Impact of aldehyde dehydrogenase 2 polymorphism on lipid profile alterations in alcohol-abstinent adolescents stratified by steatotic liver disease status.

BACKGROUND: Single-nucleotide polymorphism in aldehyde dehydrogenase 2 (ALDH2) is associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, this association in alcohol-abstinent individuals remains unknown. We assessed SLD and genotype-inferred ALDH2 activity (ALDH2 activity) in alcohol-abstinent adolescents to explore the association between ALDH2 activity and metabolism-related factors stratified by SLD status. METHODS: In this cross-sectional study, 253 university students (<20 years; 162 males, 91 females) underwent first-year health screening including abdominal ultrasonography and genotyping for ALDH2 rs671, categorized as a high-activity genotype (GG) or reduced-activity genotype (non-GG). The associations of metabolism-related parameters were analyzed across SLD and ALDH2 genotype groups, and predictive performance was assessed using ROC analysis. RESULTS: We focused on significant changes in metabolism-related parameters, particularly in adolescent males, due to their higher prevalence of SLD. Increased preperitoneal fat and aspartate aminotransferase levels and decreased high-density lipoprotein cholesterol (HDL-C) levels were observed in the non-SLD group, with high ALDH2 activity; low-density lipoprotein cholesterol (LDL-C) levels in the SLD group increased in high ALDH2 activity. In stratified analyses, univariate and multivariate logistic regression revealed that, among adolescents without SLD, those with the GG genotype had significantly lower HDL-C levels (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99, p = 0.016). Conversely, among adolescents with SLD, the high-activity GG genotype was associated with significantly higher LDL-C levels (OR, 1.03; 95% CI, 1.01-1.05, p = 0.001). Exploratory cutoffs for HDL-C (<64 mg/dL) and LDL-C (≥114 mg/dL) showed moderate discriminatory ability (AUC 0.727 and 0.701, respectively) and showed modest genotype-classification performance in an independent cohort. CONCLUSIONS: The association between ALDH2 rs671 genotype and lipid profiles differed according to SLD status under non-alcoholic conditions. Combined assessment of SLD and lipid changes may provide an exploratory approach for estimating ALDH2 genotype-inferred alcohol-metabolizing capacity in adolescents.