Alcohol-associated cirrhosis develops in only a subset of people with heavy alcohol exposure, suggesting that inherited susceptibility modifies risk. We evaluated whether PNPLA3 rs738409 carrier status modifies the association between survey-derived alcohol intensity and incident cirrhosis.

We performed a retrospective cohort analysis of adults aged 21 years or older in the All of Us Research Program Controlled Tier Dataset v8 with electronic health record, Global Diversity Array, and Lifestyle survey data. Alcohol intensity was categorized as none, light, moderate, or heavy. Participants with cirrhosis on or before the survey date were excluded. Incident cirrhosis was the first post-survey diagnosis. Logistic regression modeled alcohol intensity, PNPLA3 carrier status, and their interaction, adjusting for age, sex at birth, and self-reported race. Sensitivity analyses evaluated 1-year lagged outcomes, exclusion of competing liver disease etiologies, BMI adjustment, BMI-stratified models, and minimum observable follow-up duration.

The analytic cohort included 315,865 participants and 1,932 incident cirrhosis cases. Heavy-drinking PNPLA3 carriers had a higher crude cirrhosis rate than heavy-drinking non-carriers (1.69% vs 1.02%). In the adjusted primary model, the heavy alcohol × PNPLA3 interaction was borderline significant (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.00–1.75). The interaction strengthened in the 1-year lag analysis (OR, 1.50; 95% CI, 1.04–2.17), after excluding viral hepatitis (OR, 1.58; 95% CI, 1.02–2.45), and after excluding viral hepatitis plus nonalcoholic fatty liver disease/metabolic liver disease (OR, 1.62; 95% CI, 1.03–2.54). Median follow-up was 3.87 years (interquartile range [IQR], 1.59–4.57). The heavy alcohol × PNPLA3 interaction remained significant after adjustment for continuous BMI (OR, 1.45; 95% CI, 1.01–2.10) and categorical BMI (OR, 1.47; 95% CI, 1.02–2.12), and was strongest among participants with obesity (OR, 1.91; 95% CI, 1.07–3.44).

PNPLA3 rs738409 carrier status may amplify heavy alcohol-associated incident cirrhosis risk, supporting a clinically relevant gene-environment interaction.