4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification.

BACKGROUND AND AIMS: Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure. METHODS: Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets. RESULTS: 4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure. CONCLUSIONS: 4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure.

Commentary: Aldehyde dehydrogenase, redox balance and exercise physiology: What is missing?

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in reactive aldehyde detoxification. Approximately 560 million people (about 8% of the world's population) carry a point mutation in the aldehyde dehydrogenase 2 gene (ALDH2), identified as ALDH2*2, which leads to decreased ALDH2 catalytic activity. ALDH2*2 variant is associated with an accumulation of toxic reactive aldehydes and consequent disruption of cellular metabolism, which contributes to the establishment and progression of several degenerative diseases. Consequences of aldehyde accumulation include impaired mitochondrial functional, hindered anabolic signaling in the skeletal muscle, impaired cardiovascular and pulmonary function, and reduced osteoblastogenesis. Considering that aldehydes are endogenously produced through redox processes, it is expected that conditions that have a high energy demand, such as exercise, might be affected by impaired aldehyde clearance in ALDH2*2 individuals. Despite the large body of evidence supporting the importance of ALDH2 to ethanol metabolism, redox homeostasis and overall health, specific research investigating the impact of ALDH2*2 on phenotypes relevant to exercise performance are notoriously scarce. In this commentary, we highlight the consolidated knowledge on the impact of ALDH2*2 on physiological processes that are relevant to exercise.

The administration of Alda-1, an activator of ALDH2, inhibits relapse-like ethanol intake in female alcohol-preferring UChB rats.

AIMS: Alcohol relapse is a main limitation for the treatment of alcohol use disorders. Previous studies have shown that Alda-1, a pharmacological activator of ALDH2, inhibits both acquisition and chronic ethanol intake in rats; however, its effects on relapse-like ethanol intake are unknown. The aim of this study was to assess the effect of Alda-1 on post-deprivation and reaccess relapse-like ethanol intake in alcohol-preferring UChB rats. We also aimed to assess the possible mechanisms associated with the effects of Alda-1 by measuring the levels of glutamate transporter (GLT-1), oxidative stress and neuroinflammation markers in different regions of the mesocorticolimbic system. MAIN METHODS: In Experiment I, UChB female rats were exposed for 100 days to voluntary ethanol intake followed by 2-weeks of ethanol withdrawal and 1 week of ethanol reaccess. Alda-1 (25 mg/kg, intragastric, i.g) or vehicle was administered daily for 14 days during the withdrawal/re-access period. Experiment II was similar to Experiment I, but after the withdrawal period, ethanol re-access was not allowed, and Alda-1 was administered during the last week of withdrawal. At the end of both experiments, the levels of GLT-1, oxidative stress (GSH, MDA), and neuroinflammation markers (GFAP, Iba-1) were assessed in nucleus accumbens and/or hippocampus. KEY FINDINGS: The results showed that Alda-1 administration markedly blocked (90 %, p < 0.001) relapse-like ethanol intake in UChB rats. Alda-1 increased Iba-1 reactivity (microglial marker) in the NAc of ethanol-deprived rats. Alda-1 administration did not influence the levels of GLT-1, oxidative stress markers (MDA, GSH) or GFAP reactivity in the mesocorticolimbic system. SIGNIFICANCE: These preclinical findings support the use of activators of ALDH2, such as Alda-1, as a potential pharmacological strategy in the treatment of alcohol relapse.

ALDH2 activation attenuates oxygen-glucose deprivation/reoxygenation-induced cell apoptosis, pyroptosis, ferroptosis and autophagy.

