Asian Flush Phenotype Associated with Protective Properties Against COVID-19: Web-based Retrospective Study

Abstract ALDH2 rs671 variant is prevalent in East Asia, manifesting as skin flushing after alcohol ingestion, known as "Asian flush." Our prior web-based study was the first to report the protective effect of rs671 variant against COVID-19. To validate the association and explore potential mediating factors, we conducted two further retrospective web-based studies, involving 1300 and 8176 adult Japanese ("Google" and "Rakuten" subcohorts). Statistics included multivariate analyses that were adjusted for sex, age, residence area, occupation, disease history, and obesity. Flushing-phenotype was consistently associated with a later onset, fewer emergency transports or hospitalisations, and fewer reinfections. Based on self-reported infection sites and mediation analysis, drinking habits were unlikely to explain the association. By August 2024, COVID-19 incidence was lowest in flushing groups (e.g., 0.64/participant for "strong-flushing" in "Google" vs. 0.74 for "no-flushing"). Notably, despite the lower incidence, participants with flushing-phenotype were more likely to be unvaccinated. Flushing-phenotypes were associated with febrile-phenotypes, e.g., 40% "strong-flushing" in "Google" reported > 39°C fever during upper respiratory tract infections in youth, compared to 53% of "no-flushing". This febrile phenotype partially mediated the flushing—COVID-19 pathway. These findings contribute to understanding SARS-CoV-2 pathogenesis and may inspire microbiology, drug discovery, and personalized medicine research.