ALDH2 Gene Detail
Aldehyde dehydrogenase is an enzyme that is encoded by the ALDH2 gene located on chromosome 12. The aldehyde dehydrogenase (ALDH) gene superfamily encodes enzymes that are critical for certain life processes and detoxification of numerous endogenous and exogenous aldehyde substrates via the NAD(p)+ – dependent oxidation.
Aldehyde dehydrogenase is involved in acetaldehyde detoxification, converting it from acetaldehyde to acetic acid. It is the second enzyme of the major oxidative pathway of ethanol metabolism and functions as a protector against oxidative stress.
The human liver contains 2 major ALDH isozymes. The cytosolic ALDH1 and the mitochondrial ALDH2. The 2 isoforms can be distinguished by their kinetic properties, electrophoretic mobilities and subcellular localizations. Approximately 50% of the Asian population are “atypical” and have only the ALDH1 isozyme.
ALDH2 rs671 G>A
A variation in the ALDH2 gene has been linked to differences in alcohol metabolism. This change has been observed more within the Asian population than with any other population. The change occurs when a G allele is substituted for an A allele, changing the encoded glutamate amino acid at position 487 into a lysine.
This amino acid substitution leads to the formation the ALDH*2 form – a protein that is defective at metabolizing alcohol.
AA homozygotes have no detectable ALDH2 activity. Heterozygous individuals do not automatically have half the activity. The A allele acts in a semi-dominant manner, so GA heterozygotes will have far less than half of the ALDH2 activity of GG homozygotes. In fact, the reduction in ALDH2 activity in heterozygotes is more than 100-fold. Individuals that possess this slower migrating isozyme (either one or two copies) show alcohol-related sensitivity responses. This includes facial flushing, elevation of skin temperature, increase in pulse rate and ventilation.
Alcohol consumption is linked to approximately 3.5% of all cancer-related deaths worldwide. Most individuals with the A allele will suffer from much more severe hangovers than those with the GG genotype. Therefore, these individuals tend to not be regular drinkers and likely suffer less from alcohol-related diseases.
However if alcohol is consumed, the genetic variation that inactivates ALDH2 leads to a high level of acetaldehyde in the blood of the individual, which is considered to increase the susceptibility to carcinogenesis. There is increasing evidence that suggests that this polymorphism is correlated to many types of cancer, such as esophageal cancer, head and neck cancer, colorectal cancer and gastric cancer.
These multifactorial diseases involve a complex interplay between genetic and environmental factors. So, although the AA homozygous individuals are at a greater risk of suffering from these cancers (genetic factor), they tend to naturally consume less alcohol (environmental factor) due to the experience of negative symptoms and therefore the prevalence of these cancers is lower than expected.
Whereas individuals with the G allele will not flush due to alcohol consumption, will have normal hangovers and therefore could be more likely to consume alcohol, which increases the environmental factor risk in this equation. These individuals are at an increased risk of alcoholism, alcohol-induced liver diseases and hypertension.
In summary, AA homozygotes will have a completely inactive mitochondrial aldehyde dehydrogenase and show strong physiological reactions to alcohol. Due to these negative reactions, alcohol consumption tends to be lower, however if alcohol is consumed, these individuals will have a higher risk of alcohol-related cancers.
AG heterozygotes will show elevated blood acetaldehyde during alcohol consumption, in comparison to GG homozygotes. These individuals also have an increased risk of alcohol-related cancers if alcohol is consumed. Protection against alcohol dependence is incomplete and a sizable portion of AG individuals report moderate or heavy drinking.
GG homozygotes have an active ALDH2 enzyme, showing little or no physiological response to alcohol consumption. Be aware that these individuals may consume more alcohol due to a lack of negative symptoms.
Although AA individuals suffer more from the side effects of alcohol consumption, this unfortunately does not always deter them from doing so. If these individuals do consume alcohol, their risk of suffering from alcohol related diseases is much higher than that of individuals with the GG genotype.
Esophageal cancer is known to be associated with environmental carcinogens like tobacco use or alcohol consumption. Studies have shown that alcohol consumption together with the at-risk AA alleles increases an individual’s risk for esophageal cancer and other alcohol-related diseases. It is strongly advised that individuals with the A allele completely avoid alcohol intake.
GG individuals experience less side effects with alcohol consumption, and therefore can tend to consume larger volumes of alcohol. This means that they too can suffer for alcohol-related diseases.
More than 200 diseases can be fully or partially attributed to alcohol consumption. Alcohol-related cancer, liver cirrhosis and injury accounted for the majority of mortality attributed to alcohol consumption. Over a time period of 20 years (1990 – 2010), the global cancer deaths attributed to alcohol consumption rose by nearly 100 000 individuals. All evidence indicates that the health impact of alcohol has been on the rise and this trend will likely continue.
Besides genetics, there are a number of socio-economic and cultural factors that affect the drinking patterns in a society. These include, but are not limited to high stress levels, as well as alcohol’s inexpensive cost and ease of accessibility.
Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker’s dysphoria.
Medically, alcoholism is considered as a physical and a mental illness. Family, twin and adoption studies support the view that genes contribute between 40 and 60% of the variance in alcohol dependence risk. Besides the negative health implications of alcoholism, the economic burden associated with alcohol consumption can be tremendous. One approach for reducing alcohol-related risks is brief feedback and motivational enhancement interventions.
In GG homozygous individuals, disulfiram (for example) can be used to try to treat alcoholism. This medication causes the same symptoms as individuals with the AA genotype usually experience (facial flushing, elevation of skin temperature, increase in pulse rate and ventilation) by inactivating the ALDH2 enzyme. Individuals will therefore, have a more severe reaction to alcohol consumption, as well as worse hangovers. The idea is that the experience is so unpleasant for the individual, that they will reduce their alcohol intake.
In the small percentage of AA individuals that are alcohol dependent, this approach would obviously not work, as they already experience these effects without being deterred. These individuals are at great risk of suffering from, especially, esophageal cancer, as they have both the genetic and environmental factors working against them.
Screening for carriers of the A allele may identify individuals with a high-risk for alcohol-related cancers (if alcohol is consumed). As a preventative measure, deterring these individuals from alcohol consumption could ensure that these high-risk individuals have a greater health education, may seek alcohol cessation programs, and may undergo more frequent screening of alcohol-related cancers.
The longitudinal effect of the aldehyde dehydrogenase 2*2
allele on the risk for nonalcoholic fatty liver disease