Genetics And Alcohol: How Your Dna Affects Metabolism

Alcohol is the most widely used substance in the world, and its absorption, distribution, and metabolism have important health consequences. Many factors affect the rate of alcohol metabolism, including gender, age, the amount consumed, and genetics. Genetic variations in alcohol-metabolizing enzymes such as alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) influence the rate of alcohol metabolism and the risk of alcohol dependence. These genetic variations are also associated with various alcohol-related diseases and adverse health consequences. Understanding the genetic link to alcohol metabolism can provide insights into the development of interventions and preventive measures to address excessive alcohol consumption and related health issues.

Genetic variants of ADH1A, SRPRB, and PGM1

Alcohol is the most widely used substance in the world, and its absorption, distribution, and metabolism have important health consequences. Many factors affect the alcohol metabolic rate, including gender differences, age, the amount of alcohol consumed, fed or fasting state, and the health status of an individual.

In addition, the alcohol metabolic rate is affected by genetic factors, and variations in alcohol-metabolizing enzymes influence the use and effects of alcohol. The major pathway of alcohol metabolism involves two enzymes: alcohol dehydrogenases (ADHs) and aldehyde dehydrogenase (ALDH). Alcohol is initially oxidized into acetaldehyde by ADH in the cytosol, and then acetaldehyde is oxidized into acetate by mitochondrial ALDH. Class I ADH enzymes encoded by the ADH1A, ADH1B, and ADH1C genes contribute about 70% of the total alcohol-oxidizing capacity, and class II enzymes encoded by ADH4 contribute about 30%.

Several studies have reported genetic associations between ADH1B and ALDH2 and alcoholism, particularly in Asian populations. Functional polymorphisms in class I ADH enzymes are known for ADH1B rs1229984 (T/C); rs2066702 (C/T) and ADH1C rs1693482 (T/C); rs698 (A/G). The ADH1B rs1229984 is associated with faster alcohol oxidation, leading to enhanced alcohol elimination from the blood after alcohol consumption. The prevalence of this SNP is high among Asians, except for Indians, but is uncommon in other populations and is found at a low frequency in Caucasians, African Americans, and American Indians. The ADH1B rs2066702 is relatively common among individuals of African ancestry, and individuals carrying this polymorphism have a higher rate of metabolizing alcohol.

Gene variants encoding several of the alcohol-metabolizing enzymes, ADH, and ALDH are among the largest genetic associations with the risk for alcohol dependence. Certain genetic variants (i.e., alleles)—particularly the ADH1B*2, ADH1B*3, ADH1C*1, and ALDH2*2 alleles—have been associated with lower rates of alcohol dependence. These alleles may lead to an accumulation of acetaldehyde during alcohol metabolism, resulting in heightened subjective and objective effects. The prevalence of these alleles differs among ethnic groups. ADH1B*2 is found frequently in Northeast Asians and occasionally in Caucasians, ADH1B*3 is found predominantly in people of African ancestry, ADH1C*1 varies substantially across populations, and ALDH2*2 is found almost exclusively in Northeast Asians.

A study conducted in Korea found that genetic variations in ADH1A, SRPRB, and PGM1 were associated with variations in blood alcohol and acetaldehyde concentration after alcohol intake. The T allele of SRPRB rs17376019 and the C allele of PGM1 rs4643 were associated with lower blood alcohol levels, while the ADH1 rs1229976 C allele group exhibited markedly higher blood acetaldehyde levels than those of the ADH1 rs1229976 T allele group. These findings suggest that three SNPs are likely to be involved in alcohol metabolism, which might be associated with the development of alcohol-related diseases in Korea.

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)

The major pathway of alcohol metabolism involves these two enzymes. Alcohol is initially oxidised into acetaldehyde by ADH in the cytosol, and then acetaldehyde is oxidised into acetate by mitochondrial ALDH. Class I ADH enzymes encoded by the ADH1A, ADH1B, and ADH1C genes contribute about 70% of the total alcohol-oxidising capacity, and class II enzymes encoded by ADH4 contribute about 30%.

