Asian flush is a potential protective factor against COVID-19: a web-based retrospective survey in Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19), first reported in December 2019, spread worldwide in a short period, resulting in numerous cases and associated deaths; however, the toll was relatively low in East Asia. A genetic polymorphism unique to East Asians, Aldehyde dehydrogenase 2 rs671, has been reported to confer protection against infections. METHOD: We retrospectively investigated the association between the surrogate marker of the rs671 variant, the skin flushing phenomenon after alcohol consumption, and the timing of COVID-19 incidence using a web-based survey tool to test any protective effects of rs671 against COVID-19. RESULTS: A total of 807 valid responses were received from 362 non-flushers and 445 flushers. During the 42 months, from 12/1/2019 to 5/31/2023, 40.6% of non-flushers and 35.7% of flushers experienced COVID-19. Flushers tended to have a later onset (Spearman's partial rank correlation test, p = 0.057, adjusted for sex and age). Similarly, 2.5% of non-flushers and 0.5% of flushers were hospitalized because of COVID-19. Survival analysis estimated lower risks of COVID-19 and associated hospitalization among flushers (p = 0.03 and <0.01, respectively; generalized Wilcoxon test). With the Cox proportional hazards model covering 21 months till 8/31/2021, when approximately half of the Japanese population had received two doses of COVID-19 vaccine, the hazard ratio (95% confidence interval) of COVID-19 incidence was estimated to be 0.21 (0.10-0.46) for flusher versus non-flusher, with adjustment for sex, age, steroid use, and area of residence. CONCLUSIONS: Our study suggests an association between the flushing phenomenon after drinking and a decreased risk of COVID-19 morbidity and hospitalization, suggesting that the rs671 variant is a protective factor. This study provides valuable information for infection control and helps understand the unique constitutional diversity of East Asians.

Changes of neurofilament light chain in patients with alcohol dependence following withdrawal and the genetic effect from ALDH2 Polymorphism.

Neurofilament light chain (NFL), as a measure of neuroaxonal injury, has recently gained attention in alcohol dependence (AD). Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme which metabolizes the alcohol breakdown product acetaldehyde. An ALDH2 single nucleotide polymorphism (rs671) is associated with less ALDH2 enzyme activity and increased neurotoxicity. We examined the blood NFL levels in 147 patients with AD and 114 healthy controls using enzyme-linked immunosorbent assay and genotyped rs671. We also followed NFL level, alcohol craving and psychological symptoms in patients with AD after 1 and 2 weeks of detoxification. We found the baseline NFL level was significantly higher in patients with AD than in controls (mean ± SD: 264.2 ± 261.8 vs. 72.1 ± 35.6 pg/mL, p < 0.001). The receiver operating characteristic curve revealed that NFL concentration could discriminate patients with AD from controls (area under the curve: 0.85; p < 0.001). The NFL levels were significantly reduced following 1 and 2 weeks of detoxification, with the extent of reduction correlated with the improvement of craving, depression, and anxiety (p < 0.001). Carriers with the rs671 GA genotype, which is associated with less ALDH2 activity, had higher NLF levels either at baseline or after detoxification compared with GG carriers. In conclusion, plasma NFL level was increased in patients with AD and reduced after early abstinence. Reduction in NFL level corroborated well with the improvement of clinical symptoms. The ALDH2 rs671 polymorphism may play a role in modulating the extent of neuroaxonal injury and its recovery.

Effects of the genetic variants of alcohol-metabolizing enzymes on lipid levels in Asian populations: a systematic review and meta-analysis.

