ALDH2

Located on chromosome 12, the ALDH2 gene encodes the enzyme aldehyde dehydrogenase 2, which is crucial for detoxifying aldehydes, including acetaldehyde from alcohol metabolism. 

ALDH2 converts acetaldehyde into acetate, mitigating its toxic effects. 

Predominantly found in the liver, ALDH2 exists in both cytosolic and mitochondrial forms. 

Notably, about 50% of East Asians carry a variant that impairs ALDH2 activity, leading to slower acetaldehyde breakdown and alcohol flush reactions. 

This variant is linked to increased risks of alcoholism, certain cancers, and cardiovascular diseases. 

Understanding ALDH2's role in detoxification and its genetic variations is essential for assessing disease risks and developing targeted therapies.

What is ALDH2?

The ALDH2 gene, located on chromosome 12 at 12q24.12, provides instructions for producing the enzyme aldehyde dehydrogenase 2. 

ALDH2 is part of the aldehyde dehydrogenase superfamily, a group of phase I oxidizing enzymes that detoxify endogenous and exogenous aldehydes into their corresponding carboxylic acids. 

The first step in ethanol metabolism is the conversion of ethanol to acetaldehyde, a toxic reactive byproduct, by the enzyme alcohol dehydrogenase. ALDH2, with its high affinity for acetaldehyde, then rapidly metabolizes this toxic compound into acetate. [7.] 

The ALDH2 enzyme is primarily found in the mitochondrial matrix of cells, with the highest abundance in the liver. [7.] 

There are two major isoforms of ALDH2 in the liver: one in the cytosol of hepatocytes, the other in hepatocyte mitochondria. Most Caucasians possess both major isozymes, whereas approximately 50% of East Asians have the cytosolic isozyme but lack the mitochondrial isozyme. [1.] 

Beyond its role in alcohol metabolism, ALDH2 is involved in the detoxification of other aldehydes produced during oxidative stress. [10.]

Variants in the ALDH2 gene are associated with altered risks for alcoholism, certain cancers, and cardiovascular diseases. [1., 4., 6.] 

Thus, the ALDH2 gene and its protein product play a critical role in both alcohol metabolism and the broader detoxification of harmful aldehydes, with significant implications for health and disease risk, particularly in populations with common genetic variants.

The ALDH2 Gene Variance in East Asian Populations [5.] 

The ALDH2*2 missense variant, known for causing alcohol flushing reactions, is the single genetic polymorphism linked to the most traits in humans, affecting nearly 8% of the global population, primarily among East Asians. 

This dysfunctional ALDH2 variant impacts various blood biomarkers, clinical measurements, biometrics, drug prescriptions, dietary habits, and lifestyle behaviors. It also increases susceptibility to aldehyde-related diseases, such as cancer and cardiovascular disease. 

Despite these associations, the interaction between alcohol and ALDH2-related pathology remains unclear. Genetic evidence suggests that the ALDH2*2 variant has been favorably selected over the past 2000-3000 years.

ALDH2 plays a crucial role in detoxifying acetaldehyde, a toxic byproduct of alcohol metabolism, and other reactive aldehydes linked to diseases. 

The ALDH2*2 variant impairs this detoxification process, leading to elevated blood acetaldehyde levels and alcohol flushing reactions. This variant is associated with a higher risk of cancers, particularly in the esophagus, head, neck, and lung, among alcohol consumers. 

Recent research has focused on targeting ALDH2 in disease prevention and treatment, exploring small-molecule activators like Alda-1 that enhance ALDH2 activity and potentially reduce disease risks. 

Further understanding of ALDH2 variance's impact on health and the development of therapeutic strategies is crucial for improving health outcomes in affected populations.

ALDH2 In Health and Disease

Alterations in the ALDH2 gene have been implicated in several disease processes: 

Alcoholism [10.] 

The ALDH2 gene mutation, specifically the Glu504Lys variant (ALDH2*2), significantly impacts alcohol metabolism and drinking behavior, particularly in East Asians.

 This mutation results in reduced ALDH2 enzymatic activity, leading to a heightened sensitivity to alcohol, characterized by facial flushing and other adverse reactions. 

Studies show that individuals with the ALDH2*2 allele, especially in East Asian populations, have a lower risk of developing alcoholism and alcohol-related liver disease due to their sensitivity to alcohol. 

Conversely, those with the ALDH21 allele are more prone to alcoholism and associated liver diseases. 

Furthermore, genetic analyses reveal that the presence of ALDH2*2, alongside other polymorphisms in alcohol-metabolizing enzymes such as ADH1B and ADH1C, modifies the risk of alcoholism. 