The ADH1B gene has been associated with alcoholism, particularly in Asian populations. The ADH1B rs1229984 variant is associated with faster alcohol oxidation, leading to enhanced alcohol elimination from the blood after alcohol consumption. This variant is prevalent among Asians (excluding Indians) but is uncommon in other populations. The ADH1B rs2066702 variant is relatively common among individuals of African ancestry, and individuals carrying this variant have a higher rate of metabolising alcohol.

The ADH1B*2, ADH1B*3, ADH1C*1, and ALDH2*2 alleles have been associated with lower rates of alcohol dependence. These alleles may lead to an accumulation of acetaldehyde during alcohol metabolism, resulting in heightened subjective and objective effects. The prevalence of these alleles differs among ethnic groups.

The effects of alcohol on various tissues depend on blood alcohol concentration (BAC) over time. BAC depends on various factors, including the presence of food in the stomach, the rate of alcohol drinking, and genetic polymorphism of ADH and ALDH.

Genetic polymorphisms and alcohol metabolism

Alcohol is the most widely used substance in the world. Its absorption, distribution, metabolism, and excretion after consumption determine the blood alcohol concentration (BAC). Many factors influence the alcohol metabolic rate, including gender, age, the amount consumed, liver size, body mass, fed or fasting state, and individual health status.

Genetic polymorphisms in alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes can affect alcohol metabolism and influence the risk for alcohol dependence. ADH metabolizes alcohol into acetaldehyde, which is further oxidized into acetate by ALDH. The activity of these enzymes varies between individuals, and genetic polymorphisms in the corresponding genes can alter enzyme expression, activity, and subsequent metabolites.

Several studies have reported associations between specific genetic variants and alcoholism, particularly in Asian populations. For example, the ADH1B rs1229984 polymorphism is associated with faster alcohol oxidation and enhanced elimination from the blood. This polymorphism is prevalent in Asians (except Indians) and rare in other populations. Conversely, the ADH1B rs2066702 polymorphism is common in individuals of African ancestry and is linked to a higher alcohol metabolism rate.

Other genetic variants, such as ADH1B*2, ADH1B*3, ADH1C*1, and ALDH2*2 alleles, have been associated with lower rates of alcohol dependence. These alleles may lead to acetaldehyde accumulation during alcohol metabolism, resulting in heightened effects. The prevalence of these alleles differs among ethnic groups, contributing to variations in alcohol consumption and alcohol use disorder (AUD) prevalence.

In summary, genetic polymorphisms in alcohol metabolism genes can influence the rate of alcohol oxidation, elimination, and accumulation, impacting the risk for alcohol-related health problems and disorders. These genetic variations interact with environmental factors to influence drinking patterns and their consequences across different racial and ethnic groups.

Racial/ethnic differences in alcohol metabolism

The metabolic rate of alcohol is influenced by genetic factors and variations in alcohol-metabolizing enzymes. The major pathway of alcohol metabolism involves two enzymes: alcohol dehydrogenases (ADHs) and aldehyde dehydrogenase (ALDH).

Racial and ethnic differences in alcohol metabolism have been observed in various studies. These differences are influenced by a combination of biological, genetic, environmental, and cultural factors.

Asian populations

Among Asians, several studies have reported genetic associations between ADH1B and ALDH2 and alcoholism. The ADH1B rs1229984 polymorphism, associated with faster alcohol oxidation and enhanced alcohol elimination from the blood, is prevalent in Asians (excluding Indians) but uncommon in other populations. The ADH1B rs2066702 polymorphism is also relatively common among individuals of African ancestry and results in a higher rate of alcohol metabolism.

Additionally, the ADH1B*2 allele is frequently found in Northeast Asians and occasionally in Caucasians, while the ADH1B*3 allele is predominantly found in people of African ancestry. The ALDH2*2 allele is almost exclusively found in Northeast Asians. These genetic variations contribute to ethnic differences in alcohol consumption and alcohol use disorder (AUD).

