The interaction of genetics and physical activity in the pathogenesis of metabolic dysfunction associated liver disease.

Genetic variants associated with increased liver fat and volume have been reported, but whether physical activity (PA) can attenuate the impact of genetic susceptibility to these traits is poorly understood. We aimed to investigate whether higher PA modify genetic impact on liver-related traits in the UK Biobank cohort. PA was self-reported, while magnetic resonance images were used to estimate liver fat (n = 27,243) and liver volume (n = 24,752). Metabolic dysfunction-associated liver disease (MASLD) and chronic liver disease (CLD) were diagnosed using ICD-9 and ICD-10 codes. Ten liver fat and eleven liver volume-associated genetic variants were selected and unweighted genetic-risk scores for liver fat (GRS) and liver volume (GRS) were computed. Linear regression analyses were performed to explore interactions between GRS/ GRS and PA in relation to liver-related traits. Association between GRS and liver fat was not different among lower (β = 0.063, 95% CI 0.041-0.084) versus higher PA individuals (β = 0.065, 95% CI 0.054-0.077, p = 0.62). The association between the GRS and liver volume was not different across different PA groups (p = 0.71). Similarly, PA did not modify the effect of GRS and GRS on MASLD or CLD. Our findings show that physical activity and genetic susceptibility to liver-related phenotypes seem to act independently, benefiting all individuals regardless of genetic risk.