PURPOSE: It is previously reported that aldehyde dehydrogenase 2 family member (ALDH2) shows neuroprotective effects in cerebral ischemia/reperfusion injury. However, whether the protective effects are through mediating the programmed cell death is yet to be fully elucidated. METHODS: In vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in HT22 cells and mouse cortical neurons. Subsequently, ALDH2 expression were assessed by qRT-PCR and western blot. The methylation status was examined by methylation-specific PCR (MS-PCR). Then, ALDH2 expression was promoted and suppressed to explore the role of ALDH2 in OGD/R-treated cells. CCK-8 assay was applied to detect cell viability, and flow cytometry was applied to evaluate cell apoptosis. Western blot was applied to detect the apoptosis-related proteins (Caspase 3, Bcl-2 and Bax), necroptosis-related proteins (RIP3 and MLKL), pyroptosis-related proteins (NLRP3 and GSDMD), ferroptosis-related protein (ACSL4 and GPX4), and autophagy-related proteins (LC3B, and p62). IL-1ß and IL-18 production was evaluated by ELISA assay. Reactive oxygen species production and Fe2+ content were evaluated by the corresponding detection kit. RESULTS: In OGD/R-treated cells, ALDH2 expression was decreased, which was due to the hypermethylation of ALDH2 in the promoter region. ALDH2 overexpression improved cell viability and ALDH2 knockdown suppressed cell viability in OGD/R-treated cells. We also found that ALDH2 overexpression attenuated OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy, while ALDH2 knockdown facilitated the OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy. CONCLUSIONS: Collectively, our results implied that ALDH2 attenuated OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy to promote cell viability in HT22 cells and mouse cortical neurons.

Identification of key genes associated with the progression of liver fibrosis to hepatocellular carcinoma based on iTRAQ proteomics and GEO database.

INTRODUCTION AND OBJECTIVE: Liver fibrosis (LF) often leads to cirrhosis and even hepatocellular carcinoma (HCC), but the molecular mechanism remains unclear. The aims of the present study were to identify potential biomarkers for the progression of LF to HCC and explore the associated molecular mechanisms. MATERIALS AND METHODS: The isobaric tags for relative and absolute quantitation (iTRAQ) was used to detect changes in the protein expression profiles of liver tissues and to screen the differentially expressed proteins (DEPs). The differentially expressed genes (DEGs) of LF rats and patients were screened by Gene Expression Database (GEO). Subsequently, the clinicopathological analysis of the overlapping genes in different pathological stages in HCC patients based on GEPIA database was conducted. RESULTS: iTRAQ proteomic analysis revealed 689, 749 and 585 DEPs in the 6W, 8W and 12W groups, respectively. ALDH2, SLC27A5 and ASNS were not only the DEPs found in rats with LF with different stages but were also the DEGs related to the pathological stages and survival in patients with HCC. CONCLUSIONS: ALDH2, SLC27A5 and ASNS were the potential biomarkers associated with the progression of LF to HCC.

Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice.

Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain.

Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence.

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.

Outcomes of Japanese patients with non-alcoholic fatty liver disease according to genetic background and lifestyle-related diseases.

INTRODUCTION AND OBJECTIVES: Genetic background may be involved in the mechanisms of liver injury and the development of non-alcoholic fatty liver disease (NAFLD). However, its contributions to the long-term outcome of NAFLD have been unclear. METHODS: We enrolled 314 Japanese patients with biopsy-confirmed NAFLD from 2000 to 2018 (161 men [51.3%]; median age, 53 [14-84] years; 114 with advanced fibrosis [37.5%]) in the patients without hepatocellular carcinoma at diagnosis. Genomic DNA was extracted from peripheral blood and single nucleotide polymorphisms (SNPs) were analyzed. Associations of mortality with patatin-like phospholipase 3 (PNPLA3) and aldehyde dehydrogenase 2 (ALDH2) were analyzed. Finally, a subgroup analysis according to lifestyle-related disease was performed. RESULTS: During the median 7 years of follow-up, 20 patients (6.4%) died (13 liver-related [4.1%] and 7 non-liver-related deaths [2.2%]). Patients with ALDH2 (non-GG genotype) who had reduced alcohol metabolism tended to have a poor prognosis (p = 0.06). Patients carrying both risk SNPs of PNPLA3 (GG) and ALDH2 (non-GG) had a significantly poor prognosis (p = 0.01). In the subgroup analysis, patients with PNPLA3 (GG) who were non-diabetics (p = 0.06) or non-dyslipidemic (p = 0.03), with ALDH2 (non-GG) who were non-dyslipidemic (p = 0.01) or hypertensive (p = 0.03), also had a poor prognosis. The Cox analysis revealed that ALDH2 (non-GG) was associated with a poor prognosis (Hazard ratio: 4.568, 95% Confidence Interval: 1.294-16.131, p = 0.02) similar to the liver function tests. CONCLUSIONS: Genetic background may affect NAFLD prognosis and ALDH2 SNP could predict the outcome.

