Exploring the role of mitochondrial proteins SIRT5 and MRPL33 through Mendelian randomization in primary biliary cholangitis

Background: Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by elevated serum antimitochondrial antibody levels in 90 -95 % of cases. However, the exact causal relationship between mitochondrial proteins and PBC remains unclear. This study aims to investigate and clarify this relationship. Methods: Genome-wide association data for mitochondrial proteins and PBC were obtained from public databases. The assessment of causal relationships between exposures and outcomes employed the Inverse Variance Weighted (IVW) method, MR Egger regression, and Weighted Median. Sensitivity analyses were systematically carried out to appraise the robustness of the Mendelian Randomization (MR) findings. Results: The analysis revealed two mitochondrial proteins exhibiting a causal relationship with PBC. Elevated SIRT5 levels demonstrated a positive correlation with an augmented susceptibility to PBC in the IVW approach (odds ratio, OR: 1.2907, 95 % CI: 1.062 -1.568, p = 0.0102). Conversely, increased MRPL33 levels were associated with a decreased risk of PBC (OR: 0.8957, 95 % CI: 0.807 -0.993, p = 0.0376). Sensitivity analysis corroborated these findings consistently. Conclusion: This investigation advances the notion of a potential causal association between elevated SIRT5 levels and an increased risk of PBC, alongside a decreased risk of PBC linked to elevated MRPL33 levels. The identified mitochondrial proteins may serve as viable biomarkers, offering pertinent insights for the understanding and addressing of PBC.