Genetic analysis identifies MASLD subtype linked to lower diabetes risk

MASLD is associated with type 2 diabetes, but some genetic variants linked to liver fat have been associated with more favourable glycaemic outcomes. Researchers grouped 18 established MASLD-associated variants using genetic and triglyceride-related metabolomic profiles, then constructed mutually adjusted partitioned polygenic risk scores in UK Biobank. They assessed liver biomarkers and outcomes and diabetes risk, and tested glycaemic findings in the independent Taizhou Longitudinal Study. The source does not report participant numbers.

The analysis identified one genetic score associated with lower fasting glucose and lower type 2 diabetes risk; the other scores were associated with increases in both. All scores were associated with higher liver injury markers and adverse liver outcomes. The divergent glycaemic associations were replicated in the Chinese cohort. Fine-mapping and colocalisation prioritised GCKR rs1260326 as a shared MASLD–diabetes signal. Functional assays indicated that its T allele promotes exon-15 skipping, reducing full-length glucokinase regulatory protein (GKRP) and producing a truncated form. Structural modelling suggested weaker glucokinase binding, but this requires experimental validation.

The findings support genetic heterogeneity in MASLD, but do not establish a clinical test or justify changes to care. Genetic risk scores and a proposed molecular mechanism require further validation before they can inform individual risk stratification or prevention.