Summary

ALDH2 rs671 determines whether your body can efficiently clear acetaldehyde (a Group 1 carcinogen produced during alcohol metabolism) — the Lys504 variant causes the alcohol "flush reaction" and dramatically increases esophageal and head-neck cancer risk in carriers who drink, making this one of the most clinically consequential and clear-cut genetic variants in the entire KB.

Genotype spectrum

GG (Glu504/Glu504, ALDH2*1/*1)

Your acetaldehyde clearance system works at full capacity. Alcohol is metabolised through the toxic acetaldehyde intermediate efficiently, minimising exposure time.

GA (Glu504/Lys504, ALDH2*1/*2)

The flush reaction is genuinely protective — if you listen to it. The unpleasant symptoms discourage heavy drinking, which reduces alcoholism risk.

AA (Lys504/Lys504, ALDH2*2/*2)

Your natural aversion to alcohol is biologically rational and protective. Your body is giving you the strongest possible "don't drink" signal.

Practical takeaway

For GG Carriers (Full ALDH2 Activity)
• No ALDH2-specific alcohol restriction. Standard health guidelines apply.
• General recommendation: if you drink, moderate consumption (≤14 units/week for men, ≤7 for women, with alcohol-free days).
• Be aware: ALDH2 GG doesn't mean alcohol is harmless. Alcohol is a carcinogen regardless of ALDH2 status — it's just dramatically more carcinogenic for deficient carriers.
For GA Carriers (Dominant-Negative — ~60-80% Activity Reduction)

The critical message:

The flush reaction is not an inconvenience. It is an accurate biological alarm indicating that a Group 1 carcinogen is accumulating in your tissues. Every episode of flushing represents carcinogenic exposure that GG carriers don't experience at the same level.

Evidence-based recommendation:
• Ideal: avoid alcohol entirely. This eliminates the ALDH2-specific cancer risk completely.
• If choosing to drink: Very occasional (≤1-2 occasions per month), very small amounts (≤1 standard drink per occasion), never binge. Stop immediately if flushing occurs.
• Never attempt to "build tolerance." Tolerance to the flush sensation does occur with repeated drinking, but it does NOT reduce acetaldehyde levels or cancer risk. It merely suppresses the symptom while the carcinogenic exposure continues. This is one of the most dangerous misconceptions.
• Avoid antihistamines before drinking. Some carriers take H2 blockers (famotidine) or H1 blockers to suppress the flush. This masks the warning signal without reducing acetaldehyde. It allows continued drinking while carcinogenic exposure remains elevated.

Cancer screening consideration:
• If you have a history of regular alcohol consumption, discuss esophageal cancer screening with your GP. Upper GI endoscopy may be appropriate, especially with additional risk factors (smoking, hot beverage consumption, family history).
For AA Carriers (Near-Zero Activity)
• Natural aversion to alcohol is the expected and biologically appropriate response.
• Social strategies: normalise non-drinking. Frame as a "genetic thing" if helpful. Non-alcoholic alternatives are increasingly available and socially accepted.
• Be aware of hidden alcohol in medicatio

Evidence detail

What This Gene Does

ALDH2 (aldehyde dehydrogenase 2) is a mitochondrial enzyme responsible for the second step of alcohol metabolism: converting acetaldehyde to acetate. Alcohol metabolism is a two-step process. First, alcohol dehydrogenase (ADH) converts ethanol to acetaldehyde. Then, ALDH2 converts acetaldehyde to acetate (harmless, eventually metabolised to CO₂ and water). Acetaldehyde is the toxic intermediate — it's a Group 1 carcinogen (IARC), causes DNA damage, protein adducts, and oxidative stress. The speed at which ALDH2 clears acetaldehyde determines how long your body is exposed to this toxin after drinking.

The rs671 variant (G>A) causes a Glu→Lys substitution at position 504 (sometimes reported as position 487 depending on the numbering convention). This is a critical position in the enzyme's active site. ALDH2 functions as a tetramer (four subunits working together). The Lys504 variant (ALDH2*2) has a dominant-negative effect: even a single variant subunit in the tetramer disrupts the enzyme's catalytic efficiency. Heterozygotes (one wild-type + one variant allele) produce mixed tetramers with dramatically reduced activity — approximately 60-80% reduction. Homozygotes for the variant have near-zero ALDH2 activity.

This is not a subtle effect. When carriers drink alcohol, acetaldehyde accumulates rapidly, causing the characteristic "Asian flush" or "alcohol flush reaction": facial flushing, rapid heartbeat, nausea, headache. This is the body's distress signal that a toxic intermediate is building up.

The variant is present in approximately 30-40% of East Asian populations (Chinese, Japanese, Korean) and is extremely rare in European and African populations. It is the single most important pharmacogenomic variant for alcohol-related cancer risk.

Mechanism

Alcohol metabolism pathway:

Ethanol → [ADH1B] → Acetaldehyde → [ALDH2] → Acetate → CO₂ + H₂O
(step 1) (TOXIC) (step 2) (harmless)

Step 1 (ADH1B): Ethanol is oxidised to acetaldehyde in the cytosol. NAD+ is reduced to NADH. Rate varies by ADH1B genotype (see adh1b_alcohol entry).

Step 2 (ALDH2): Acetaldehyde enters mitochondria and is oxidised to acetate by ALDH2. NAD+ is again reduced to NADH. This is the rate-limiting step for acetaldehyde clearance.

The dominant-negative mechanism:

ALDH2 works as a homotetramer. Each subunit has a catalytic site. But the subunits must be properly folded and interfaced for the tetramer to function. The Lys504 substitution (ALDH2*2) disrupts a critical hydrogen bond at the subunit interface. Because heterozygotes produce both wild-type and variant subunits in roughly equal proportions, their tetramers are a random mix. The probability math is brutal:
• All-wild-type tetramers: ~6.25% (1/16)
• Tetramers with at least one variant subunit: ~93.75% (15/16)
• Even one variant subunit impairs the tetramer

This is why heterozygotes lose 60-80% of activity, not 50% — the variant doesn't just fail to contribute, it actively poisons the enzyme complexes it joins.

Acetaldehyde accumulation:

In GG individuals, acetaldehyde is cleared within minutes of production. In GA carriers, acetaldehyde levels after a standard drink peak ~6x higher and persist ~2-3x longer. In AA carriers, acetaldehyde reaches toxic concentrations that produce immediate severe symptoms.

The flush reaction:

Acetaldehyde causes histamine release from mast cells, vasodilation (facial flushing), tachycardia, bronchospasm, and nausea. This is a pharmacological effect of the toxin, not an allergic reaction. It's the body's accurate alarm system — every symptom reflects genuine tissue damage occurring at the cellular level.

The cancer mechanism:

Elevated acetaldehyde in the oral cavity, pharynx, and esophagus directly damages the mucosal epithelium:
1. Forms DNA adducts (N2-ethylidene-deoxyguanosine) → mutagenesis
2. Generates reactive oxygen species → oxidative DNA damage
3. Inhibits DNA repair enzymes → mutations accumulate
4. Causes sister chromatid excha

ALDH2 Alcohol

Summary

Genotype spectrum

Practical takeaway

Evidence detail

Sources (9)