ALDH2 Human

What is ALDH2 and what role does it play in human metabolism?

ALDH2 (Aldehyde Dehydrogenase 2) is a mitochondrial enzyme that plays a crucial role in detoxifying reactive aldehydes in the body. Its primary function is metabolizing acetaldehyde, a direct metabolite of alcohol generated by alcohol dehydrogenase (ADH). Additionally, ALDH2 metabolizes other reactive and oxidative stress-generated aldehydes, such as 4-hydroxynonenal (4-HNE) formed by lipid oxidation, which are associated with various human diseases . The enzyme's importance is highlighted by its evolutionary conservation and expression across multiple tissues, particularly in the liver where most alcohol metabolism occurs.

What is the ALDH2*2 variant and how prevalent is it globally?

The ALDH22 variant (also known as rs671 polymorphism) is one of the most common genetic polymorphisms in humans, affecting approximately 8% of the world population, equivalent to about 540 million people . This variant is highly concentrated among East Asian populations, including those from China, Japan, and Korea. The mutation involves a glutamate to lysine substitution at position 487 (E487K in the mouse model, corresponding to E504K in humans), which significantly reduces the enzyme's catalytic activity . Beyond the ALDH22 variant, researchers have identified five additional common ALDH2 missense variants with allele frequencies ranging from 0.6% to 2.5% in populations of African, Latino, South Asian, and Finnish genetic ancestries .

How does the ALDH2*2 variant affect alcohol metabolism?

The ALDH22 variant results in a drastically reduced enzymatic activity for acetaldehyde degradation. Consequently, carriers of this variant experience acetaldehyde accumulation in the bloodstream after alcohol consumption, causing the characteristic "alcohol flushing reaction." This reaction includes symptoms of facial flushing, palpitation, tachycardia, muscle weakness, headache, and nausea, presenting in approximately 43% of Japanese individuals studied by Harada et al. in 1981 . This physiological response typically leads to alcohol avoidance, although this aversion can be overcome by cultural and social factors. Research has shown that the number of heavy drinkers with the heterozygous ALDH22 genotype has increased rapidly in recent decades in Japan and Taiwan, from 2-3% to 17-26% .

How are ALDH2 knockout and knock-in mouse models created for studying the ALDH2*2 variant?

Researchers have developed knock-in mouse models expressing either human ALDH21 (wild-type allele) or ALDH22 (mutant allele) through homologous recombination techniques . The targeting vector design for these models includes:

• A 5' homologous arm consisting of a 2.6 kbp mouse genomic fragment containing the 5' untranslated region (UTR) of exon 1 of the Aldh2 gene

• Human ALDH2 (ALDH21 or ALDH22) complementary DNA (cDNA) (1554 bp)

• A 3' homologous arm consisting of a 5.1 kbp fragment

These knock-in mice are validated through PCR amplification using DNA extracted from mouse tails, with specific primers designed to identify mouse Aldh2 and human ALDH2 variants . The resulting mouse models recapitulate essentially all human phenotypes, including impaired acetaldehyde clearance, increased sensitivity to alcohol-induced toxicity, and reduced ALDH2 expression due to the dominant-negative effect of the mutation .

What methodological approaches are most effective for ALDH2 genotyping in population studies?

Genotyping for ALDH2 variants in population studies typically employs PCR-based methods. According to research protocols, mouse genotyping uses specific primers (forward: 5′-GAGGACTGTGTTGGGAGGTC-3′; reverse: 5′-GTAGGTCCGGTCCCGTTC-3′) to amplify a 264 bp fragment under specific PCR conditions (94°C for 3 min, followed by 30 cycles of 94°C for 30 s, 62°C for 30 s, and 72°C for 30 s, with a final extension at 72°C for 3 min) .

For large-scale population studies, genome-wide association studies (GWAS) and phenome-wide association studies (PheWAS) have been instrumental in correlating ALDH2 variants with numerous traits. The BioBank Japan project, for example, correlated genetic data with electronic medical records for 159 different diseases, 38 biomarkers, and 23 medication usage reports among 179,000 Japanese patients . These methodologies have revealed that the ALDH2*2 missense variant is associated with the largest number of different human traits among functional SNPs studied in Japanese populations.

What are the key methodological challenges in studying ALDH2 variant-environment interactions?

Several methodological challenges exist when studying interactions between ALDH2 polymorphisms and environmental factors:

• Establishing causal relationships between alcohol consumption and specific phenotypes is difficult because the ALDH2*2 variant often leads to alcohol avoidance due to the unpleasant flushing response .

