Sex differences and alcohol modulation in the heritability of MASLD: a twin study of the 2023 definition

The baseline heritability of the newly defined metabolic dysfunction-associated steatotic liver disease (MASLD) is unknown. Given that sex and alcohol consumption are well-recognized determinants of fatty liver disease, it is important to understand whether they are also associated with variation in its underlying genetic susceptibility. We aimed to quantify the baseline heritability and investigate these potential effects in a classical twin study of 710 Chinese adults using structural equation modeling. We observed a baseline narrow-sense heritability (A) of 0.57 (95% CI 0.46-0.67) in the lower alcohol intake group. This genetic contribution was not uniform and showed a potential difference by sex, with heritability tending to be higher in females (0.63) than in males (0.30). Furthermore, the genetic architecture appeared to vary across alcohol exposure levels. In contrast to the additive (AE) model observed in lower drinkers, the higher alcohol intake group was better fitted by a dominant/non-additive (DE) model, yielding a broad-sense heritability (D) of 0.60 (95% CI 0.34-0.77). In conclusion, our findings suggest that the genetic architecture of MASLD may vary according to sex and alcohol consumption, highlighting potential gene-environment interactions and the context-dependent nature of genetic susceptibility. These results may have implications for future risk stratification and targeted prevention strategies.