Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes' toxicity

EBioMedicine. 2020 May:55:102753. doi: 10.1016/j.ebiom.2020.102753. Epub 2020 May 8.


Background: Aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of aliphatic aldehydes, including acetaldehyde. About 45% of Han Chinese (East Asians), accounting for 8% of humans, carry a single point mutation in ALDH2*2 (E504K) that leads to accumulation of toxic reactive aldehydes.

Methods: Sequencing of a small Mexican cohort and a search in the ExAC genomic database for additional ALDH2 variants common in various ethnic groups was set to identify missense variants. These were evaluated in vitro, and in cultured cells expressing these new and common variants.

Findings: In a cohort of Hispanic donors, we identified 2 novel mutations in ALDH2. Using the ExAC genomic database, we found these identified variants and at least three other ALDH2 variants with a single point mutation among Latino, African, South Asian, and Finnish ethnic groups, at a frequency of >5/1000. Although located in different parts of the ALDH2 molecule, these common ALDH2 mutants exhibited a significant reduction in activity compared with the wild type enzyme in vitro and in 3T3 cells overexpressing each of the variants, and a greater ethanol-induced toxicity. As Alda-1, previously identified activator, did not activate some of the new mutant ALDH2 enzymes, we continued the screen and identified Alda-64, which is effective in correcting the loss of activity in most of these new and common ALDH2 variants.

Interpretation: Since ~80% of the world population consumes ethanol and since acetaldehyde accumulation contributes to a variety of diseases, the identification of additional inactivating variants of ALDH2 in different ethnic groups may help develop new 'precision medicine' for carriers of these inactive ALDH2.

Keywords: ALDH2 deficiency; Alcohol toxicity; Alda-1 and -64; Health burden; Novel mutations.

MeSH terms

  • Acetaldehyde / metabolism*
  • Acetaldehyde / toxicity
  • Alcoholic Intoxication / enzymology
  • Alcoholic Intoxication / genetics*
  • Alcoholic Intoxication / physiopathology
  • Aldehyde Dehydrogenase, Mitochondrial / chemistry
  • Aldehyde Dehydrogenase, Mitochondrial / genetics*
  • Aldehyde Dehydrogenase, Mitochondrial / metabolism
  • Animals
  • Asian People / genetics
  • Benzamides
  • Benzodioxoles
  • Binding Sites
  • Biotransformation
  • Black People / genetics
  • Cloning, Molecular
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Ethanol / metabolism*
  • Gene Expression
  • Hispanic or Latino / genetics
  • Humans
  • Mice
  • Models, Molecular
  • Mutation*
  • NIH 3T3 Cells
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Substrate Specificity
  • White People / genetics


  • Benzamides
  • Benzodioxoles
  • N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide
  • Recombinant Proteins
  • Ethanol
  • ALDH2 protein, human
  • Aldehyde Dehydrogenase, Mitochondrial
  • Acetaldehyde