CONTEXT: Emerging evidence indicates that variants of alcohol-metabolizing enzymes may influence lipid metabolism. OBJECTIVE: This study aimed to investigate whether the rs671 and rs1229984 variants affect lipid levels in East Asian individuals. DATA SOURCES: PubMed, Foreign Medical Journal Service, Embase, Cochrane Library, Scopus, MEDLINE, Web of Science, Web of Knowledge, Wanfang, and Chinese Biomedical Literature databases were searched until December 31, 2021. DATA EXTRACTION: Meta-analyses of studies that examined the effects of alcohol-metabolizing enzyme variants on lipid levels, as well as the interaction with alcohol intake, were selected. Data extraction was conducted independently by two investigators and confirmed by the third. DATA ANALYSIS: In total, 86 studies (179 640 individuals) were analyzed. The A allele of rs671 (a functional variant in the ALDH2 gene) was linked to higher levels of low-density lipoprotein cholesterol (LDL-C) and lower levels of triglycerides and high-density lipoprotein cholesterol. In contrast, the A allele of the rs1229984 (a functional variant in the ADH2 gene) was associated only with lower levels of LDL-C. The effects of rs671 and rs1229984 on lipid levels were much stronger in Japanese than in Chinese individuals and in males than in females. Regression analysis indicated that the effects of rs671 on lipid levels were independent of alcohol intake in an integrated East Asian population (ie, Japanese, Chinese, and Korean individuals). Intriguingly, alcohol intake had a statistical influence on lipid levels when the sample analyzed was restricted to Japanese individuals or to males. CONCLUSIONS: The rs671 and rs1229984 variants of alcohol-metabolizing enzymes have significant effects on lipid levels and may serve as genetic markers for lipid dyslipidemia in East Asian populations. Circulating lipid levels in Japanese individuals and in males were modulated by the interaction between rs671 and alcohol intake.

Impacts of ADH1B rs1229984 and ALDH2 rs671 polymorphisms on risks of alcohol-related disorder and cancer.

BACKGROUND: ADH1B rs1229984 and ALDH2 rs671 are the specifically prevalent functional variants in the East Asians. These variants, which result in a dramatic change in enzyme activity, are highly associated with alcohol-related disorders and cancer. Previous studies focusing on the additive and synergic effects of the variants are few and inconsistent. The aim of the research was to evaluate the associations of ADH1B rs1229984 and ALDH2 rs671 with the risks of alcohol-related disorder and cancer. METHODS: This cohort study enrolled 42,665 participants from the Taiwan Precision Medicine Initiative database, including 19,522 and 20,534, ADH1B and ALDH2 carriers, respectively. The associations between the two variants and cancer risk were analyzed by univariable and multivariable logistic regression. RESULTS: Compared with the noncarriers, the ADH1B rs1229984 variant had a stronger effect on alcohol-related disorders and was related to an increased risk of alcohol-related cancers. The CC genotype of ADH1B rs1229984 was significantly associated with cancer of the larynx, pharynx, and nasal cavities [odds ratio (OR) = 1.56, p = 0.0009], cancer of the pancreas (OR = 1.66, p = 0.018), and cancer of the esophagus (OR = 4.10, p < 0.001). Participants who carried the rs1229984 TC/CC and rs671 GG genotypes were at higher risk of esophageal cancer (OR = 3.02, p < 0.001). The risk of esophageal cancer was increased by 381% (OR = 4.81, p < 0.001) in those carrying the rs1229984 TC/CC and rs671 GA/AA genotypes. CONCLUSION: rs1229984 and rs671 are common and functionally important genetic variants in the Taiwanese population. Our findings provide strong evidence of additive and synergic risks of ADH1B and ALDH2 variants for alcohol-related disorders and cancer. The results suggested that are reduction in alcohol consumption should be advised as a preventive measure for high-risk patients carrying ADH1B rs1229984 C or the ALDH2 rs671 A allele.

Association between Dietary Behaviors and BMI Stratified by Sex and the ALDH2 rs671 Polymorphism in Japanese Adults.

The rs671 polymorphism, unique to East Asians, is well known to change the sensitivity to alcohol. Moreover, this polymorphism is associated not only with alcohol intake but also with several dietary behaviors (DBs), chronic diseases, and BMI, but the triadic association among the rs671 genotype, DBs, and BMI is unclear. This study included 12,271 Japanese subjects and aimed to observe this three-way association using the rs671 polymorphism, data of 56 DBs, and BMI. All analyses were stratified by participant sex. First, linear regression analyses resulted in significant associations between 18 and 21 DBs and BMI in males and females, respectively. Next, genetic heterogeneity was observed in all sub-groups via interaction analysis of the rs671 genotype stratified by drinking habits. Finally, we observed the characteristics of BMI-related DBs based on the rs671 genotype via stepwise regression analyses stratified by the rs671 genotype and drinking habits. Notably, positive associations were observed between lactobacillus beverage intake and BMI among participants with the rs671 polymorphism AA genotype in both sexes. This study suggests that the rs671 polymorphism modifies the association between DBs and BMI independently of drinking habits, providing evidence for the potential use of rs671 polymorphism information for precision nutrition with East Asians.

