ALCOHOL INTOLERANCE

SCIENTIFIC BACKGROUND

Alcohol intolerance is characterized by acute symptoms such as flushing, heart palpitations or muscle weakness that occur after ingestion of small amounts of alcohol. Alcohol intolerance is caused by an increased concentration of the alcohol metabolite acetaldehyde in the body. This increased concentration may be due to altered activity of the enzymes involved in the degradation of alcohol. The amino acid substitution p.(Arg48His) in the alcohol dehydrogenase 1B gene (ADH1B, formerly alcohol dehydrogenase type 2, ADH2) results in an enzyme with highly increased activity. This leads to increased degradation of alcohol into acetaldehyde, causing accumulation of this metabolite in the body. In addition, the amino acid exchange p.(Glu504Lys) in the acetaldehyde dehydrogenase type 2 gene (ALDH2) causes increased acetaldehyde accumulation, since the variant enzyme is no longer active and thus acetaldehyde cannot be degraded.

Ethanol metabolism: The enzyme ADH1B degrades ethanol to the toxic intermediate acetaldehyde. The enzyme ALDH2 detoxifies acetaldehyde by converting it to acetyl-CoA. If the enzyme ADH1B works too fast or ALDH2 too slow, acetaldehyde accumulates in the body and leads to the typical symptoms of alcohol intolerance.

Genetic alcohol intolerance occurs predominantly in Asian populations. The variant p.Arg48His in the ADH1B gene (ADH1B*2 allele) and p.Glu504Lys in the ALDH2 gene (ALDH2*2 allele) is associated with increased alcohol sensitivity and is examined as part of routine diagnostics.

Allele frequencies for ADH1B and ALDH2 variants in European and Asian populations (adapted from Wernicke, Biospektrum 2005). The variants associated with alcohol intolerance are marked with "!".

• ADH1B*1 (> 90% North and West European Populations; 10-30% Asian Populations)
• ADH1B*2 ! (< 5%; 70-90%)
• ALDH2*1 (Very frequent; ~ 50%)
• ALDH2*2 ! (Rarely; < 50%)

References

Wall et al. 2016, Alcohol Res. 38:59 / Morozova et al. 2014, Mol Genet Genomics 289:253 / Martinez et al. 2010, Hepatology 51:491 / Wernicke 2005, BIOspektrum 4:389 / Osier et al. 2002, Am J Hum Genet 71:84