• The interaction between genetic influence and alcohol consumption behavior is complex, as alcohol aversion can be overcome by cultural and social factors, resulting in heterozygous ALDH2*2 carriers becoming habitual heavy drinkers .

• Controlling for confounding factors is essential. Meta-analyses must carefully account for potential confounders such as gender, although some research has shown gender differences to be insignificant (P gender>0.05) in relation to ALDH2 effects on certain outcomes .

• Study heterogeneity can lead to inconsistent results, particularly regarding associations between ALDH2*2 and conditions like type 2 diabetes in different populations .

• The pleiotropic effects of the ALDH2*2 variant necessitate simultaneous consideration of multiple phenotypes, complicating study design and analysis .

How does the ALDH2 rs671 polymorphism affect cardiometabolic risk factors?

A recent comprehensive meta-analysis demonstrated significant associations between ALDH2 rs671 genotypes and cardiometabolic risk factors . The findings showed that individuals with the GG genotype (homozygous wild-type) had significantly:

• Higher BMI levels (MD=-0.26 [-0.32, -0.19], P<0.001)

• Higher blood pressure (SBP MD=-1.48 [-1.82, -1.14], P<0.001; DBP MD=-1.09 [-1.58, -0.61], P<0.001)

• Higher fasting blood glucose (FBG MD=-0.10 [-0.13, -0.07], P<0.001)

• Higher triglyceride levels (TG MD=-0.07 [-0.09, -0.04], P<0.001)

• Higher LDL cholesterol (LDL-C MD=-0.04 [-0.05, -0.02])

• Greater risk of hypertension (OR=0.83 [0.80, 0.86], P<0.001) compared to those with GA/AA genotypes (heterozygous/homozygous for the mutant allele)

Other studies have also found positive correlations between the ALDH2*2 variant and metabolic syndrome, obesity, and body mass index, while negative correlations have been observed with gout and alcohol use disorder .

What is the relationship between ALDH2 genotypes and type 2 diabetes mellitus?

The relationship between ALDH2 genotypes and type 2 diabetes mellitus (T2DM) appears to be context-dependent. Recent meta-analysis research revealed that GG genotype carriers (wild-type) had a higher risk of T2DM in populations without severe cardiovascular diseases, while GA/AA genotype carriers (with the ALDH2*2 variant) had a higher risk of T2DM in populations with severe cardiovascular diseases . This nuanced relationship suggests complex interactions between ALDH2 function, cardiovascular health, and glucose metabolism that warrant further investigation.

How do ALDH2*2 carriers differ in clinical biomarkers compared to non-carriers?

Multiple studies have documented significant differences in clinical biomarkers between ALDH22 carriers and non-carriers. Research has shown that individuals with the heterozygous (ALDH21/2) or homozygous (ALDH22/*2) genotypes exhibit significantly lower levels of:

• Systolic and diastolic blood pressure (SBP, DBP)

• Liver enzymes (AST, ALT, γ-GTP)

• Total cholesterol (TC)

• HDL cholesterol

• Triglycerides (TG)

• Daily alcohol intake

These findings highlight the extensive influence of ALDH2 genetic status on multiple physiological parameters beyond just alcohol metabolism, suggesting broader effects on metabolic and cardiovascular systems.

What evidence supports ALDH2's role as a tumor suppressor in liver cancer?

Multiple lines of evidence support ALDH2's role as a tumor suppressor in the liver:

• Engineered mouse models with the ALDH2(E487K) mutation (equivalent to the human variant) exhibit increased DNA damage response in hepatocytes, pronounced liver injury, and accelerated development of hepatocellular carcinoma (HCC) when treated with chemical carcinogens .

• ALDH2 protein levels are significantly lower in human HCC samples compared to peritumor or normal liver tissues .

• The ALDH2*2 variant increases ALDH2 protein turnover, potentially contributing to its tumor-promoting effect .

• Research concludes that "ALDH2 functions as a tumor suppressor by maintaining genomic stability in the liver, and the common human ALDH2 variant would present a significant risk factor for hepatocarcinoma" .

This evidence suggests that deficient ALDH2 activity, particularly in ALDH2*2 carriers, compromises the liver's ability to clear toxic aldehydes, potentially leading to increased DNA damage and subsequent carcinogenesis.

How does the ALDH2*2 variant influence esophageal DNA damage from alcohol exposure?

