at the first quartile, higher transcript levels of ALDH2 predicted poorer overall (5-year OS 20.2% vs 41.7% for high vs low expression, respectively), event-free (5-year EFS 11.9% vs 30.0%) and relapse-free survival (5-year RFS 22.1% vs 45.0%) (log-rank test: P < 0.001 for all variables). Patients with higher ALDH2 levels had significantly lower rates of complete remission on induction chemotherapy (53% vs 63%; P < 0.05). In multivariate Cox regression analyses including age, gender, primary vs secondary AML, ECOG, WBC, LDH, cytogenetic risk and molecular risk, high ALDH2 expression, among others, remained an independent adverse prognostic factor for OS (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.11 to 2.04; P= 0.008), EFS (HR, 1.43; 95% CI, 1.08 to 1.90; P= 0.012) and RFS (HR, 1.82; 95% CI, 1.24 to 2.67; P= 0.002). Finally, the prognostic impact of ALDH2 was confirmed in a second cohort of 270 intensively treated younger AML patients from the HOVON group (GSE6891). Again, when dichotomized at the first quartile, high ALDH2 significantly predicted inferior OS (5-year OS 37.3% vs 59.4%; P= 0.003) and EFS (5-year EFS 28.8% vs 53.0%; P < 0.001).Conclusion: We identified high ALDH2 expression as an adverse prognostic factor in two large independent cohorts of intensively treated AML patients. DisclosuresLenz:Celgene, JJ, Hexal, Roche, BMS, Novartis, Bayer: Consultancy; AstraZeneca, Gilead, JJ, Celgene, Novartis, Bayer: Research Funding. Hiddemann:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Association between aldehyde dehydrogenase 2 gene rs671 G>A polymorphism and alcoholic liver cirrhosis in southern Chinese Hakka population.

BackgroundAlcoholic liver cirrhosis (ALC) endangering people's health. The association between aldehyde dehydrogenase 2 (ALDH2) gene polymorphisms and ALC is not clear. To analyze the relationship between ALDH2 and ALC among Hakka population in southern China.MethodsA total of 292 ALC patients and 278 controls were included in the study. The ALDH2 gene rs671 polymorphism was analyzed by polymerase chain reaction (PCR)‐gene chip. Relevant information and medical records of these participants were collected.ResultsThe ALC patients had higher percentage of smoking, lower prevalence of hypertension, higher level of alanine aminotransferase (ALT), aspertate aminotransferase (AST), alkaline phosphatase (ALP), gamma‐glutamyltransferase (GGT), total bile acid (TBA), total bilirubin (Tbil), and direct bilirubin (Dbil), lower level of total cholesterol (TC), high‐density lipoprotein‐cholesterol (HDL‐C), and low‐density lipoprotein‐cholesterol (LDL‐C) than controls. The proportions of the G/A genotype (p = 0.017), G/A plus A/A genotype (p = 0.023) and A allele (p = 0.031) were significantly higher in ALC patients than that of controls. ALC patients with G/A genotype had higher TC, HDL‐C, and Apo‐A1 than those with G/G genotype, while with A allele had higher HDL‐C, and Apo‐A1 than those with G allele. Logistic regression analysis indicated that ALDH2 SNP rs671 G/A plus A/A genotypes (A allele carriers) (OR 2.030, 95% CI 1.109–3.715, p = 0.022) in the dominant model was the risk factor for ALC.Conclusions ALDH2 A allele (G/A + A/A genotypes) increased the risk of developing ALC among Hakka people in southern China. The results should enrich the relevant data and provide valuable information for the future related research.