Aldehyde dehydrogenase 2 rs671 polymorphism and multiple diseases: protocol for a quantitative umbrella review of meta-analyses.

BACKGROUND: The mutant allele (*2) of aldehyde dehydrogenase type 2 (ALDH2) caused by a single nucleotide variant (rs671) inhibits enzymatic activity and is associated with multiple diseases. In recent years, an explosive number of original studies and meta-analyses have been conducted to examine the associations of ALDH2 rs671 polymorphism with diseases. Due to conflicting results, the overall associations of ALDH2 rs671 polymorphism and multiple diseases remain unclear. METHODS: A quantitative umbrella review will be conducted on meta-analyses of genetic association studies to examine the pleiotropic effects of ALDH2 rs671, mainly including cardio-cerebral vascular disease, diabetes mellitus, cancer, neurodegenerative disease, and alcohol-induced medical disease. A search of relevant literature according to comprehensive search strategies will be performed on studies published before July 1st, 2022 in PubMed, MEDLINE Ovid, Embase, Cochrane Database of Systematic Reviews, and Web of Science. Study selection, data extraction, methodology quality assessment, and strength of evidence assessment will be conducted by two reviewers independently and in duplicate. Included meta-analyses will be grouped by outcomes. Data conflicts and overlap between meta-analyses will be managed through updated standardized and customized methods including the calculation of CCA for study selection reference, application of Doi plots to assess small-study effects and others. Evidence from included meta-analyses will be quantitatively synthesized by overlap-corrected analyses and meta-analysis using primary studies. DISCUSSION: This umbrella review is expected to generate systematic evidence on the association between ALDH2 rs671 and diseases. Specific approaches were developed to address key challenges in conducting an umbrella review, including assessment tools of methodology and evidence quality of meta-analyses, methods to manage overlap between meta-analyses, a "stop-light" plot to summarize key findings. These approaches provide applicable methods for future umbrella reviews of meta-analyses on genetic association studies. TRIAL REGISTRATION: CRD42021223812.

The association of AGER and ALDH2 gene polymorphisms with diabetic retinopathy.

PURPOSE: To evaluate the possible associations between AGER (rs1051993, rs2070600) and ALDH2 (rs671) gene polymorphisms with nonproliferative (NPDR) and proliferative (PDR) diabetic retinopathy, in a well-defined Greek population. MATERIALS: 66 NPDR patients and 57 PDR patients participated in our study, along with 156 age- and gender-matched healthy-control subjects (CL). All the participants underwent a complete ophthalmological examination, while clinical and demographic data were collected. Furthermore, they were genotyped for the studied polymorphisms. RESULTS: No significant differences were detected among the studied groups regarding the participants' age and gender status. We found that the ALDH2 AA genotype was significantly more frequent in PDR patients than in CL (p = 0.014). Furthermore, between NPDR and PDR groups, the AGER rs1051993 GT and TT genotype frequencies were significantly elevated in PDR patients (p < 0.0001 and 0.04, respectively). Moreover, we demonstrated that the heterozygous GT genotype in DR patients is accompanied by 71.11 times higher risk of developing PDR (OR = 71.11: 95% CI- 4.14-1215.2), while the homozygous TT genotype is associated with 12.71 times elevated risk for PDR development (OR = 12.71: 95% CI- 0.63-254.1). CONCLUSIONS: We documented that the ALDH2 AA and AGER rs1051993 GT and TT genotypes were observed significantly more frequently in PDR Greek diabetic patients. Our findings also support the genetic theory, suggesting that heritability is significantly implicated in the development of DR, providing additional evidence in the understanding of DR pathogenesis.

Variant Allele of ALDH2, rs671, Associates with Attenuated Post-Vaccination Response in Anti-SARS-CoV-2 Spike Protein IgG: A Prospective Study in the Japanese General Population.

