Identification of potential novel targets for treating inflammatory bowel disease using Mendelian randomization analysis

• Published in: International journal of colorectal disease Vol. 39; no. 1; p. 165
• Main Authors: Fan, Ji-Chang, Lu, Yuan, Gan, Jin-Heng, Lu, Hao
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 16.10.2024; Springer Nature B.V
• Subjects: Angiopoietin-Like Protein 3; Bayes Theorem; Bayesian analysis; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - genetics; Crohn's disease; Fc receptors; Gastroenterology; Genetic diversity; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomic analysis; Hepatology; Humans; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - genetics; Internal Medicine; Intestine; Localization; Medicine; Medicine & Public Health; Mendelian Randomization Analysis; Molecular Targeted Therapy; Phenotype; Plasma proteins; Polymorphism, Single Nucleotide - genetics; Proctology; Proteins; Side effects; Surgery; Therapeutic targets; Ulcerative colitis; Inflammatory bowel disease; Drug targets; Mendelian randomization
• ISSN: 1432-1262; 0179-1958; 1432-1262
• DOI: 10.1007/s00384-024-04744-2

Background Inflammatory bowel disease (IBD) is a complex autoimmune disorder, although some medications are available for its treatment. However, the long-term efficacy of these drugs remains unsatisfactory. Therefore, there is a need to develop novel drug targets for IBD treatment. Methods We conducted two-sample Mendelian randomization (MR) analysis using Genome-Wide Association Study (GWAS) data to assess the causal relationships between plasma proteins and IBD and its subtypes. Subsequently, the presence of shared genetic variants between the identified plasma proteins and traits was explored using Bayesian co-localization. Phenome-wide MR was used to evaluate evaluated adverse effects, and drug target databases were examined for therapeutic potential. Results Using the Bonferroni correction ( P  < 3.56e-05), 17 protein-IBD pairs were identified. Notably, the genetic associations of IBD shared a common variant locus (PP.H4 > 0.7) with five proteins (MST1, IL12B, HGFAC, FCGR2A, and IL18R1). As a subtype of IBD, ulcerative colitis shares common variant loci with FCGR2A, IL12B, and MST1. In addition, we found that ANGPTL3, IL18R1, and MST1 share a common variant locus with Crohn’s disease. Furthermore, phenome-wide MR analysis revealed that except for ANGPTL3, no other proteins showed potential adverse effects. In the drug database, identified plasma proteins such as FCGR2A and IL18R1 were found to be potential drug targets for the treatment of IBD and its subtypes. Conclusion Six proteins (FCGR2A, IL18R1, MST1, HGFAC, IL12B, and ANGPTL3) were identified as potential drug targets for the treatment of IBD and its subtypes.