1,400 genetically predicted plasma metabolites in relation to risk of primary biliary cholangitis: a bi-directional, two-sample Mendelian randomization analysis

Aim of the study:
Primary biliary cholangitis (PBC) is a complex, chronic, cholestatic liver disease with an autoimmune etiology. While plasma metabolites are crucial indicators of physiological and pathological states, their involvement in PBC pathogenesis remains unclear. To address this knowledge gap, we performed a rigorous two-sample Mendelian randomization (MR) analysis to assess the causal associations of 1,400 plasma metabolites with PBC.

Material and methods:
Genome-wide association data for 1,400 plasma metabolites and PBC were obtained from established public databases. The inverse-variance weighted (IVW) method was the primary method used for MR analysis. Sensitivity analyses and heterogeneity tests were conducted to assess the stability of the MR results. A reverse MR analysis was performed to investigate the possibility of reverse causality.

Results:
Four plasma metabolites were identified as potential predictors for the occurrence of PBC. Specifically, sphingosine 1-phosphate (OR = 0.65, 95% CI: 0.42-0.98, p = 0.04) and docosadienoate (22:2n6) (OR = 0.57, 95% CI: 0.36-0.90, p = 0.01) were implicated in conferring a protective effect against PBC. Conversely, homoarginine (OR = 1.34, 95% CI: 1.04-1.72, p = 0.02) and campesterol (OR = 1.19, 95% CI: 1.01-1.40, p = 0.03) were associated with an increased risk of PBC. There was no evidence of reverse causality between PBC and the identified plasma metabolites.

Conclusions:
This study utilized a two-sample Mendelian randomization approach to explore the causal relationship between 1,400 plasma metabolites and PBC. We identified four plasma metabolites that may have a causal relationship with the development of PBC. The metabolites identified hold promise as prognostic indicators and could illuminate novel pathways for therapeutic intervention in PBC.