Uncovering the predictors of vaccine immunogenicity is essential for infection control. We have reported that the most prevalent polymorphism of the aldehyde dehydrogenase 2 gene (ALDH2), rs671, may be associated with an attenuated immune system. To test the inverse relationship between rs671 and antibody production after COVID-19 vaccination, the levels of anti-SARS-CoV-2 Spike protein S1 subunit (S1) IgG were repeatedly measured for four months before and after vaccination with BNT162b2 or mRNA-1273, in 88 Japanese workers and students (including 45 females, aged 21-56 years, with an rs671 variant allele frequency of 0.3). The mixed model including fixed effects of the vaccine type, weeks post vaccination (categorical variable), sex, age, height, smoking status, ethanol intake, exercise habit, perceived stress, steroid use, allergic diseases, and dyslipidemia, indicated an inverse association between log-transformed anti-S1 IgG levels and the number of rs671 variant alleles (partial regression coefficient = -0.15, p = 0.002). Our study indicated for the first time that the variant allele of ALDH2, rs671, is associated with the attenuated immunogenicity of COVID-19 mRNA vaccines. Our finding may provide a basis for personalized disease prevention based on a genetic polymorphism that is prevalent among East Asians.

Association Study and Meta-Analysis of Polymorphisms and Blood mRNA Expression of the ALDH2 Gene in Patients with Alzheimer's Disease.

BACKGROUND: Late-onset Alzheimer's disease (LOAD) is a complex disease in which neuroinflammation plays an important pathophysiological role, and exposure to neurotoxic substrates such as aldehydes may contribute. Blood mRNA expression levels of neuroinflammation-related genes appear to be potential biological markers of LOAD. A relationship between ALDH2 and LOAD has been suggested. OBJECTIVE: Our objective was to examine blood ALDH2 expression in Japanese LOAD patients, conduct a genetic association study, and add new studies to an extended meta-analysis of the Asian population. METHODS: A blood expression study (45 AD subjects, 54 controls) in which total RNA was isolated from whole peripheral blood samples and ALDH2 expression measured was conducted. In addition, a genetic association study (271 AD subjects, 492 controls) using genomic DNA from whole peripheral blood samples was conducted. Finally, a meta-analysis examined the relationship between ALDH2*2 frequency and the risk of LOAD. RESULTS: ALDH2 mRNA expression was significantly higher in LOAD than in controls, and also higher in men with LOAD than in women with LOAD (p = 0.043). The genotypes in the two classified groups and the allele frequency were significantly different between AD and control subjects. The meta-analysis showed a significant difference in the ALDH2*2 allele, with an increased AD risk (OR = 1.38; 95% CI = 1.02-1.85; p = 0.0348, I2 = 81.1%). CONCLUSION: There was a significant increase in blood ALDH2 expression, and a genetic association with ALDH2*2 in LOAD. ALDH2 may have significant roles in the pathogenesis of LOAD in the Asian population.

Genetic Variations of ALDH (rs671) Are Associated With the Persistence of HBV Infection Among the Chinese Han Population.

Alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2), members of the alcohol dehydrogenase family, have important roles in liver diseases. The roles of the polymorphisms of ADH1B rs1229984 and ALDH2 rs671 in hepatitis B virus (HBV) susceptibility and persistent infection were investigated in the present study. Total 1,034 patients with hepatitis B [99 acute hepatitis B (AHB), 521 chronic hepatitis B (CHB), 158 acute-on-chronic liver failure (ACLF), 159 liver cirrhosis (LC), and 97 hepatocellular carcinoma (HCC)] and 1,262 healthy controls (HCs) of the Chinese Han population were recruited, and single nucleotide polymorphisms (SNPs) of rs671 and rs1229984 were genotyped. Independent and joint roles of rs671 and rs1229984 in HBV infection were analyzed. The results showed that rs671 genotypes had a significantly different distribution among different subgroups. Compared with HCs, the frequency of rs671-AA genotype was higher in hepatitis B individuals, especially in the CHB group [adjusted OR (95%CI) = 1.899 (1.232-2.928), p = 0.003, in the co-dominant model], which showed a significant positive association. It was further confirmed that CHB individuals who carried ALDH2 rs671-AA genotype had a higher risk of persistent HBV infection and higher HBV-DNA quantitation compared with those with GG/GA genotype. In addition, the rs671-AA genotype might predict HCC incidence in patients with CHB. There were no different distributions of alleles or genotypes in rs671 mutant among AHB, ACLF, LC, or HCC groups compared with HCs. These data suggested the possible hazardous role of rs671-AA variant in HBV infection and persistence.