Brain ethanol-metabolizing enzymes are differentially expressed in lead-exposed animals after voluntary ethanol consumption: Pharmacological approaches.

Developmentally-lead (Pb)-exposed rats showed an enhanced vulnerability to the stimulating and motivational effects of ethanol (EtOH). This is accompanied by differential activity of the brain EtOH-metabolizing enzymes catalase (CAT) and mitochondrial aldehyde dehydrogenase (ALDH2). Based on the theory that brain acetaldehyde accumulation is associated with the reinforcing properties of EtOH, this study sought to determine brain CAT and ALDH2 expression in limbic areas of control and Pb-exposed animals after voluntary EtOH intake. Thirty-five-day-old rats perinatally exposed to 220 ppm Pb were offered with water or increasing EtOH solutions (2-10% v/v) during 28 days until postnatal day (PND) 63. Once intake was stable, the animals were administered: 1) saline (SAL; test days 21-24 or 21-28, as corresponds), or 2) a CAT inhibitor: 3-amine 1, 2, 4-triazole (AT; 250 mg/kg intraperitoneally [i.p.], 5 h before the last eight EtOH intake sessions -test days 21-24 and 25-28), or 3) a CAT booster: 3-nitropropionic acid (3NPA; 20 mg/kg subcutaneously [s.c.], 45 min before the last four EtOH intake sessions -test days 25-28). Two additional groups were centrally-administered cyanamide (CY, an ALDH2 inhibitor, 0.3 mg i.c.v. immediately before the last four EtOH sessions, test days 25-28) or its corresponding vehicle (VEH). Lead exposure increased EtOH intake, an effect potentiated in both groups by 3NPA or CY pretreatments and reduced by AT, albeit selectivity in the Pb group. Catalase abundance in limbic areas parallels these observations in the Pb group, showing higher CAT expression in all areas after EtOH consumption respect to the controls, an effect prevented by AT administration. In contrast, ALDH2 expression was reduced in the Pb animals after EtOH intake, with CY potentiating this effect in all brain areas under study. Based on these results and on previous evidences, we suggest that Pb exposure promotes acetaldehyde accumulation in limbic regions, providing some insights into the mechanism of action that underlies the vulnerability to the excessive EtOH consumption reported in these animals.

Aldehyde dehydrogenase 2 in the spotlight: The link between mitochondria and neurodegeneration.

Growing body of evidence suggests that mitochondrial dysfunctions and resultant oxidative stress are likely responsible for many neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Aldehyde dehydrogenase (ALDH) superfamily plays a crucial role in several biological processes including development and detoxification pathways in the organism. In particular, ALDH2 is crucial in the oxidative metabolism of toxic aldehydes in the brain, such as catecholaminergic metabolites (DOPAL and DOPEGAL) and the principal product of lipid peroxidation process 4-HNE. This review aims to deepen the current knowledge regarding to ALDH2 function and its relation with brain-damaging processes that increase the risk to develop neurodegenerative disorders. We focused on relevant literature of what is currently known at molecular and cellular levels in experimental models of these pathologies. The understanding of ALDH2 contributions could be a potential target in new therapeutic approaches for PD and AD due to its crucial role in mitochondrial normal function maintenance that protects against neurotoxicity.

Cardioprotection induced by a brief exposure to acetaldehyde: role of aldehyde dehydrogenase 2.

Aims: We previously demonstrated that acute ethanol administration protects the heart from ischaemia/reperfusion (I/R) injury thorough activation of aldehyde dehydrogenase 2 (ALDH2). Here, we characterized the role of acetaldehyde, an intermediate product from ethanol metabolism, and its metabolizing enzyme, ALDH2, in an ex vivo model of cardiac I/R injury. Methods and results: We used a combination of homozygous knock-in mice (ALDH2*2), carrying the human inactivating point mutation ALDH2 (E487K), and a direct activator of ALDH2, Alda-1, to investigate the cardiac effect of acetaldehyde. The ALDH2*2 mice have impaired acetaldehyde clearance, recapitulating the human phenotype. Yet, we found a similar infarct size in wild type (WT) and ALDH2*2 mice. Similar to ethanol-induced preconditioning, pre-treatment with 50 µM acetaldehyde increased ALDH2 activity and reduced cardiac injury in hearts of WT mice without affecting cardiac acetaldehyde levels. However, acetaldehyde pre-treatment of hearts of ALDH2*2 mice resulted in a three-fold increase in cardiac acetaldehyde levels and exacerbated I/R injury. Therefore, exogenous acetaldehyde appears to have a bimodal effect in I/R, depending on the ALDH2 genotype. Further supporting an ALDH2 role in cardiac preconditioning, pharmacological ALDH2 inhibition abolished ethanol-induced cardioprotection in hearts of WT mice, whereas a selective activator, Alda-1, protected ALDH2*2 against ethanol-induced cardiotoxicity. Finally, either genetic or pharmacological inhibition of ALDH2 mitigated ischaemic preconditioning. Conclusion: Taken together, our findings suggest that low levels of acetaldehyde are cardioprotective whereas high levels are damaging in an ex vivo model of I/R injury and that ALDH2 is a major, but not the only, regulator of cardiac acetaldehyde levels and protection from I/R.