Caucasians

Caucasians have the highest drinking rates compared to other races. They exhibit a higher risk of AUD compared to Asians but lower than Hispanics and Blacks. Caucasians also experience an increased incidence of flushing, which is associated with a familial risk of developing alcoholism.

African Americans

African Americans have higher binge-drinking rates than most other races, with 19.88% for males, compared to 18.51% for Caucasian males. The ADH1B*3 allele, related to lower rates of alcohol dependence, is prevalent in individuals of African ancestry.

Hispanic Americans

Hispanic Americans have higher rates of heavy drinking than Whites and are more likely to experience health and social problems from drinking.

Native Americans

Native Americans, including American Indians, Alaska Natives, and First Nations people, have a higher tendency towards heavy drinking due to economic, circumstantial, and historical reasons. While they share a similar genetic sequence for enzyme production with American Indians, resulting in no genetically higher levels of alcohol tolerance, they experience higher rates of alcoholism and alcohol-related problems.

Other ethnic groups

Other ethnic groups also exhibit racial and ethnic differences in alcohol metabolism. For example, individuals of Korean ancestry have higher rates of AUD than those of Chinese ancestry. North and South American Indian populations differ in phenotypes for alcohol dehydrogenase and aldehyde dehydrogenase.

These racial and ethnic differences in alcohol metabolism highlight the complex interplay between genetics, biology, environment, and cultural factors in alcohol sensitivity, tolerance, and dependence.

Alcohol metabolism and cancer risk

Acetaldehyde Toxicity

Alcohol metabolism involves the conversion of ethanol (beverage alcohol) to acetaldehyde, a highly toxic and carcinogenic metabolite. This conversion is primarily catalysed by the enzyme alcohol dehydrogenase (ADH). Certain genetic variants of ADH, such as specific alleles of the ADH1B and ADH1C genes, can lead to increased acetaldehyde production or impaired acetaldehyde breakdown. Accumulation of acetaldehyde can cause DNA damage, increase oxidative stress, and contribute to cancer development.

Ethnic and Genetic Variations

The prevalence of certain ADH and ALDH gene variants differs among ethnic groups. For example, individuals of East Asian descent often have a "superactive" form of ADH, resulting in rapid ethanol-to-acetaldehyde conversion. This increases their risk of developing alcohol-related cancers, especially if they also have an ALDH2 variant that impairs the breakdown of acetaldehyde. Genetic variations in alcohol-metabolising enzymes, such as ADH1A, SRPRB, and PGM1, have been associated with variations in blood alcohol and acetaldehyde concentrations, influencing cancer risk.

Reactive Oxygen Species

Alcohol metabolism can generate reactive oxygen species (ROS), which are chemically reactive molecules containing oxygen. ROS can damage DNA, proteins, and lipids through oxidation, contributing to cancer development. The presence of certain genetic variants may influence the production or detoxification of ROS during alcohol metabolism, thereby modulating cancer risk.

Nutritional Deficiencies

Chronic alcohol consumption can negatively impact the absorption and metabolism of various nutrients, including vitamins A, B complex, C, D, and E, as well as carotenoids. These nutritional deficiencies can contribute to DNA damage and increase the risk of certain types of cancers.

Interactions with Other Carcinogens

Alcohol use combined with other carcinogens, such as tobacco, significantly increases the risk of developing cancers of the oral cavity, pharynx, larynx, and oesophagus. Alcohol can also enhance the absorption of harmful chemicals in the mouth and throat, such as those found in cigarette smoke, further elevating the risk of oral and throat cancers.

Hormonal Imbalances

Alcohol metabolism can disrupt hormonal balance, particularly by increasing blood levels of estrogen. Elevated estrogen levels are associated with an increased risk of breast cancer.

While genetic factors play a role in alcohol metabolism and cancer risk, it is important to note that environmental and behavioural factors also contribute significantly. The interaction between these factors is complex and influences an individual's overall risk of alcohol-related cancers.

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