A genome-wide association study on meat consumption in a Japanese population: the Japan Multi-Institutional Collaborative Cohort study.

Recent genome-wide association studies (GWAS) on the dietary habits of the Japanese population have shown that an effect rs671 allele was inversely associated with fish consumption, whereas it was directly associated with coffee consumption. Although meat is a major source of protein and fat in the diet, whether genetic factors that influence meat-eating habits in healthy populations are unknown. This study aimed to conduct a GWAS to find genetic variations that affect meat consumption in a Japanese population. We analysed GWAS data using 14 076 participants from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. We used a semi-quantitative food frequency questionnaire to estimate food intake that was validated previously. Association of the imputed variants with total meat consumption per 1000 kcal energy was performed by linear regression analysis with adjustments for age, sex, and principal component analysis components 1-10. We found that no genetic variant, including rs671, was associated with meat consumption. The previously reported single nucleotide polymorphisms that were associated with meat consumption in samples of European ancestry could not be replicated in our J-MICC data. In conclusion, significant genetic factors that affect meat consumption were not observed in a Japanese population.

ALDH2 p.E504K Variation and Sex Are Major Factors Associated with Current and Quitting Alcohol Drinking in Japanese Oldest Old.

This study identified the factors associated with current and quitting alcohol drinking in the Oldest Old to better understand the associated factors and mechanisms underlying drinking behaviors in this age group. Results of a questionnaire for drinking behavior in 1015 Japanese Oldest Old citizens aged 85 to 89 years revealed that 56.0% of men and 24.0% of women were current drinkers. A genome-wide association study revealed that the rs671 G > A variation, which corresponds to the aldehyde dehydrogenase 2 (ALDH2) p.E504K missense variant, was significantly associated with current drinking (odds ratio: 3.8, p = 3.33 × 10-31). Variable selection with 41 factors and multivariate regression logistic analysis for current drinking indicated that the rs671 genotype and sex were the most significant factors in the Oldest Old. Further analysis revealed that the rs671 genotype, alcohol-associated biomarkers, a history of heart or kidney disease, and frailty score are factors associated with quitting drinking in the Oldest Old men, whereas smoking history, walking time, and depression score were factors associated with quitting drinking in the Oldest Old women. These results indicate that the ALDH2 p.E504K variation is a major factor associated with current and quitting drinking in the Japanese Oldest Old.

ALDH2 polymorphism rs671 is a predictor of PD-1/PD-L1 inhibitor efficacy against thoracic malignancies.

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) plays an important role in the endogenous aldehyde detoxification of various types of cells. ALDH2*2, a variant allele of the ALDH2 polymorphism rs671, leads to decreased enzymatic activity. ALDH2*2 may enhance tumor antigen presentation due to aldehyde-induced DNA damage while suppressing peripheral blood T cell counts and T cell activation. METHODS: On the basis of our hypothesis that rs671 affects the sensitivity of immune checkpoint inhibitors (ICIs), we evaluated the effects of rs671 on patients with thoracic malignancies who started ICI therapy in 2016-2019. The cohort consisted of 105 cases, including 64 cases with adenocarcinoma and 30 cases with squamous cell carcinoma, 49 of whom were ALDH2*2 carriers. The first ICI was PD-1/PD-L1 inhibitor (Nivolumab, Pembrolizumab, or Atezolizumab) in all cases. RESULTS: The best response to anti-PD-1/PD-L1 therapy (partial response/stable disease/progressive disease) was 36%/50%/14% in the rs671(-) cases; however, the response was relatively poor in the rs671(+) cases (27%/29%/45%, respectively) (p = 0.002). The hazard ratio (95% confidence interval) of disease progression within the observation period of 6 months for the rs671(+) cases was estimated to be 5.0 (2.5-10) after the adjustment for covariates, including sex, Brinkman index, treatment line, tumor tissue programmed death-ligand 1 positivity rate, tumor tissue EGFR mutation. This association was also maintained in a stratified analysis, suggesting that ALDH2*2 is an independent negative predictive factor for the short-term prognosis of anti-PD-1/PD-L1 therapy. Thus, the progression-free survival (PFS) ratio of the rs671(+) cases decreased rapidly after ICI initiation but was eventually higher than that of the rs671(-) cases (restricted mean survival time in 12 months from 2 to 3 years afterward was 1.3 times that of the rs671(-) cases). Moreover, the highest PFS ratio after 2 years among sub-groups was found in the first-line treatment sub-group of rs671(+) group (40%). CONCLUSIONS: Our study suggests that rs671 may be an accurate and cost-effective predictor of PD-1/PD-L1 inhibitor treatment, in which optimal case selection is an important issue.

