rs671 — ALDH2 *2

ALDH2 - The Alcohol Flush Gene

ALDH2 (aldehyde dehydrogenase 2) is the mitochondrial enzyme responsible for converting acetaldehyde to acetate during alcohol metabolism. Acetaldehyde is the toxic intermediate that causes many of the unpleasant effects of excessive drinking. The ALDH2*2 variant (rs671) is one of the most clinically significant pharmacogenomic variants known, primarily affecting East Asian populations.

The Mechanism

The rs671 variant causes a glutamic acid-to-lysine substitution at position 504¹¹ Amino acid change: glutamic acid to lysine at position 504 (E504K) of the ALDH2 protein. This change occurs in the active site and has a dominant-negative effect²² Dominant-negative: a single defective copy sabotages the protein complex even when a normal copy is present - even one copy of the *2 allele dramatically reduces enzyme activity because ALDH2 functions as a tetramer³³ A tetramer is a protein complex assembled from four subunits, and incorporating even one defective subunit impairs the entire complex. Heterozygous carriers retain only about 6% of normal activity, while homozygous carriers have essentially zero activity. This variant is classified as pathogenic by ClinVar⁴⁴ ClinVar
VCV000018390.

The Flush Reaction

When ALDH2 activity is impaired, acetaldehyde accumulates rapidly after drinking alcohol. This triggers the characteristic "Asian flush" or "alcohol flush reaction": facial flushing, rapid heartbeat, nausea, headache, and general discomfort. These symptoms are caused by acetaldehyde's direct toxic effects on blood vessels and tissues. The reaction is the body's warning that a carcinogenic compound is accumulating.

The Cancer Connection

The most serious consequence of ALDH2 deficiency is cancer risk. Acetaldehyde is classified as a Group 1 carcinogen⁵⁵ Group 1 carcinogen
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lancet Oncol, 2009 by the IARC⁶⁶ Group 1: sufficient evidence of carcinogenicity in humans, the highest IARC classification. Heterozygous carriers who drink regularly have a 6-10 fold increased risk of esophageal squamous cell carcinoma. This risk is so significant that the World Health Organization has identified ALDH2 deficiency combined with alcohol consumption as a major preventable cause of cancer in East Asia.

Nitroglycerin Interaction

ALDH2 is also involved in the bioactivation of nitroglycerin (glyceryl trinitrate), a medication used for angina chest pain. Li et al. showed⁷⁷ Li et al. showed
Li Y et al. ALDH2 bioactivation of nitroglycerin. Arterioscler Thromb Vasc Biol, 2006 that ALDH2*2 carriers had a reduced vasodilatory response to nitroglycerin, which could be clinically important during cardiac emergencies.

Practical Implications

If you carry the *2 allele, the flush reaction is not just an inconvenience - it is a cancer warning signal. The safest approach is to avoid or severely limit alcohol consumption. If you do not experience flushing (GG genotype), standard alcohol guidelines apply, though moderation remains advisable for overall health. Note that in European populations, this variant is extremely rare (less than 0.01%), while in East Asian populations it is the most common pharmacogenomic variant, affecting nearly 1 in 3 people.