Each person’s body responds differently to alcohol intake. Some people turn red in the face and become intoxicated quickly even with a small amount of alcohol, while others remain calm even after drinking large amounts. Genetic factors are deeply involved behind these differences. Furthermore, recent research has revealed that genes also affect the risk of developing alcoholism. In this article, we will explain in detail the mechanisms of genes related to alcohol tolerance and dependence, and how to utilize genetic testing.
1. Mechanism of alcohol metabolism and the role of genes
1-1. Alcohol decomposition process
Alcohol (ethanol) is metabolized in the body in a two-step process:
It is broken down into acetaldehyde by alcohol dehydrogenase (ADH).
It is converted into harmless acetic acid by **acetaldehyde dehydrogenase (ALDH)**.
When this process isn’t working properly, acetaldehyde builds up in the body and causes a “flushing reaction” that includes facial flushing, nausea, and palpitations.
1-2. Major genes that determine alcohol tolerance
The ability to metabolize alcohol is primarily determined by the ADH1B and ALDH2 genes.
Gene
Role
Main variants
Features
ADH1B
Converts alcohol to acetaldehyde
ADH1B (Arg48His)
When the activity is high, acetaldehyde accumulates rapidly, causing discomfort when drinking alcohol.
ALDH2
Breaks down acetaldehyde
ALDH2 (Glu504Lys)
Mutant (Lys) type reduces ALDH2 activity, causing a flushing reaction.
Approximately 40% of Japanese people have a mutation in the ALDH2 gene (Lys type) and are known to have low alcohol tolerance.
1-3. Genetic differences in individuals and ethnicities
Differences in alcohol tolerance are also evident among ethnic groups. For example, people in East Asia (Japan, China, and Korea) tend to have low ALDH2 activity, whereas most Westerners have active ALDH2.
Distribution of alcohol tolerance
High resistance (ALDH2 activation type) : Caucasian and African
Intermediate resistance (ADH1B active type) : Middle East, India
Low resistance (ALDH2 inactive type) : Japan, China, Korea
Such genetic backgrounds influence each country’s drinking culture and the incidence of alcohol-related diseases.
2. Alcoholism and genetic factors
2-1. What is alcoholism?
Alcoholism is a chronic disease that results in loss of control over drinking and is a complex relationship between genetic and environmental factors. According to the World Health Organization (WHO), more than 50% of the risk of developing alcoholism is attributable to genetic factors.
2-2. Genes related to alcoholism
Genes that have been identified that increase the risk of alcoholism include the following:
Gene
Role
Impact
GABRA2
Regulation of neurotransmission
Alters the sensitivity of GABA receptors, enhancing the sedative effects of alcohol
DRD2
Dopamine Receptors
Changes the activity of the reward system, affecting how you feel about the pleasure of drinking alcohol
CYP2E1
Alcohol breakdown
High enzyme activity leads to faster decomposition of alcohol and easier development of tolerance
In particular, it has been reported that individuals with a specific variant of the DRD2 gene (the A1 allele) experience stronger rewarding effects from alcohol and are at higher risk of developing addiction.
2-3. Assessment of alcohol dependence risk using genetic testing
Genetic testing can help you know in advance whether you are at risk for developing alcoholism. It can provide you with the following information:
Assessment of alcohol metabolism (ALDH2, ADH1B)
Reward system sensitivity (DRD2, GABRA2)
Risk of developing resistance (CYP2E1)
This will help you know the appropriate amount of alcohol to drink and help prevent addiction.
3. Alcohol countermeasures using genetic testing
3-1. Alcohol consumption management according to genotype
It is important to adjust your drinking habits based on the results of your genetic test.
Genotype
Recommended actions
ALDH2 mutant type (Lys type)
Avoid excessive drinking and increase the number of days off drinking
ADH1B high activity type
Slows down the rate of alcohol consumption and reduces the accumulation of acetaldehyde
DRD2 A1 allele carrier
High risk of addiction, so use in moderation and consider alternative treatments
3-2. Use in medical institutions
Medical institutions are increasingly using the results of genetic testing to assess the risk of alcohol dependence and determine treatment plans.
