The role of inflammatory proteins in mediating the effect of cathepsins on cholelithiasis: A mendelian randomization...

ObjectivePrevious studies have suggested potential associations between cathepsins and cholelithiasis. This study aimed to investigate the potential causal relationships among cathepsins, inflammatory proteins, and cholelithiasis using Mendelian randomization (MR), and to explore whether inflammatory proteins mediate the association between cathepsins and cholelithiasis.MethodsWe conducted a two-sample MR study using genome-wide association study (GWAS) summary statistics for cathepsins, inflammatory proteins, and cholelithiasis. Genetic associations for cathepsins were obtained from the INTERVAL study of European-ancestry individuals. GWAS data for inflammatory proteins and cholelithiasis were obtained from publicly available datasets, including European-ancestry cholelithiasis datasets from FinnGen and GCST90044196. The inverse variance weighted method was used as the primary MR analysis, with complementary and sensitivity analyses performed to assess the robustness of the findings. Multivariable and mediation MR analyses were performed to evaluate whether inflammatory proteins mediated the pathway from cathepsins to cholelithiasis.ResultsAfter correction for multiple testing, genetically predicted cathepsin B was associated with an increased risk of cholelithiasis. Mediation analyses suggested that part of the effect of cathepsin B on cholelithiasis may be mediated by fibroblast growth factor 19 (FGF19) and interleukin-6 levels. In the reverse MR analysis, genetically predicted cholelithiasis showed potential associations with two cathepsins and twelve inflammatory proteins.ConclusionsThis MR study provides genetic evidence for a potential association between cathepsin B and increased cholelithiasis risk. FGF19 and interleukin-6 may serve as partial mediators in this association.