ALDH2 variants amplify alcohol-related cardiac dysfunction at levels below international guidelines
Y Y Liu, H I Yeh, C L HungAbstract
Background/Introduction
Current alcohol guidelines do not account for genetic susceptibility. The ALDH2*2 variant, affecting 30-40% of East Asians, impairs acetaldehyde metabolism and may amplify alcohol-related cardiac injury at consumption levels considered safe by international standards.
Purpose
To investigate gene-alcohol interactions in subclinical cardiac dysfunction using advanced strain imaging and determine optimal alcohol thresholds for genetically susceptible individuals.
Methods
We studied 1,871 participants from Northern Taiwan cohorts (967 genotyped). Cardiac function was evaluated using speckle-tracking echocardiography to measure left atrial (LA) and left ventricular (LV) strain. ALDH2 genotype (rs671) and daily alcohol consumption were assessed. Restricted cubic spline (RCS) regression was used to evaluate non-linear dose-response relationships. ROC analysis determined optimal alcohol thresholds for predicting subclinical cardiac dysfunction defined by strain cut-offs (LA <23%, LV ≤18%). Gene-alcohol interactions and sex-specific effects were analysed using regression models.
Results
RCS analysis revealed progressive, non-linear deterioration in both chambers even at low alcohol doses. Continuous analysis demonstrated dose-dependent deterioration (LA: β = -0.035 % per g/day; LV: β = -0.013 % per g/day, p < 0.001). ALDH2 variants significantly amplified alcohol's effects through gene-alcohol interactions (LA: β = -0.063, p = 0.001; LV: β = -0.023, p < 0.001). ROC analysis identified 6 g/day as the optimal cut-off for predicting dysfunction, far below international guidelines (10-48 g/day). Variant carriers showed 2-2.5-fold higher dysfunction odds despite consuming less alcohol (7.6 vs 16.7 g/day, p<0.001). Males demonstrated vulnerability to both chambers, whilst females showed predominantly ventricular susceptibility. Additional interactions involving ADH1B, ADH1C, and CYP2E1 polymorphisms further amplified alcohol-related cardiac dysfunction.
Conclusions
Subclinical cardiac dysfunction occurs at 6 g/day, substantially below current guideline thresholds. ALDH2 genetic polymorphisms critically modify alcohol-related cardiac injury through gene-alcohol interactions. These findings support precision medicine approaches integrating genetic risk stratification and sensitive cardiac imaging to guide individualised alcohol recommendations.Alcohol intake vs cardiac strain (RCS curves)Alcohol and ALDH2 predict dysfunction (ROC)