Determining whether pharmacotherapy (e.g., naltrexone) is appropriate
Combination with behavioral therapy (cognitive behavioral therapy)
Family Genetic Risk Assessment
It is hoped that by providing personalized medicine based on genetic information, measures to combat alcohol problems will become more effective.
4. Detailed relationship between alcohol sensitivity and genes
4-1. Detailed mechanism of the ALDH2 gene
The ALDH2 gene is one of the important enzymes responsible for the breakdown of acetaldehyde. In people with the mutant type (Lys type), the activity of ALDH2 is greatly reduced, slowing down the breakdown of acetaldehyde. As a result, the concentration of acetaldehyde in the blood rises rapidly, causing the following symptoms:
Facial flushing (flushing reaction)
Palpitations, nausea, dizziness
Headache and fatigue
Increased risk of cancer due to alcohol consumption
In addition, people with low ALDH2 activity feel strong discomfort even with small amounts of alcohol, so they naturally limit their drinking and are less likely to develop alcoholism.
4-2. ADH1B gene and alcohol metabolism rate
The ADH1B gene plays a role in breaking down alcohol into acetaldehyde. When ADH1B activity is high, alcohol is rapidly converted into acetaldehyde, resulting in a stronger flushing reaction and increased discomfort when drinking.
ADH1B gene variants
variant
Metabolic capacity
Features
**ADH1B1/1
Low
They metabolize alcohol slowly and do not get drunk easily.
**ADH1B1/2
Medium
Acetaldehyde accumulates rather quickly, which can cause discomfort when drinking alcohol.
**ADH1B2/2
High
Very rapid metabolism causes a strong flushing reaction
People with ADH1B*2/*2 metabolize alcohol too quickly, making even small amounts of alcohol more uncomfortable.
4-3. Effects of the combination of ALDH2 and ADH1B genes
Both the ALDH2 and ADH1B genes are involved in alcohol metabolism, so different combinations of genotypes affect how you respond to alcohol after drinking.
ALDH2
ADH1B
Alcohol tolerance
Features
Active type (Glu type)
Low activity (*1/*1)
High
Enjoys drinking alcohol but has high risk of dependence
Active type (Glu type)
High activity (*2/*2)
Medium
It has a fast metabolism and gets you drunk quickly
Inactive type (Lys type)
Low activity (*1/*1)
Low
I easily get sick from drinking even a small amount of alcohol
Inactive type (Lys type)
High activity (*2/*2)
Extremely low
I feel very uncomfortable when drinking alcohol and I tend to avoid it.
People with inactive ALDH2 (Lys type) are at increased risk of health risks from drinking alcohol, so proper management is required.
5. Genetics and the risk of alcohol-related diseases
5-1. Alcohol and cancer risk
People with inactive ALDH2 have a higher risk of cancer because acetaldehyde remains in the body for a longer period of time. In particular, a link has been pointed out between this and esophageal and liver cancer .
Increased cancer risk due to drinking alcohol (influence of ALDH2)
ALDH2 active type (Glu type): normal risk
ALDH2 partially active type (Glu/Lys type): risk of esophageal cancer is approximately 10 times higher when drinking alcohol
ALDH2 completely inactive type (Lys/Lys type) : Risk of esophageal cancer is approximately 50 times higher when drinking alcohol
Given this risk, people with inactive ALDH2 are advised to avoid excessive alcohol consumption.
5-2. Alcoholic liver disease and genetics
The risk of progression of alcoholic hepatitis and cirrhosis varies depending on genetic factors.
Related genes
PNPLA3 gene: Involved in lipid metabolism in the liver, and carrying the mutant type (I148M) increases the risk of alcoholic fatty liver.
TM6SF2 gene: Regulates fat accumulation in liver cells, and mutant forms accelerate the progression of liver disease.