First description and evaluation of SNPs in the ADH and ALDH genes in a population of alcoholics in Central-West Brazil.

Worldwide, different studies have reported an association of alcohol-use disorder (AUD) with different types of Single Nucleotide Polymorphisms (SNPs) in the genes for aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH). In Brazil, there is little information about the occurrence of these SNPs in the AUD population and an absence of studies characterizing the population in the Central-West Region of Brazil. Actually, in Brazil, there are more than 4 million people with AUD. Despite the major health hazards of AUD, information on alcohol consumption and its consequences are not well understood. Therefore, it is extremely important to characterize these SNPs for the better understanding of AUD as a genetic disease in the Brazilian population. The present study, unlike other studies in other countries, is done with a subject population that shows a significant amount of racial homogenization. We evaluated the presence of SNPs in the ADH (ADH1B, ADH1C, and ADH4) and ALDH (ALDH2) genes in alcohol users of Goiânia, State of Goiás - Brazil, and then we established a possible relationship with AUD by allelic and genotypic study. This study was conducted with a population of people with AUD (n = 99) from Goiás Alcohol Dependence Recovery Center (GO CEREA) and Psychosocial Care Center for Alcohol and Drugs (CAPS AD), and with a population of people without AUD as controls (n = 100). DNA was extracted from whole-blood samples and the genotyping was performed using TaqMan® SNP genotyping assays. For characterization and evaluation of SNPs in the population, genotype frequency, allele frequency, haplotype frequency, Hardy-Weinberg equilibrium, and linkage disequilibrium were analyzed. Statistical analyses were calculated by GENEPOP 4.5 and Haploview software. The allele 1 was considered as "wild" (or *1) and allele 2 as mutant (or *2). Significant differences were found for ADH1B*, ADH4*2, and ALDH2*2 SNPs when the genotype and allele frequencies were analyzed. In addition, four haplotypes were observed between ADH1B*2 and ADH1C*2 through linkage disequilibrium analysis. The genetic variants may be associated with protection against AUD in the population studied.

AAV Gene Therapy for Alcoholism: Inhibition of Mitochondrial Aldehyde Dehydrogenase Enzyme Expression in Hepatoma Cells.

Most ethanol is broken down in the liver in two steps by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH2) enzymes, which metabolize down ethanol into acetaldehyde and then acetate. Some individuals from the Asian population who carry a mutation in the aldehyde dehydrogenase gene (ALDH2*2) cannot metabolize acetaldehyde as efficiently, producing strong effects, including facial flushing, dizziness, hypotension, and palpitations. This results in an aversion to alcohol intake and protection against alcoholism. The large prevalence of this mutation in the human population strongly suggests that modulation of ALDH2 expression by genetic technologies could result in a similar phenotype. scAAV2 vectors encoding ALDH2 small hairpin RNA (shRNA) were utilized to validate this hypothesis by silencing ALDH2 gene expression in human cell lines. Human cell lines HEK-293 and HepG2 were transduced with scAAV2/shRNA, showing a reduction in ALDH2 RNA and protein expression with the two viral concentration assayed (1 × 104 and 1 × 105 vg/cell) at two different time points. In both cell lines, ALDH2 RNA levels were reduced by 90% and protein expression was inhibited by 90% and 52%, respectively, 5 days post infection. Transduced HepG2 VL17A cells (ADH+) exposed to ethanol resulted in a 50% increase in acetaldehyde levels. These results suggest that gene therapy could be a useful tool for the treatment of alcoholism by knocking down ALDH2 expression using shRNA technology delivered by AAV vectors.

