Differential type 2 diabetes risk and weight-loss associations across MASLD genetic susceptibility patterns.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is heterogeneous, but whether hepatic and systemic genetic susceptibility patterns differ in their associations with type 2 diabetes (T2D), vascular complications, and longitudinal weight change remains unclear. METHODS AND RESULTS: The source population included 502,536 UK Biobank participants. Eligible participants without diabetes at baseline were followed through 2022. Hepatic and systemic MASLD genetic susceptibility was quantified using previously developed partitioned polygenic risk scores (PRSs). Cox models assessed incident T2D; vascular outcomes and weight change were evaluated using risk ratios and penalized splines. After adjustment for basic covariates, hepatic genetic susceptibility was associated with incident T2D (HR 2.01, 95% CI 1.58-2.56), whereas the systemic association was weaker (HR 1.19, 95% CI 1.06-1.35). Following additional adjustment for HbA1c and triglycerides, the association remained significant for the hepatic PRS (HR 2.25, 95% CI 1.76-2.86) but not for the systemic PRS (HR 0.98, 95% CI 0.87-1.11). Observed weight decreases were associated with lower T2D risk in both genetic-risk groups, with a numerically stronger association in the high hepatic PRS group. Vascular outcome differences were small and absent among participants with established diabetes. CONCLUSIONS: Hepatic and systemic MASLD genetic susceptibility patterns showed heterogeneous associations with incident T2D, vascular outcomes, and longitudinal weight change. These findings support biological heterogeneity in MASLD-related genetic pathways and warrant further evaluation of their potential relevance for risk stratification.