Genetic risk amplifies lifestyle effects on hepatic steatosis and its progression: Insights from a population-based cohort.

Background: Steatotic liver disease (SLD) is influenced by both genetics and lifestyle factors, with lifestyle effects varying by genetic susceptibility. We aimed to evaluate gene-lifestyle interactions on SLD risk.
Methods: We included 28,215 UK Biobank participants with available data. Predictors were healthy lifestyle patterns, PNPLA3-rs738409, TM6SF2-rs58542926, a 16-variant hepatic steatosis polygenic risk score (PRS), and gene-environment interactions. Primary outcome was liver fat content (LFC); secondary outcomes were cT1 (a measure of liver inflammation/fibrosis) and SLD-related events.
Results: Lifestyle predictors, except smoking, reduced LFC, while genetic predictors increased it. Genetic predictors significantly interacted with healthy lifestyle patterns, sedentary behavior and social connection. Lifestyle effects on lower LFC were up to 6.3-fold stronger in PNPLA3-rs738409-GG vs. -CC individuals, and 1.5-7.0 times higher in the top vs. bottom PRS quartile. PRS and PNPLA3 also interacted with alcohol consumption, diet, and PNPLA3 further interacted with physical activity. These interactions were more pronounced in overweight participants. Genetic factors and physical activity interacted to influence cT1, while PRS, PNPLA3 and sleep duration were associated with cardiovascular events.
Conclusions: Lifestyle effects on LFC, cT1 and cardiovascular events were accentuated in individuals at higher SLD genetic risk, implying lifestyle interventions may be more impactful in these populations.
Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare and nothing to disclose.
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