ADH ALDH genetics
Key principle
Genetics are the single largest source of inter-individual variation in alcohol metabolism, affecting both acute responses and long-term disease risk.
ALDH2*2 (rs671, Glu504Lys) — East Asian Flush
What it is
ADH1B2 and ALDH22 are the two most studied protective polymorphisms. ALDH2*2 dramatically reduces acetaldehyde metabolism.
Frequency
- ~36% of East Asians carry at least one allele; 5–10% homozygous
- Virtually absent in European and African populations
Enzyme kinetics
- ALDH2*1 (normal): Km = 0.2 µM, Vmax = 280 min⁻¹ — extremely high affinity, saturated at normal acetaldehyde levels
- ALDH2*2: Km = 1.4 µM (7× higher), Vmax = 20 min⁻¹ (14× lower) — severely compromised
Clinical effects
- Heterozygotes: 17–40% normal ALDH activity → acetaldehyde accumulates with drinking
- Homozygotes: near-zero ALDH activity → severe flushing, nausea, tachycardia even at small doses
- Almost completely protected against alcohol dependence (aversive response)
Paradox
ALDH2*2 carriers who DO drink have elevated oesophageal cancer risk (acetaldehyde is carcinogenic; forms DNA adducts): OR 14.5× (heterozygotes), 17.3× (homozygotes) at <30 g/day. Yet paradoxically: >70% reduction in alcoholic cirrhosis (reduced Kupffer cell TNF-α despite higher acetaldehyde).
ADH1B*2 (rs1229984, His48Arg) — Fast Metaboliser
Enzyme kinetics
- ADH1B*1 (ref): Km = 0.05 mM, Vmax = 4 min⁻¹
- ADH1B*2: Km = 0.9 mM, Vmax = 350 min⁻¹ → 87× higher Vmax
Frequency
- ~75% East Asian; ~20% Middle Eastern; <4% European
Effect
- Rapid conversion of ethanol → acetaldehyde → transiently elevated acetaldehyde → flushing → aversion
- Protective against alcohol dependence: OR ~0.2–0.4 (heterozygotes)
- Jews with ADH1B*2 show only <15% faster elimination — protective via aversion, not clearance
ADH1B*3 (Cys370) — African Ancestry
- Km = 40 mM, Vmax = 300 min⁻¹; frequency ~27% Yoruba, ~24% African Americans
- Protective against alcohol dependence in African populations
Clinical implications for Vitals
| Variant | Acute effect | Hangover risk | Cancer risk | Notes |
|---|---|---|---|---|
| ALDH2*2 | Flushing, nausea, tachycardia | Lower (drink less) | ↑↑ oesophageal | Aversion protective |
| ADH1B*2 | Flushing | Higher (faster acetaldehyde) | Lower | Protective overall |
| ALDH2*1/1 + ADH1B1/*1 | Normal | Average | Average | Majority of population |