Evaluating the Causal Effect of Circulating Proteome on the Risk of Inflammatory Bowel Disease-Related Traits

Objective: This study sought to identify circulating proteins causally linked to Inflammatory Bowel Disease (IBD) traits through a Mendelian Randomization (MR) analytical framework. Methods: Using a large-scale, two-sample MR approach, we estimated the genetic links of numerous plasma proteins with IBD and its subtypes, leveraging information from the Inflammatory Bowel Disease Genetics Consortium (25,024 cases and 34,915 controls). To assess the robustness of MR findings, methods like Bayesian colocalization, Steiger filtering analysis, evaluation of protein-altering variants, and mapping expression quantitative trait loci (eQTL) to protein quantitative trait loci (pQTL) were utilized. Further insights into IBD's underlying mechanisms and therapeutic targets were gleaned from single-cell sequencing analyses, protein-protein interaction assessments, pathway enrichment analyses, and evaluation of drug targets. Results: Numerous circulating proteins were identified as potentially having a causal effect on IBD-related traits, with the majority being drug targets or druggable entities. Conclusion: MR analysis facilitated the identification of numerous circulating proteins associated with IBD traits, unveiling protein-mediated mechanisms and promising therapeutic targets. Funding: This research was supported by the National Natural Science Foundation of China (grant 81800531 to X.L.Z.). Declaration of Interest: The authors declare that they have no competing interests.