Why Do Many East Asians Turn Red When They Drink? The Evolution and Health Code of Alcohol-Metabolism Genes

At any dinner table, there are always people who turn red after a single sip, their faces flushed, hearts racing. This \’facial flushing\’, so familiar across East Asia, is an evolutionary imprint written into the genome. The protagonist is aldehyde dehydrogenase 2 (ALDH2), a key enzyme that breaks down acetaldehyde, the intermediate metabolite of alcohol. In East Asia, roughly 40–50% of people carry a loss-of-function variant of this enzyme, known as ALDH2*2 (rs671). Almost absent in European and African populations, it has become one of the most distinctive genetic features of East Asians.

A study published in JHEP Reports on 16 October 2026 focused on the collision between this ancient variant and modern medical practice: carriers of ALDH2*2 who drink often show \’surprisingly normal\’ readings of serum alanine aminotransferase (ALT) — the most widely used blood marker of liver injury in routine check-ups — even though their livers may already be damaged. Combining data from 91,743 participants in the Taiwan Biobank with mechanistic mouse experiments, the study exposed a blind spot long overlooked in the clinic.

The human evidence comes first. In the Taiwan Biobank cohort, 48.7% of participants were ALDH2*2 carriers (mostly heterozygous *1/*2). Male ALDH2*1/*2 drinkers had significantly lower serum ALT than ALDH2*1/*1 (wild-type) drinkers, even after adjusting for age, sex and BMI: drinking lowered ALT by 4.97 U/L in wild-type men but by 7.56 U/L in carriers, whose γ-glutamyl transferase (GGT, another liver enzyme) was nevertheless higher. In the high-risk subgroup (BMI≥25 and GGT≥50), carriers who drank had ALT about 20 U/L lower than non-drinkers, while AST differed by less than 2 U/L. In other words, with the same drinking habits, the ALT \’alarm\’ in carriers\’ blood simply does not rise.

Why? The conventional explanation was that the aversive effects of alcohol and acetaldehyde make carriers drink less, thereby \’protecting\’ their livers. The mouse experiments tell a very different story. The team generated ALDH2*2 knock-in mice carrying the human rs671 mutation. After a single oral dose of ethanol, serum ALT rose only slightly in ALDH2*1/*2 mice, yet hepatic accumulation of the lipid peroxidation product 4-hydroxynonenal (4-HNE) was equal to or greater than in wild-type animals, MAPK inflammatory signalling was enhanced, chemokine expression was upregulated, and histological necrosis was equally pronounced. The liver was clearly being injured — but the blood marker stayed quiet.

Mechanistic analysis found the switch. After ethanol treatment, hepatic Alt1 mRNA and ALT protein expression fell markedly in ALDH2*1/*2 mice — ALT synthesis itself was downregulated, rather than leaking less from damaged cells. Integrating ChIP-seq data, the GTEx human liver transcriptome, and hepatocyte-specific Hnf4a knockout mouse models, the study confirmed that the transcription factor HNF4A is a key regulator maintaining hepatic ALT1 expression, and that ALDH2 deficiency (especially after ethanol exposure) suppresses HNF4A and in turn depresses ALT1 synthesis. Transcriptomic data from patients with alcoholic hepatitis corroborated the mechanism: hepatic ALT1 expression is also reduced in inflammatory states.

The clinical implications are clear and important: for male drinkers carrying ALDH2*2, serum ALT may systematically underestimate true liver injury. In prediction models, 52.7% of carriers likely to reach ALT≥40 U/L measured 30 U/L or below; lowering the screening cut-off from 30 to 25 U/L means only 5.3 people need to be screened to find one with potential liver injury. Liver-disease assessment tools that rely on ALT — such as FIB-4 and NAFLD fibrosis scores — should therefore account for genotype.

From an evolutionary perspective, ALDH2*2 is not simply a \’defect\’. The prevailing hypothesis holds that this variant was positively selected in East Asian ancestors roughly 10,000 to 3,000 years ago, possibly linked to the heavy acetaldehyde exposure from fermented foods (rice wine, pickled vegetables) that came with early rice agriculture — by reducing acetaldehyde breakdown and creating an aversive response, it protected people from dietary acetaldehyde toxicity. Today, this ancient \’self-protection switch\’ adds a layer of complexity that modern health screening must learn to see. Only by reading the genome can we hear the body\’s signals more accurately.