Revisiting the causal impact of lipid traits on metabolic dysfunction-associated fatty liver disease: Insights from a multidimensional plasma lipid profile.

Abstract

Aims: Recent advancements in plasma lipidomes genome-wide association studies data have enhanced our understanding of lipid categories, significantly improving risk assessments for metabolic dysfunction-associated fatty liver disease (MAFLD) beyond traditional lipid biomarkers.

Materials and methods: This study utilized Mendelian randomization (MR) to assess the causal relationships between 179 lipid species across 13 subclasses and MAFLD, primarily using the Wald ratio and IVW methods. Corrections were made using false discovery rate (FDR), supplemented by Bayesian colocalization analysis.

Results: Elevated levels of genetically predicted phosphatidylcholine (16:0_16:1) [OR_{Wald ratio} = 2.638, 95% CI 1.557-4.469, P = 3.11 × 10^-4], phosphatidylcholine (16:1_18:0) (OR_{Wald ratio} = 2.644, 95% CI 1.559-4.486, P = 3.11 × 10^-4), triacylglycerol (46:2) (OR_{Wald ratio} = 2.515, 95% CI 1.524-4.153, P = 3.11 × 10^-4), and triacylglycerol (48:2) (OR_IVW = 1.863, 95% CI 1.300-2.669, P = 6.95 × 10^-4) were significantly associated with increased MAFLD risk, with rs1260326 within the GCKR gene playing a crucial role. Colocalization analysis indicated that in significant evidences, the posterior probability for hypothesis 4 was over 80%, identifying rs780093 as a shared causal variant. Additionally, 16 suggestive evidences were identified.

Conclusion: The study confirmed the significant role of specific lipid molecules in influencing MAFLD risk, providing new scientific bases and potential therapeutic targets for future treatment strategies.