Research has investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage . This suggests that normal ALDH2 function is important for preventing alcohol-related DNA damage in the esophagus, and that carriers of the ALDH2*2 variant may be at increased risk for such damage due to impaired acetaldehyde metabolism.

The study utilized human ALDH2*1/1, ALDH21/2, and ALDH22/2 knock-in mice to investigate these effects . This approach allows researchers to directly examine how different ALDH2 genotypes influence tissue responses to alcohol exposure, providing insights into the mechanisms by which ALDH22 carriers may face increased cancer risk, particularly in the upper gastrointestinal tract.

What mechanisms explain the association between ALDH2 deficiency and increased disease susceptibility?

Several mechanisms may explain the association between ALDH2 deficiency and increased disease susceptibility:

• Impaired detoxification of acetaldehyde leads to its accumulation, which can form DNA adducts, cause protein modifications, and induce oxidative stress .

• Reduced capacity to metabolize other reactive aldehydes generated by oxidative stress, such as 4-hydroxynonenal (4-HNE), compromises cellular defense mechanisms against oxidative damage .

• Increased protein turnover of ALDH2 in carriers of the ALDH2*2 variant results in lower steady-state levels of this protective enzyme .

• Alterations in genomic stability, as evidenced by increased DNA damage response in hepatocytes of ALDH2(E487K) mice .

• Potential interactions with other metabolic pathways, as suggested by the associations between ALDH2*2 and multiple blood biomarkers, clinical measurements, biometrics, drug prescriptions, dietary habits, and lifestyle behaviors .

What explains the evolutionary positive selection of the ALDH2*2 variant despite its apparent disadvantages?

The ALDH2*2 variant has undergone positive selection within the past 2000-3000 years (approximately 100 generations) of human history, despite its apparent disadvantages related to alcohol metabolism . This evolutionary paradox remains largely unexplained. Singleton density score analysis has identified a strong selection signature in both the alcohol dehydrogenase 1B (ADH1B; 4q23) and ALDH2 (12q24) chromosome regions .

Several hypotheses might explain this selection:

• The ALDH2*2 variant may confer protection against certain endemic diseases or environmental toxins prevalent in East Asia during the selection period.

• Cultural or dietary practices involving fermented foods or beverages might have created selection pressure favoring individuals who consumed less alcohol.

• The variant may provide metabolic advantages unrelated to alcohol processing that outweigh its disadvantages.

• There may be pleiotropic effects of the ALDH2*2 variant that were beneficial in specific environmental or social contexts.

The simultaneous positive selection of both ADH1B and ALDH2 variants suggests some coordinated advantage related to altered alcohol metabolism, though the exact nature of this advantage remains a scientific mystery .

How do other ALDH2 variants outside East Asian populations affect enzyme function?

Beyond the well-studied ALDH2*2 variant, researchers have identified five additional common ALDH2 missense variants with allele frequencies ranging from 0.6% to 2.5% in populations of African, Latino, South Asian, and Finnish genetic ancestries . In vitro and cell-based studies have demonstrated that these additional variants also result in reduced ALDH2 enzymatic activity.

These findings suggest that approximately 120 million people of non-East Asian genetic ancestry, representing about 1.5% of the world population, may harbor reduced ALDH2 activity . The association of these variants with human disease has yet to be thoroughly explored, but due to their decreased enzymatic activity, carriers may face similar disease risks as those associated with the ALDH22 variant. This represents an important area for future research, as most studies to date have focused primarily on the East Asian ALDH22 variant.

What therapeutic approaches are being developed to address ALDH2 deficiency?

One promising therapeutic approach being investigated is Alda-1, a small molecule ALDH2 activator . Research has examined its protective effects on alcohol-mediated esophageal DNA damage, suggesting potential applications for reducing cancer risk in ALDH2*2 carriers who consume alcohol.

Animal models have been crucial for these studies, with researchers generating genetically engineered knock-in mice expressing human ALDH21 (wild-type) or ALDH22 (mutant) genes . These models allow for the evaluation of therapeutic interventions in a controlled environment that recapitulates the human condition.

Further therapeutic developments might include:

• Other small molecule activators that could enhance the residual activity of the ALDH2*2 enzyme

• Antioxidant therapies targeting the increased oxidative stress resulting from aldehyde accumulation

• Dietary or lifestyle interventions specifically designed for ALDH2*2 carriers

• Gene therapy approaches to introduce functional ALDH2 in tissues most affected by ALDH2 deficiency