ADH1C gene: Affects the body’s ability to metabolize alcohol, and variants increase the risk of liver damage.
Genetic testing makes it possible to assess the risk of alcohol-related liver disease and take preventative measures.
6. Genetic-based alcohol management strategies
6-1. Optimizing drinking habits according to genotype
By utilizing genetic testing, you can learn about the drinking habits that are best for you.
Genotype
Recommended drinking practices
ALDH2 active type
Drink in moderation and take several days off from drinking each week.
ALDH2 inactive type
Limit your alcohol intake and use alternative drinks
PNPLA3 mutations
Get regular liver function tests and adjust your alcohol intake
6-2. Using genetics to prevent alcoholism
It is important for people with genotypes that put them at high risk for alcohol dependence (e.g., carriers of the DRD2 A1 allele) to manage their drinking habits.
Specific preventive measures
Manage stress thoroughly and find ways to relax other than drinking alcohol.
Record your drinking volume and become aware of the increased risk of addiction.
If necessary, receive counseling and treatment at a medical institution.
7. Application of genetic testing to alcohol risk management
7-1. Types and accuracy of genetic tests
Genetic testing can provide a more accurate assessment of an individual’s ability to metabolize alcohol and their risk of becoming addicted. The following genetic tests are currently available to the public:
Main types of genetic testing
Test name
Analysis target
the purpose
ALDH2/ADH1B genetic testing
Alcohol Metabolizing Enzymes
Assessment of alcohol tolerance
GABRA2/DRD2 genetic testing
Central Nervous System Receptors
Alcoholism risk assessment
PNPLA3/TM6SF2 genetic testing
Hepatic lipid metabolism
Assessment of liver disease risk
Many genetic tests can be easily performed using saliva or blood, and results are typically available within a few weeks.
7-2. Individualized drinking guidelines using genetic information
Setting alcohol consumption recommendations based on genotype can help reduce the risk of alcohol-related diseases.
Recommended alcohol intake by genotype
Genotype
Recommended alcohol intake
Reason
ALDH2 active type (Glu/Glu)
1-2 cups per day
High decomposition capacity allows for moderate drinking
ALDH2 partially activated type (Glu/Lys)
1-2 times a week
Moderate risk from acetaldehyde accumulation
ALDH2 inactive type (Lys/Lys)
Drinking alcohol is not recommended
High health risk due to acetaldehyde accumulation
Using these guidelines can help you establish drinking habits that are right for you.
7-3. The need for alcohol education using genetic information
Providing alcohol education using genetic information will help prevent excessive drinking and addiction among young people.
Examples of educational programs using genetic information
Genotype-based drinking risk education in high schools and universities
Introducing genetic testing into corporate health management programs
Reviewing drinking habits through individual guidance at medical institutions
In particular, since there are many people in Japan who have inactive ALDH2, it is important to understand the genetic factors and form appropriate drinking habits.
8. Genetic and Alcohol-Related Pharmacological Approaches
8-1. Use of genetic information in alcoholism treatment
Individualized treatment using genetic information is effective in treating alcoholism.
Genotype-specific treatment strategies
Genotype
Treatment Recommendation
DRD2 A1 allele carrier
Uses naltrexone, which targets dopamine receptors
GABRA2 mutations
Uses baclofen, which acts on GABA receptors
CYP2E1 High Activity
Use of drugs that regulate alcohol metabolism in the liver
8-2. Development of new drugs using genetic information
In recent years, there has been progress in the development of new gene-targeting drugs to treat alcoholism.
Gene-targeted drugs under development
DRD2 receptor antagonist: Suppresses excessive dopamine activity and reduces the desire to drink alcohol
GABRA2 Modulator: Adjusting the balance of neurotransmission and suppressing stress-induced drinking
ALDH2 activators: Supports the function of ALDH2 and promotes the breakdown of acetaldehyde
If these treatments are established, it will be possible to treat alcoholism more effectively according to genotype.