Risk of gout among Taiwanese adults with ALDH-2 rs671 polymorphism according to BMI and alcohol intake.

BACKGROUND: Gout stems from both modifiable and genetic sources. We evaluated the risk of gout among Taiwanese adults with aldehyde dehydrogenase-2 (ALDH2) rs671 single nucleotide polymorphism (SNP) according to body mass index (BMI) and alcohol drinking. METHODS: We obtained information of 9253 individuals having no personal history of cancer from the Taiwan Biobank (2008-2016) and estimated the association between gout and independent variables (e.g., rs671, BMI, and alcohol drinking) using multiple logistic regression. RESULTS: Alcohol drinking and abnormal BMI were associated with a higher risk of gout whereas the rs671 GA+AA genotype was associated with a lower risk. The odds ratios (ORs) and 95% confidence intervals (CIs) were 1.297 and 1.098-1.532 for alcohol drinking, 1.550 and 1.368-1.755 for abnormal BMI, and 0.887 and 0.800-0.984 for GA+AA. The interaction between BMI and alcohol on gout was significant for GG (p-value = 0.0102) and GA+AA (p-value = 0.0175). When we stratified genotypes by BMI, alcohol drinking was significantly associated with gout only among individuals with a normal BMI (OR; 95% CI = 1.533; 1.036-2.269 for GG and 2.109; 1.202-3.699 for GA+AA). Concerning the combination of BMI and alcohol drinking among participants stratified by genotypes (reference, GG genotype, normal BMI, and no alcohol drinking), the risk of gout was significantly higher in the following categories: GG, normal BMI, and alcohol drinking (OR, 95% CI = 1.929, 1.385-2.688); GG, abnormal BMI, and no alcohol drinking (OR, 95% CI, = 1.721, 1.442-2.052); GG, abnormal BMI, and alcohol drinking (OR, 95% CI = 1.941, 1.501-2.511); GA+AA, normal BMI, and alcohol drinking (OR, 95% CI = 1.971, 1.167-3.327); GA+AA, abnormal BMI, and no alcohol drinking (OR, 95% CI = 1.498, 1.256-1.586); and GA+AA, abnormal BMI, and alcohol drinking (OR, 95% CI = 1.545, 1.088-2.194). CONCLUSIONS: Alcohol and abnormal BMI were associated with a higher risk of gout, whereas the rs671 GA+AA genotype was associated with a lower risk. Noteworthy, BMI and alcohol had a significant interaction on gout risk. Stratified analyses revealed that alcohol drinking especially among normal-weight individuals might elevate the risk of gout irrespective of the genotype.

The effect of ALDH2 rs671 gene mutation on clustering of cardiovascular risk factors in a big data study of Chinese population: associations differ between the sexes.

BACKGROUND: The ALDH2 rs671 genetic polymorphism has been linked with cardiovascular diseases (CVDs), but comprehensive epidemiological studies are lacking. An observational, retrospective big data study was carried out to evaluate the associations between this polymorphism and clustering cardiovascular risk factors (CRFs) in a Chinese population. METHODS: A total of 13,101 individuals (8431 males and 4670 females) were enrolled. Genetic polymorphism was assessed using gene mutation detection kits, coupled with an automatic fluorescent analyzer. Other data were obtained from the records of the Department of Health Care at Peking Union Medical College Hospital. RESULTS: Comparing the concentrations of common biochemical analytes, including BMI, SBP, DBP, ALT, AST, γ-GT, TBil, Cr, Glu, TC, TG, and HDL-C among individuals with the GG, GA, and AA genotypes of ALDH2 rs671, we found significant differences in males (all p < 0.001), but not in females. For males, the frequencies of hypertension, diabetes, and obesity were significantly higher for GG than for GA or AA (all p < 0.05). However, there was no significant difference for dyslipidemia, and no significant associations were observed for all frequencies in females. The prevalence of individuals with 1-4 CRFs was significantly higher among GG males than those carrying GA or AA, and fewer GG males had non-CRFs (all p < 0.05). CONCLUSION: Polymorphisms of ALDH2 rs671 are associated with clustering CRFs, especially hypertension and diabetes in males, but not in females. These associations are likely mediated by alcohol intake, which is also associated with this gene.

