Think of a person’s genetic makeup as a gigantic orchestra. Each of the instruments’ notes represents a gene, a protein. Various cell types can combine notes and chords into simple or complex variations. Sometimes the music flows seamlessly, sometimes a wayward note can destroy a certain passage, even the entire concert. Gene mutations are like discordant musical notes. Just as mutation of the hemoglobin gene can cause sickle-cell anemia, so too can genetic mutation of the liver enzyme aldehyde dehydrogenase (ALDH) cause a person to have an aversive reaction to alcohol.
"The major way you eliminate alcohol is via the liver," said Matt McGue, professor and chair of the Department of Psychology at the University of Minnesota. "There are two enzymes that regulate the metabolism of alcohol. First, alcohol dehydrogenase (ADH) converts alcohol into acetaldehyde. Second, ALDH converts acetaldehyde to acetate." Acetate is then metabolized by tissues outside of the liver.
"Acetaldehyde is a toxic compound," said Ting-Kai Li, Distinguished Professor at the Indiana University School of Medicine and one of the study’s authors, "and the body has an aversive reaction to it." This aversion can manifest itself through cardiovascular complications, hypothermia, nausea, asthma and facial flushing. "If the ALDH enzyme is normal then the acetaldehyde is metabolized very quickly and people don’t have this reaction," said Li. "If there is a genetic mutation of that enzyme, it becomes very inefficient and cannot metabolize acetaldehyde."
Both Li and McGue noted that a pharmacological treatment used with alcoholics, called Antabuse, essentially facilitates the toxic effects of acetaldehyde. Antabuse blocks the conversion of acetaldehyde to acetate, which basically makes alcoholics sick when they drink. McGue calls it a kind of "aversion therapy" that’s used in combination with other types of treatment.
The bad news is that people who naturally have this genetic mutation and nonetheless drink alcohol will likely experience unpleasant consequences. The good news is that people with this genetic mutation rarely develop alcohol disorders such as alcoholism. Approximately 50 percent of Chinese and Japanese, but only two percent of Chinese and Japanese alcoholics, inherit the mutated form of ALDH. There is a virtual absence of the mutated ALDH gene among European and African ancestry. When compared to other ethnic groups, people of Asian descent experience lower rates of alcoholism and higher rates of abstinence from alcohol.
"Through 30 years of reports," said McGue, "most East Asians who had one mutation of the gene were thought to have a pretty strong reduction in risk of developing alcoholism. Never had there been found an East Asian alcoholic that had two copies of this mutation." That is, until now. Researchers in Taiwan recently made this extremely rare discovery, publishing their findings in the December edition of Alcoholism: Clinical & Experimental Research.
McGue called this finding "fascinating and potentially significant." He explained that "this is someone who should have, by all rights, never have been able to become alcoholic. Yet he did, and the question is why. It’s important to understand how someone could inherit so much protection and nonetheless go on to develop alcoholism." McGue speculated that some contributing factors could be physiological, some could be socio-cultural, and some could be genetic.
"This case report presents us with an unusual, unexpected finding," said Li. "Does it teach us anything? Yes, it teaches us that protection isn’t absolute."
Funding for this Addiction Science Made Easy project is provided by the Addiction Technology Transfer Center National Office, under the cooperative agreement from the Center for Substance Abuse Treatment of SAMHSA.
Articles were written based on the following published research:
Li, T., Chen, Y., Lu, R., Peng, G., Wang, M., Wang, H., Ko, H., Chang, Y., Lu, J., Yin, S. (1999, December). Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2 2 variant gene allele. Alcoholism: Clinical and Experimental Research, 23(12), 1853.