9. Ethical and social issues of genetic testing
9-1. Privacy management of genetic information
Genetic information is extremely sensitive data that reflects an individual’s health condition and physical constitution, so it must be managed with great care.
Main challenges in privacy protection
Misuse of genetic information (such as disadvantages when applying for life insurance)
Personal information leaks due to data breaches
Social discrimination based on genetic information
Currently, many countries are moving to regulate the use of genetic information, and in Japan, the handling of genetic data is strictly controlled under the Personal Information Protection Act.
9-2. Social impact of alcohol countermeasures using genetic information
If alcohol control measures using genetic testing become widespread, it could have a significant impact not only on individual health management but on society as a whole.
Social impact examples
Introducing genetic testing into corporate health check-up programs
Improving insurance companies’ assessment of drinking risk
Strengthening early detection and prevention measures for alcoholism
While utilizing genetic information can be useful for optimizing drinking habits and preventing addiction, appropriate guidelines are needed.
10. The future of alcohol risk management using genetic information
10-1. Risk prediction using AI and big data
In the future, alcohol risk prediction systems that utilize artificial intelligence (AI) and big data may emerge.
Example of risk assessment using AI
Correlation analysis between genetic data and lifestyle habits
Development of an app that predicts individual drinking risks and issues warnings
Real-time feedback on the health effects of drinking
10-2. Adjusting alcohol sensitivity using gene editing technology
Advances in gene editing technologies such as CRISPR-Cas9 may one day lead to the development of treatments that can regulate alcohol metabolism.
Investigative gene editing approaches
Regulates ALDH2 activity and reduces discomfort when drinking alcohol
Adjusting DRD2 to reduce dependency risk
Strengthen liver metabolism and prevent alcohol-related diseases
If these technologies are established, it may become possible to manage alcohol risk at the genetic level.
11. Genes and the evolutionary background of alcohol tolerance
11-1. Why are East Asians more sensitive to alcohol?
Several hypotheses have been proposed from the perspective of evolutionary adaptation as to why the inactive form of ALDH2 (Lys form) is prevalent in East Asia.
Evolutionary factors hypothesis
Pathogen defense theory
The accumulation of acetaldehyde may serve as a defense against parasites and bacteria.
It is possible that people with inactive ALDH2 were more likely to survive in a humid environment, where pathogens can easily thrive.
Rice culture and fermented food theory
Rice cultivation was popular in East Asia, and fermented foods were common in the food culture.
Consuming fermented foods provides more opportunities to take in a consistent amount of ethanol, creating diversity in alcohol metabolism.
Social and cultural influence theory
It is possible that a low alcohol tolerance curbed excessive drinking and maintained social order.
Cultures with low alcohol consumption had a lower risk of alcohol-related diseases and did not select for the genetic variant.
11-2. Global distribution of alcohol metabolism genes
Research has shown that variants in genes involved in alcohol metabolism are distributed differently across regions.
Proportion of inactive ALDH2
Region
Proportion of inactive forms
Japan
Approximately 40%
China
Approximately 30-35%
South Korea
Approximately 30%
India
Approximately 5-10%
Europe
Almost 0%
As such, it can be seen that the inactive form of ALDH2 is concentrated in East Asia.
12. Alcohol metabolism and epigenetics of gene expression
12-1. What is epigenetics?
Epigenetics refers to the mechanism by which gene expression can be regulated without changing the DNA sequence.
Epigenetic changes caused by alcohol consumption have been studied, and it has been found that DNA methylation and histone modifications in particular affect alcohol metabolism.
12-2. Alcohol intake and DNA methylation
Long-term alcohol consumption may alter the methylation of the promoter regions of ALDH2 and ADH1B.
Changes in DNA methylation may alter the expression levels of alcohol-metabolizing enzymes, leading to fluctuations in drinking habits.
It has been reported that methylation levels of genes associated with the onset of addiction (e.g., the BDNF gene) are increased.