Developmental lead exposure induces opposite effects on ethanol intake and locomotion in response to central vs. systemic cyanamide administration.

Lead (Pb) is a developmental neurotoxicant that elicits differential responses to drugs of abuse. Particularly, ethanol consumption has been demonstrated to be increased as a consequence of environmental Pb exposure, with catalase (CAT) and brain acetaldehyde (ACD, the first metabolite of ethanol) playing a role. The present study sought to interfere with ethanol metabolism by inhibiting ALDH2 (mitochondrial aldehyde dehydrogenase) activity in both liver and brain from control and Pb-exposed rats as a strategy to accumulate ACD, a substance that plays a major role in the drug's reinforcing and/or aversive effects. To evaluate the impact on a 2-h chronic voluntary ethanol intake test, developmentally Pb-exposed and control rats were administered with cyanamide (CY, an ALDH inhibitor) either systemically or intracerebroventricularly (i.c.v.) on the last 4 sessions of the experiment. Furthermore, on the last session and after locomotor activity was assessed, all animals were sacrificed to obtain brain and liver samples for ALDH2 and CAT activity determination. Systemic CY administration reduced the elevated ethanol intake already reported in the Pb-exposed animals (but not in the controls) accompanied by liver (but not brain) ALDH2 inactivation. On the other hand, a 0.3 mg i.c.v. CY administration enhanced both ethanol intake and locomotor activity accompanied by brain ALDH2 inactivation in control animals, while an increase in ethanol consumption was also observed in the Pb-exposed group, although in the absence of brain ALDH2 blockade. No changes were observed in CAT activity as a consequence of CY administration. These results support the participation of liver and brain ACD in ethanol intake and locomotor activity, responses that are modulated by developmental Pb exposure.

Analysis of ADH1B Arg47His, ALDH2 Glu487Lys, and CYP4502E1 polymorphisms in gastric cancer risk and interaction with environmental factors.

Gastric cancer is the fourth commonly diagnosed cancer and the second most frequent cause of cancer death worldwide. Genetic variations in ADH1B and ALDH2 may alter the function and activity of the corresponding enzymes, leading to differences in acetaldehyde exposure between drinkers. Cytochrome P4502E1 (CYP4502E1) is a phase I enzyme that plays an important role in metabolizing nitrosamine compounds and the bioactivation of procarcinogens. During the period of July 2013 to July 2015, 246 patients and 274 controls were enrolled from the First Affiliated Hospital of Jinan University. In the codominant model, the AA genotype of ALDH2 Glu487Lys significantly elevated the risk of gastric cancer in comparison with the GG genotype of ALDH2 Glu487Lys. In the recessive model, the AA genotype of ALDH2 Glu487Lys significantly increased the risk of gastric cancer compared to the GG+GA genotype (OR = 2.34 95%CI = 1.02-5.70). We found in the codominant model that individuals harboring the C2/C2 genotype of CYP4502E1 had a higher risk of developing gastric cancer than those with the C1/C1 genotype. In addition, in the recessive model, we found that the C2/C2 genotype correlated with an elevated risk of gastric cancer in comparison with the C1/C1+C1/C2 genotype (OR = 4.90, 95%CI = 2.04-13.51). However, no significant relationship was measured between ADH1B Arg47His and gastric cancer risk. In summary, the results of our study indicate that ALDH2 Glu487Lys and CYP4502E1 polymorphisms could be risk factors for the development of gastric cancer in the Chinese population.

Role of ADH1B rs1229984 and ALDH2 rs671 gene polymorphisms in the development of Alzheimer's disease.

