Asian Flush (ALDH2 and its story associated with Asian rice cultivation)

If you have ever gone out to a bar with three friends of East Asian descent (Chinese, Japanese or Korean), you would probably have noticed that the face of at least one of the three would turn red after just a few sips of alcoholic drinks. This change may alarm you so much that you even feel the urge to inquire about his/her wellbeing. Then most likely, this friend of yours would tell you that there is nothing to worry about. It is just an “Asian flush.”

The Asian flush, sometimes called the “Asian glow”, refers to a common reaction to alcohol among East Asians. The cause of facial flushing as a reaction to alcohol was revealed in a 1981 article in Lancet, as a deficiency of a liver enzyme called ALDH2.

The chemical breakdown of alcohol happens primarily in the human liver and is facilitated by two major enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH).  The process is illustrated below:

ALDH2 was cloned and sequenced in the mid-90s. The defective allele of the ALDH2 gene is called ALDH2*2 which bears a single point mutation (G-A transition at the DNA level) from its active counterpart ALDH2*1 allele. This mutation translates to a substitution of lysine (K) for the glutamic acid (E) and reduces the enzyme’s ability to convert acetaldehyde, a metabolic byproduct of alcohol, into acetate. Flushing is a result of an accumulation of acetaldehyde in blood and causes dilation of capillaries.  Acetaldehyde is a carcinogen in human.  Research has shown that a history of facial flushing when drinking is indicative of ALDH2 deficiency, and that an ALDH2-deficient drinker who drinks two beers per day has six to ten times the risk of developing esophageal cancer as a drinker not deficient in the enzyme.

What’s interesting about this ALDH2*2 allele is that it is carried only by people of East Asian decent. The following figure shows the geographic distribution of ALDH2*2 allele in red, together with other four major haplotypes consist of five SNPs genotyped. The area of each section is proportional to the frequency of the haplotype it represented. Roughly one third of the eastern Asian population carries this mutation.

The geographic and racial distribution of the ALDH2*2 allele has led to a hypothesis which links its origin to the rice cultivation in this area. One theory says that this allele is derived from the ancient Pai-Yuei or Baiyue (百越) tribe, which was widely distributed along the southeast coast of China down to the Yunnan Province and the northern part of Southeast Asia 2000–3000 years ago. This ancient tribe was thought to be the creator of HEMUDU (河姆渡文化) culture, the rice cultivation, and tea.
A similar conclusion was made in the study of another alcohol metabolizing enzyme, ADH. A point mutation in ADH1B gene causes an amino acid substitution from Arg to His at location 47. This mutant allele (called ADH1B*47His) produces a mutant enzyme that converts alcohol to acetaldehyde at a much faster rate than the wild type enzyme. This results in the accumulation of acetaldehyde in liver and blood, the exact the same effect as having the defective ALDH2*2 allele.  Same as ALDH2*2 allele, ADH1B*47His is almost exclusively found in Asian populations with the highest frequency centered on the regions where rice was first cultivated. The following plot shows the gradient of mutant allele ADH1B*47His, covering China, Korea, Japan and other Asian countries. Also spotted on the map are locations where relics of ancient rice culture have been confirmed by archeological records.

This data begs the question of why people who discovered rice ended up carrying a faster alcohol converting enzyme and slower acetaldehyde converting enzyme, both of which result in a toxic compound accumulating in one’s liver and blood. One theory is that people who held these mutated genes were discouraged from consuming too much alcohol. Alcohol production is almost as ancient as rice culture. It provided a safe source of drinkable liquids, and it helped preserve the surplus of rice. It has also been speculated that excessive alcohol consumption could have had the same social, economic and health related problems that we see in contemporary society. Therefore in this rice/alcoholic culture, people without the mutations mentioned above were at a disadvantage because they were more likely to develop heavy drinking problems. This line of reasoning may not be entirely straightforward, however, there is statistical evidence to demonstrate that modern people with either mutant alleles (ADH1B*47His or ALDH2*2) are less likely to become alcoholics.

Finally, there are two more important facts regarding the “Asian flush”. First, some people of European descent experience a similar phenomenon, even though they may not carry the ALDH2*2 allele. The exact genetic cause for the “European flush” is not yet known, but the “protective” effect against alcoholism seems to be the same. Second, the “Asian flush” can disappear for some people later in their lives, especially if they continuously “practice” drinking. However, for anyone who has ever experienced the “Asian flush”, there is a higher risk of getting esophageal cancer and other types of cancers if they practice heavy alcohol consumption.