Interaction of alcohol consumption and genetic variants in alcohol metabolism on all-cause and disease-specific mortality: a cohort study

Background: In studies regarding the association between alcohol consumption and mortality, controversy exists regarding the effects of light to moderate alcohol intake, and no study considered the role of alcohol metabolism related genetic variants in this relationship. Similarly, study investigating impact of alcohol consumption on the relationship between these genetic variations and mortality is also lacking. We therefore investigated the associations of alcohol consumption and alcohol metabolism related genetic variants with all-cause and disease-specific mortality, as well as the multiplicative interaction of alcohol consumption and the genetic variants on mortality. Methods: This prospective cohort study utilized data from the UK Biobank. Restricted cubic splines were used to evaluate the shapes of the associations between alcohol consumption and all-cause and disease-specific mortality. Cox proportional hazards models were used to estimate hazard ratios for associations between alcohol intake and mortality, both before and after stratifying by the genetic variants. Similarly, associations between the genetic variants and mortality were also examined before and after stratifying by alcohol intake. Results: Alcohol consumption had a J-shaped link with all-cause and most disease-specific mortality, except neurological. Similarly, beverage-specific intake showed a J-shaped relationship with all-cause mortality. The rs1229984 variant in ADH1B modifies the associations between alcohol consumption and mortality, resulting in elevated risks of all-cause and disease-specific mortality for individuals without the T allele when compared to carriers. Carriers of the rs1229984 C allele exhibited an increased risk of overall mortality. In stratified analyses, the hazard ratios of the rs1229984 C allele progressively rose from never drinkers to light drinkers, moderate drinkers, and ultimately to heavy drinkers. Conclusion: This study underscores the necessity of curbing excessive alcohol consumption to reduce mortality, particularly among individuals lacking the T allele of rs1229984.