12-3. Histone modifications and alcohol tolerance
Histone acetylation may promote ADH1B expression and improve alcohol metabolism.
Histone deacetylase (HDAC) activity has been suggested to be involved in the risk of alcohol dependence.
These studies indicate that alcohol metabolism varies not only at the genetic level, but also by environmental factors and lifestyle.
13. Genotype and organs susceptible to alcohol
13-1. Liver genotype and alcohol sensitivity
Because alcohol is primarily metabolized in the liver, genetic differences in liver function determine risk for alcohol-related diseases.
Genes associated with liver disease
Gene
Contributing diseases
Impact
PNPLA3
Fatty liver, cirrhosis
Mutation (I148M) increases fat accumulation
TM6SF2
Fatty liver, cirrhosis
Mutation accelerates progression of alcoholic liver disease
HSD17B13
Hepatoprotective effect
The variant reduces the risk of cirrhosis
Genetic testing makes it possible to know in advance the effects of alcohol on the liver, enabling people to review their lifestyle habits.
13-2. The brain and the effects of alcohol
Alcohol has a profound effect on the nervous system, and the brain responds differently depending on your genotype.
Genes involved in the nervous system
BDNF gene: Involved in the development of nerve cells, and variants increase the risk of alcoholism.
GABRA2 gene: Regulates GABA receptors and influences the sedative effects of alcohol.
CHRM2 gene: Related to cognitive function and affects memory decline caused by long-term drinking.
Utilizing this genetic information could allow for individualized measures to minimize the effects of alcohol.
14. Genetic testing and personalized nutrition
14-1. The relationship between nutrition and alcohol metabolism
It is known that the intake of vitamins and minerals affects alcohol metabolism.
Niacin (Vitamin B3): Supports ADH and ALDH activity
Zinc: Involved in alcohol metabolism in the liver
14-2. Nutritional management according to genotype
By utilizing genetic information, it is possible to reduce the risks of alcoholism through proper nutritional intake.
Examples of nutritional management by genotype
Genotype
Nutritional recommendations
ALDH2 inactive type
B vitamins, antioxidants
PNPLA3 mutations
Omega-3 fatty acids, low-fat diet
BDNF mutations
Magnesium, an anti-inflammatory food
Combining nutritional and genetic information may help reduce the health risks of alcohol.
15. The future of alcohol control using genetic information
15-1. Advances in preventive medicine using genetic testing
It is expected that the spread of genetic testing will lead to further advances in preventive medicine for alcohol-related diseases in the future. For example, it will be possible to assess drinking risk according to an individual’s genotype and incorporate this into health checkups at hospitals and clinics.
Additionally, as part of personalized medical care, knowing in advance the burden on the liver associated with drinking and the risk of alcoholism will enable more appropriate health management.
15-2. Adjusting alcohol tolerance using gene editing technology
In the future, it may be possible to develop a treatment that restores the function of ALDH2 using gene editing techniques such as CRISPR-Cas9 . This could allow people with inactive ALDH2 to suppress the accumulation of acetaldehyde and reduce the health risks of drinking alcohol.
15-3. Integration of digital health and genetic data
It is possible that technology will emerge that will integrate genetic data with smartphone apps and wearable devices to monitor the state of alcohol metabolism in real time. For example, a system is being considered in which AI will analyze blood alcohol concentration and metabolic rate and suggest appropriate drinking amounts in real time.
It is expected that these technological innovations will further advance alcohol risk management using genetic information, making it possible to provide optimal health management for each individual.
Summary
Alcohol tolerance and risk of dependence are mainly determined by genes such as ALDH2 and ADH1B. Knowing these genotypes can help you establish appropriate drinking habits and reduce the risk of alcohol-related diseases.
In addition, advances in genetic testing are making personalized drinking guidelines and the prevention of alcoholism a reality, and advances in AI and gene editing technologies will likely lead to a more effective management of alcohol-related health risks in the future.
