Independent associations of gluteofemoral fat depots with hepatocellular carcinoma and the mediating role of the plasma lipidome: a mendelian randomization study

As metabolic etiologies become increasingly important in hepatocellular carcinoma (HCC), the causal roles of specific adipose depots independent of overall body size remain unclear. This study used Mendelian randomization (MR) to investigate the associations of MRI-derived fat-depot phenotypes with HCC and to explore potential mediation by plasma lipids. GWAS summary statistics for BMI- and height-adjusted fat-depot phenotypes were obtained from the UK Biobank, and HCC summary statistics were obtained from FinnGen, with replication in the Million Veteran Program. Univariable and multivariable MR were used to estimate total and independent effects, including analyses adjusted for smoking, alcohol consumption, type 2 diabetes, and childhood BMI. A two-step MR framework was applied to assess mediation by 179 plasma lipid species. Genetically predicted gluteofemoral adipose tissue adjusted for BMI and height (GFATadj) was associated with a lower risk of HCC (OR = 0.444, P = 1.00 × 10 -4 ). This association remained robust after adjustment for other risk factors, and it was replicated in the Million Veteran Program (OR = 0.766). Mediation analysis identified six lipid species as potential partial mediators, each accounting for an estimated 7.0%–15.4% of the protective total effect, and colocalization provided only limited support for shared causal variants. Our results provide insight into depot-specific adiposity and lipid metabolic pathways in hepatocarcinogenesis, although further validation is needed to confirm the underlying causal mechanisms.