Evidence map›Paper›PMID 39075523›Full record

ArticleJournal of translational medicine2024

Uncovering newly identified aldehyde dehydrogenase 2 genetic variants that lead to acetaldehyde accumulation after an alcohol challenge.

Freeborn Rwere, Joseph R White, Rafaela C R Hell, Xuan Yu, Xiaocong Zeng, Leslie McNeil, Kevin N Zhou, Martin S Angst, Che-Hong Chen, Daria Mochly-Rosen and 1 more

Abstract read
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In one paragraph

Article in Journal of translational medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed.

  1. Observational
  2. Review
  3. Article
  4. Article
  5. Review
  6. Observational
  7. Review
  8. Review
  9. DownregulatedCells · 2025
    Article
  10. Article
  11. Article
  12. Alcohol exposure alters the diversity and composition of oral microbiome.Frontiers in cellular and infection microbiology · 2025
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Freeborn RwereDepartment of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Joseph R WhiteDepartment of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Rafaela C R HellDepartment of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Xuan YuDepartment of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Xiaocong ZengDepartment of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Leslie McNeilDepartment of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Kevin N ZhouDepartment of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Martin S AngstDepartment of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Che-Hong ChenDepartment of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Daria Mochly-RosenDepartment of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Eric R GrossDepartment of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, 94305, USA. ergross@stanford.edu.ORCID 0000-0002-0589-6446

Funding

MECHANISMS OF ETHANOL-INDUCED CARDIAC PROTECTIONR01AA011147 · NIAAA · STANFORD UNIVERSITY · PI DARIA MOCHLY-ROSEN · 1996 to 2026
$8.2M
Mechanisms of Ethanol-Induced Cardiac ProtectionR37AA011147 · NIAAA · STANFORD UNIVERSITY · PI MOCHLY-ROSEN, DARIA · 2009 to 2018
$5.3M
Precision Targeting of Aldehyde Pathways for Patients Requiring AnesthesiaR35GM119522 · NIGMS · STANFORD UNIVERSITY · PI Eric Richard Gross · 2016 to 2026
$5.1M
NIAAA NIH HHS AA011147NIAAA NIH HHS R01 AA011147NIAAA NIH HHS R37 AA011147NIGMS NIH HHS GM119522NIGMS NIH HHS R35 GM119522
6 · The paper itself

Abstract

backgroundAldehyde dehydrogenase 2 (ALDH2) is critical for alcohol metabolism by converting acetaldehyde to acetic acid. In East Asian descendants, an inactive genetic variant in ALDH2, rs671, triggers an alcohol flushing response due to acetaldehyde accumulation. As alcohol flushing is not exclusive to those of East Asian descent, we questioned whether additional ALDH2 genetic variants can drive facial flushing and inefficient acetaldehyde metabolism using human testing and biochemical assays.

methodsAfter IRB approval, human subjects were given an alcohol challenge (0.25 g/kg) while quantifying acetaldehyde levels and the physiological response (heart rate and skin temperature) to alcohol. Further, by employing biochemical techniques including human purified ALDH2 proteins and transiently transfected NIH 3T3 cells, we characterized two newly identified ALDH2 variants for ALDH2 enzymatic activity, ALDH2 dimer/tetramer formation, and reactive oxygen species production after alcohol treatment.

resultsHumans heterozygous for rs747096195 (R101G) or rs190764869 (R114W) had facial flushing and a 2-fold increase in acetaldehyde levels, while rs671 (E504K) had facial flushing and a 6-fold increase in acetaldehyde levels relative to wild type ALDH2 carriers. In vitro studies with recombinant R101G and R114W ALDH2 enzyme showed a reduced efficiency in acetaldehyde metabolism that is unique when compared to E504K or wild-type ALDH2. The effect is caused by a lack of functional dimer/tetramer formation for R101G and decreased V

conclusionsWe identified two additional ALDH2 variants in humans causing facial flushing and acetaldehyde accumulation after alcohol consumption. As alcohol use is associated with a several-fold higher risk for esophageal cancer for the E504K variant, the methodology developed here to characterize ALDH2 genetic variant response to alcohol can lead the way precision medicine strategies to further understand the interplay of alcohol consumption, ALDH2 genetics, and cancer.

Indexed as

AcetaldehydeAldehyde Dehydrogenase, MitochondrialEthanolGenetic VariationAdultAnimalsFemaleFlushingHumansMaleMiceNIH 3T3 CellsReactive Oxygen SpeciesAcetaldehydeAldehyde Dehydrogenase, MitochondrialALDH2 protein, humanEthanolReactive Oxygen SpeciesAcetaldehydeAlcoholAlcohol challengeAldehyde dehydrogenase 2 (ALDH2)Enzyme kineticsGenetic variant

Identifiers

PMID39075523
PMCPMC11288122

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.