While ALDH2*2 generally acts as a protective factor against alcoholism, some individuals with this allele still develop alcoholism, possibly due to other genetic factors affecting the brain's reward system, such as variations in the DRD4 gene.

Certain Cancers [5., 13., 14., 15.] 

Alterations in ALDH2 function, particularly the ALDH2*2 variant, are associated with an increased risk of several types of cancer. The most strongly linked cancers are those of the upper aerodigestive tract including esophageal cancer, head and neck cancers, and gastric cancer. 

Hepatocellular carcinoma (liver cancer) is also significantly associated with ALDH2 dysfunction. 

Additionally, studies have found connections between ALDH2 alterations and colorectal cancer, pancreatic cancer, and breast cancer. [13., 15.]

In urological cancers, there is evidence linking ALDH2 variants to an increased risk of bladder cancer and potentially prostate cancer. [16.]

Lung cancer has also been associated with ALDH2 repression or dysfunction. [8.] 

The relationship between ALDH2 and cancer risk is particularly pronounced in East Asian populations, where the ALDH22 variant is more prevalent, especially when combined with alcohol consumption.

Mechanisms of ALDH2-Mediated Cancers [13., 15.]

Endogenous Aldehydes Metabolism

ALDH2 detoxifies aldehydes like 4-HNE and MDA, whose accumulation can promote cancer development.

Exogenous Acetaldehyde Metabolism

ALDH2 detoxifies acetaldehyde from ethanol metabolism, preventing DNA damage and adduct formation that lead to cancer.

DNA Damage Repair

ALDH2 deficiency impairs DNA repair mechanisms, such as the FA pathway, leading to genomic instability and increased cancer risk.

Autophagy

ALDH2 influences autophagy, which helps maintain cellular homeostasis. ALDH2 deficiency can impair autophagy, contributing to cancer progression.

Immune System Dysfunction

ALDH2 deficiency affects immune responses, promoting chronic inflammation and immune evasion in cancer.

ALDH2 and Cancer Therapy [13., 15.] 

Chemotherapy

ALDH2 impacts chemotherapy resistance. Disulfiram (DSF) targets ALDH2 and enhances chemotherapy effectiveness.

Molecular Targeted Treatment

Combining ALDH2 inhibition with targeted therapies, like trastuzumab for HER2-positive cancers, can improve treatment outcomes.

Immunotherapy

ALDH2 levels influence immunotherapy responses. Targeting ALDH2 can potentiate immunotherapy efficacy.

Cardiovascular Diseases

Variants in the ALDH2 gene are associated with a higher incidence of cardiovascular conditions like angina and myocardial infarction, and it reduces the clinical benefit of nitroglycerine for angina treatment due to impaired conversion to nitric oxide. [5.] 

Osteoporosis

The ALDH2*2 variant is linked to an increased risk of osteoporosis, potentially due to impaired aldehyde detoxification affecting bone health. [5., 12.] 

Neurodegenerative Diseases

The ALDH2*2 variant is associated with a higher risk of Alzheimer's disease, likely due to the accumulation of toxic aldehydes affecting neuronal health. [5.]

Fanconi Anemia

ALDH2 deficiency accelerates bone marrow failure in Fanconi anemia patients, indicating a link between aldehyde toxicity and this rare genetic disease. [5., 13., 15.] 

Metabolic Disorders Including Obesity, Type 2 Diabetes, and Non-Alcoholic Fatty Liver Disease (NAFLD) [3.]

Individuals with the ALDH2 Glu504Lys mutation have a higher risk of obesity, insulin resistance, type 2 diabetes, and fatty liver disease. 

Mutations in the ALDH2 gene have demonstrated  lower energy expenditure and impaired thermogenesis, especially in the brown adipose tissue (BAT), which is critical for maintaining body temperature and energy balance.

Genetic Alterations in the ALDH2 Gene

The gene for the ALDH2 protein may contain alterations or mutations that cause increase or decrease of function of the ALDH2 protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Specific SNPs Associated with Alterations in ALDH2 Function

The following SNPs (single nucleotide polymorphisms) are associated with altered ALDH2 function:

rs671 (ALDH2*2)

This is the most well-known SNP, resulting in a missense mutation (Glu504Lys) that significantly reduces the enzymatic activity of ALDH2. It is associated with a variety of conditions, including alcohol flush reaction, increased risk of esophageal cancer, osteoporosis, cardiovascular diseases, and type 2 diabetes. [5., 12., 13.]

rs886205 

This SNP has been identified as a risk marker for esophageal cancer in certain populations, although results are conflicting and some studies associate this SNP with a decreased risk. [14.] 

rs441, rs4646778, rs11066028 [14.] 

