Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes’ toxicity
Che-Hong Chen,
Julio C.B. Ferreira,
Amit U. Joshi,
Matthew C. Stevens,
Sin-Jin Li,
Jade H.-M. Hsu,
Rory Maclean,
Nikolas D. Ferreira,
Pilar R. Cervantes,
Diana D. Martinez,
Fernando L. Barrientos,
Gibran H.R. Quintanares,
Daria Mochly-Rosen
Affiliations
Che-Hong Chen
Department of Chemical and Systems Biology, School of Medicine, Stanford University, CA, USA
Julio C.B. Ferreira
Department of Chemical and Systems Biology, School of Medicine, Stanford University, CA, USA; Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
Amit U. Joshi
Department of Chemical and Systems Biology, School of Medicine, Stanford University, CA, USA
Matthew C. Stevens
Department of Chemical and Systems Biology, School of Medicine, Stanford University, CA, USA
Sin-Jin Li
Department of Chemical and Systems Biology, School of Medicine, Stanford University, CA, USA; Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
Jade H.-M. Hsu
Department of Chemical and Systems Biology, School of Medicine, Stanford University, CA, USA; Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan
Rory Maclean
Department of Chemical and Systems Biology, School of Medicine, Stanford University, CA, USA
Nikolas D. Ferreira
Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
Pilar R. Cervantes
Translational Medicine and Innovation Unit, Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
Diana D. Martinez
Translational Medicine and Innovation Unit, Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
Fernando L. Barrientos
Translational Medicine and Innovation Unit, Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
Gibran H.R. Quintanares
Translational Medicine and Innovation Unit, Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
Daria Mochly-Rosen
Department of Chemical and Systems Biology, School of Medicine, Stanford University, CA, USA; Corresponding author.
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.