In the present study, we investigated the association between ADH1B rs1229984 and ALDH2 rs671 polymorphisms and the development of Alzheimer's disease in a Chinese population. Genotyping of the ADH1B rs1229984 and ALDH2 rs671 polymorphisms was carried out by polymerase chain reaction-restriction fragment length polymorphism. Logistic regression analyses revealed that the AA genotype of ADH1B rs1229984 was associated with an increased risk of Alzheimer's disease (OR = 2.54, 95%CI = 1.19-5.41). In addition, ADH1B rs1229984 was also associated with elevated risk of Alzheimer's disease in both dominant (OR = 1.78, 95%CI = 1.09-2.93) and recessive (OR = 2.33, 95%CI = 1.18-4.57) models. For ALDH2 rs671, the AA genotype was correlated with an increased risk of Alzheimer's disease as compared to the GG genotype (OR = 4.57, 95%CI = 1.60-14.01). The ALDH2 rs671 polymorphism was associated with Alzheimer's in both dominant (OR = 1.79, 95%CI = 1.08-2.97) and recessive (OR = 4.17, 95%CI = 1.49-12.67) models. In conclusion, we observed that ADH1B rs1229984 and ALDH2 rs671 polymorphisms increased the risk of Alzheimer's disease in all the genetic models.

Association between aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphism and susceptibility to colorectal cancer: a meta-analysis.

Numerous studies have evaluated the association between Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene and colorectal cancer (CRC) risk. However, the specific association remains controversial. To assess the relationship between the ALDH2 Glu504Lys polymorphism and CRC, we conducted a comprehensive meta-analysis of five case-control studies comprising 1664 patients with CRC and 2777 controls. The results of this meta-analysis showed that the ALDH2 Glu504Lys polymorphism was associated with a significantly reduced risk of CRC [Lys/Lys vs Glu/Glu: odds ratio (OR) = 0.95, 95% confidence interval (CI) = 0.58-1.54; Glu/Lys vs Glu/Glu: OR = 0.85, 95%CI = 0.75-0.97; dominant model: OR = 0.86, 95%CI = 0.76-0.98; recessive model: OR = 1.00, 95%CI = 0.62-1.61]. No significant heterogeneity or publication bias was observed in our meta-analysis. Based on the statistical data, our meta-analysis indicates that the ALDH2 Glu504Lys polymorphism is associated with reduced risk of developing CRC.

Role of ADH2 and ALDH2 gene polymorphisms in the development of Parkinson's disease in a Chinese population.

In this study, we investigated the role of ADH2 Arg47His and ALDH2 Glu487Lys genetic polymorphisms in the development of Parkinson's disease in a Chinese population. Between January 2013 and May 2014, 115 patients with Parkinson's disease and 214 healthy controls were recruited in our study. Genotyping of ADH2 Arg47His and ALDH2 Glu487Lys polymorphisms was performed by the polymerase chain reaction-restriction fragment length polymorphism method. In the dominant model, the GA + AA genotype of ALDH2 Glu487Lys was found to be significantly associated with elevated risk of Parkinson's disease when compared with the GG genotype [odds ratio = 1.71, 95% confidence interval (CI) = 1.02-2.84]. In the recessive model, the AA genotype of ALDH2 Glu487Lys showed a 4.87-fold increase (95%CI = 1.54-18.03) in the risk of Parkinson's disease when compared to the GG and GA genotypes. However, no significant association was found between the ADH2 Arg47His polymorphism and risk of Parkinson's disease in the co-dominant, dominant, or recessive models. In conclusion, our study suggests that the ALDH2 polymorphism could influence the development of Parkinson's disease in the Chinese population studied here.

Association of ADH1B Arg47His and ALDH2 Glu487Lys polymorphisms with risk of colorectal cancer and their interaction with environmental factors in a Chinese population.

Human colorectal cancer (CRC) is a major worldwide health concern, and its development has been shown to be associated with alcohol intake. We carried out a study to investigate the effect of the ADH1B Arg47His and ALDH2 Glu487Lys genetic polymorphisms and their interaction with alcohol consumption on development of CRC. Between March 2013 and May 2015, a total of 274 CRC patients and 358 healthy controls were recruited. Genotyping of sequence variations was performed using the polymerase chain reaction-restriction fragment length polymorphism method. Under a co-dominant model, individuals with the ADH1B Arg47His AA genotype showed increased CRC risk compared to those carrying the GG genotype, with an adjusted odds ratio (and 95% confidence interval) of 3.37 (2.00-5.70). Moreover, under dominant and recessive models, ADH1B Arg47His variant genotypes were associated with greater susceptibility to CRC when compared with the wild-type sequence. Both polymorphisms examined were positively associated with alcohol consumption in a Spearman correlation analysis of CRC risk. In conclusion, our study suggests that the ADH1B Arg47His polymorphism, but not the ALDH2 Glu487Lys variation, may influence development of CRC in the Chinese population.