These SNPs are part of a haplotype block in the ALDH2 gene and have been studied in the context of drug addiction risk.

Laboratory Testing for ALDH2

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing. Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

Biomarkers Related to ALDH2 [9.]

Fasting Plasma Glucose (FPG)

ALDH2*2 carriers often exhibit higher fasting plasma glucose levels, which can be a marker for insulin resistance and type 2 diabetes risk.

Lipid Profile

Monitoring cholesterol and triglyceride levels can help assess the risk of cardiovascular diseases associated with ALDH2 mutations.  Some genotypes are associated with elevated triglyceride and lipid levels. [9.] 

Body Mass Index (BMI)

ALDH2 mutations are associated with higher BMI levels, which can be relevant for metabolic health assessment.

Blood Pressure

In one metaanalysis, individuals with the GG genotype had a significantly higher risk of hypertension, higher systolic blood pressure, and higher diastolic blood pressure compared to those with GA/AA genotypes. [9.] 

FAQ: ALDH2 (Aldehyde Dehydrogenase 2)

What is ALDH2?

ALDH2 (Aldehyde Dehydrogenase 2) is an enzyme that plays a crucial role in the metabolism of alcohol. It helps break down acetaldehyde, a toxic byproduct of alcohol metabolism, into acetate, which is then converted into carbon dioxide and water for elimination from the body.

What is the ALDH2 Gene?

The ALDH2 gene provides instructions for making the ALDH2 enzyme. Variations in this gene can affect the enzyme's activity and efficiency in metabolizing acetaldehyde.

What is ALDH2 Deficiency?

ALDH2 deficiency is a condition where the ALDH2 enzyme is less effective at breaking down acetaldehyde due to genetic variations in the ALDH2 gene. This condition is common among East Asian populations and can lead to adverse reactions to alcohol consumption.

What Are the Symptoms of ALDH2 Deficiency?

Symptoms of ALDH2 deficiency, particularly after alcohol consumption, can include:

• Facial flushing

• Nausea and vomiting

• Rapid heartbeat (tachycardia)

• Headache

• Dizziness

• Increased risk of esophageal cancer with chronic alcohol consumption

How is ALDH2 Deficiency Diagnosed?

ALDH2 deficiency can be diagnosed through a genetic test that identifies variations in the ALDH2 gene. Additionally, blood tests measuring acetaldehyde levels after alcohol consumption can indicate reduced ALDH2 enzyme activity.

What is the ALDH2 Deficiency Test?

The ALDH2 deficiency test involves genetic testing to detect the presence of the ALDH2*2 variant, which reduces enzyme activity. This test can confirm whether an individual has ALDH2 deficiency.

What Foods Should Be Avoided With ALDH2 Deficiency? [CARTUS, SINHAROY>>>>>

Individuals with ALDH2 deficiency should avoid:

• Alcohol: the primary trigger for adverse reactions.

• Fermented foods: fermented foods including soy sauce, kimchi, and certain cheeses, which can contain acetaldehyde or its precursors.

• Certain fruits and juices: such as citrus, apples and grapes, which can produce acetaldehyde during digestion.

• Processed foods with alcohol: Such as certain sauces, desserts, and medications containing alcohol.

What Are the Health Implications of ALDH2 Deficiency?

ALDH2 deficiency can lead to several health issues, including:

• Increased sensitivity to alcohol: leading to discomfort and adverse reactions even with small amounts of alcohol.

• Higher risk of alcohol-related cancers: especially esophageal cancer due to the buildup of toxic acetaldehyde.

• Potential cardiovascular effects: chronic exposure to acetaldehyde can affect heart health.

How Can Individuals With ALDH2 Deficiency Manage Their Condition?

Managing ALDH2 deficiency involves:

• Avoiding alcohol: the most effective way to prevent symptoms and reduce the risk of long-term health issues.

• Monitoring health: regular check-ups with a healthcare provider to monitor for potential complications.

• Diet and lifestyle: avoiding other sources of aldehydes and maintaining a healthy lifestyle to support overall health.

Where Can I Find More Information About ALDH2 and Related Conditions?

For more information about ALDH2 and related conditions, consider consulting:

• Healthcare providers: medical professionals can provide personalized advice and diagnosis.

• Scientific literature: research articles and reviews on ALDH2 and its role in metabolism and health.

• Reputable health organizations: websites of organizations such as the National Institutes of Health (NIH), Genetic and Rare Diseases Information Center (GARD), and American Society of Human Genetics (ASHG).

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