The Association and Interaction of Aldehyde Dehydrogenase 2 Polymorphisms with Food Group Intake and Probability of Having Non-Alcoholic Fatty Liver Disease.

PURPOSE: This study investigated the association between the aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, food group intake, and the probability of having non-alcoholic fatty liver disease (NAFLD) in a Chinese population. PATIENTS AND METHODS: A total of 3506 adults were enrolled in this study, and all underwent physical examinations and genotyping of polymorphisms with polymerase chain reaction. Participants filled out a dietary questionnaire that was used to assess the frequency and quantity of food consumption. RESULTS: We found that milk groups were associated with a lower probability of developing NAFLD. On the contrary, meat and salted and smoked foods were associated with a higher probability of NAFLD. However, the influences of salted and smoked foods and fresh fruit and vegetables on NAFLD were obviously different in the two genotype groups. Salted and smoked foods intake was a factor associated with a higher probability of having NAFLD or nonalcoholic steatohepatitis (NASH) in the A genotype group, but there was no effect in the G genotype group. Moreover, eating salted and smoked foods several times per week was associated with a higher probability of having NAFLD than seldom consuming them. Consumption of fresh fruit and vegetables was not a factor influencing the probability of having NAFLD in the A genotype group, and there was no effect in the G genotype group. Further analysis of the interaction indicated that the GA +AA genotype showed an interaction with fresh fruit and vegetables and salted and smoked foods. Moreover, it was not obvious that meat intake increased the probability of having NAFLD or NASH among different genotypes. CONCLUSION: Our results indicate that ALDH2 rs671 GA and AA genotypes are factors associated with increased probability of NAFLD among Chinese subjects. This could stimulate the development of novel approaches for preventing NAFLD.

Alcohol Use and Depression: A Mendelian Randomization Study From China.

Background: Alcohol use has been linked to a number of physical conditions, but the relationship between alcohol drinking and depression, one of the most common mental disorders that is a significant contributor to the global burden of disease, is still under debate. We aim to help fill the literature gap on the causal effect of alcohol use on depression by using genetic instruments of ALDH2 rs671 and ADH1B rs1229984 in the Mendelian randomization (MR) framework. Materials and Methods: We collected a sample of 476 middle-aged and older adults from mainland China. The 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) was used to measure the status of depression. The frequency and intensity of alcohol consumption were measured by (1) a binary indicator of drinking or not, (2) the total number of drinking occasions during the past 30 days, and (3) the weekly ethanol consumption in grams. Results: MR estimates indicated that alcohol use was causally associated with a lower risk of depression. Parameter estimates of drinking or not (b = -0.127, p = 0.048), number of drinking occasions (b = -0.012, p = 0.040), and weekly ethanol consumption (b = -0.001, p = 0.039) were all negative and statistically significant. The results were robust after adjustments for potential confounders (e.g., income, smoking, and parental drinking behaviors), and the exclusion of heavy or former drinkers. Conclusions: This is one of the first study to investigate the causal relationship between alcohol use and mental health using an MR design in East Asian populations. Further studies are needed to clarify the mechanisms of this causal link.

Association Between ALDH-2 rs671 and Essential Hypertension Risk or Blood Pressure Levels: A Systematic Review and Meta-Analysis.

Background: The association between Aldehyde dehydrogenase II (ALDH-2) rs671 polymorphism and essential hypertension (EH) risk or blood pressure (BP) levels remains unclear. Objective: To systematically review the influence of the aldehyde dehydrogenase II rs671 polymorphism on essential hypertension risk and blood pressure levels. Methods: The PubMed, EMbase, Web of Science, Cochrane Library, CNKI and CBM databases were electronically searched to identify case-control or cohort studies published prior to July 2019 that examined the association between the rs671 polymorphism and the risk of essential hypertension or blood pressure levels. A meta-analysis was conducted with Stata 15.1 software. Results: Twenty-two articles were included. Among these articles, 20 incorporated 30 individual studies evaluating the association between the rs671 polymorphism and EH (11,051 hypertensive patients and 15,926 normotensive controls), and 8 incorporated 12 individual studies evaluating the association between the rs671 polymorphism and BP (20,512 subjects). The results of the meta-analysis showed that the mutation of the rs671 polymorphism was associated with a significantly decreased risk of EH in all models: allelic model (OR = 0.80, 95% CI: 0.73-0.87), homozygous model (OR = 0.71, 95% CI: 0.63-0.80), heterozygous model (OR = 0.79, 95% CI: 0.72-0.87), dominant model (OR = 0.79, 95% CI: 0.71-0.87), and recessive model (OR = 0.76, 95% CI: 0.68-0.85). In the stratified analyses, significant associations were found for males, drinkers and population-based studies. Simultaneously, the A carriers had lower SBP (WMD = -1.78, 95% CI: -3.02 to -0.53) and DBP (WMD = -1.09, 95% CI: -1.58 to -0.61) levels than individuals with the GG homozygote. Conclusion: The collective findings of this meta-analysis suggested that the ALDH-2 rs671 polymorphism represented an important genetic marker in the development of hypertension. Considering the overall quality of evidence and the relatively small pooled sample size, more well-conducted high-quality studies are required to verify the above conclusion. Systematic Review Registration Number: PROSPERO (CRD42019129746).

[Microanalysis of Acetaldehyde Dehydrogenase 2 Genotype Based on SNaPShot-FCA].

OBJECTIVE: To establish SNaPShot-fluorescence capillary analysis (SNaPShot-FCA) assay for rapid detection of the genotype of aldehyde dehydrogenase 2 gene (ALDH2) rs671 locus. METHODS: The genomic DNA was extracted from peripheral blood cells. Using R6G-ddATP and cy5-ddGTP as fluorescent substrates, the ALDH2 gene was amplified by SNaPShot to generate DNA products with different fluorescent dyes at the 3' end. FCA was used to detect the products separated by agarose gel electrophoresis and recovered by gel recovery kit, and the genetype of ALDH2 polymorphism was analyzed by fluorescence spectrum. The samples were tested three times repeatedly and compared with the results of DNA sequencing. RESULTS: The optimal concentrations of R6G-ddATP and cy5-ddGTP were 1.4 µmol/L and 8.0 µmol/L, respectively. 106 samples were tested for ALDH2 genotype by SNaPShot-FCA under optimal conditions, including 67 of wild type (GG), 38 of hybrid type (AG), and 1 of mutant type (AA), which were consistent with the sequencing results. CONCLUSION: This study successfully established the SNaPShot-FCA for the micro-detection of ALDH2 genotype for the rapid screening and identification of ALDH2 gene.

The Bidirectional Effect of Defective ALDH2 Polymorphism and Disease Prevention.

Despite the role of aldehyde dehydrogenase 2 (ALDH2) in the detoxification of endogenous aldehydes, the defective polymorphism (rs671), which is highly prevalent among East Asians, does not show a serious phenotype, such as congenital abnormality. However, unfavorable and favorable impacts of the variant allele, ALDH2*2, on various disease risks have been reported. The underlying mechanisms are often complicated due to the compensatory aldehyde detoxification systems. As the phenotypes emerge due to overlapping environmental factors (e.g., alcohol intake and tobacco smoke) or individual vulnerabilities (e.g., aging and apolipoprotein E ε4 allele), polymorphism is therefore considered to be important in the field of preventative medicine. For example, it is important to recognize that ALDH2*2 carriers are at a high risk of alcohol drinking-related cancers; however, their drinking habit has less adverse effects on physiological indices, such as blood pressure, body mass index, levels of lipids, and hepatic deviation enzymes in the blood, than in non-ALDH2*2 carriers. Therefore, opportunities to reconsider their excessive drinking habit before adverse events occur can be missed. To perform effective disease prevention, the effects of ALDH2*2 on various diseases and the biological mechanisms should be clarified.