Análisis multiómico integrador identifica dianas genéticas tratables para la enfermedad inflamatoria intestinal

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), represents a set of chronic, immune-mediated gastrointestinal disorders with increasing global prevalence. Current therapeutic options are limited, highlighting the need for novel drug targets.

To systematically identify druggable genes with potential causal roles in IBD through integrative multi-omics analyses, leveraging genetic, transcriptomic, and epigenomic datasets.

We implemented summary-data-based Mendelian randomization (SMR) to assess the causal relevance of druggable genes in IBD, using large-scale genome-wide association study (GWAS) data from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). Replication analyses were performed in the FinnGen cohort. Genetic instruments for druggable genes were derived from the methylation and gene expression levels. To strengthen the causal inference, Bayesian colocalization was applied to distinguish true causal loci from linkage between candidate druggable genes and IBD. Phenome-wide association studies (PheWAS), in silico drug repurposing predictions, and molecular docking simulations were conducted to implicate the possibility of targeted therapeutic drugs for future clinical applications.

The study identified Thrombospondin-3 (THBS3), Retinoic Acid Receptor-Related Orphan Receptor C (RORC), and Tumor Necrosis Factor Receptor Superfamily Member 25 (TNFRSF25) as potential drug targets for IBD and its subtypes. These genes showed consistent associations with IBD across different biological levels and replication datasets. Molecular docking analyses predicted candidate drugs, including AM580, Dasatinib, 25-Hydroxycholesterol, Medroxyprogesterone acetate, 3,3'-Diindolylmethane, and Hesperidin, which exhibited strong binding affinities to the target proteins.

Our multi-layered omics framework provided genetically anchored evidence for the role of THBS3, RORC, and TNFRSF25 as druggable targets in IBD. The identified candidate drugs offered new avenues for therapeutic intervention. Further clinical validation is warranted to harness these targets for the development of effective IBD treatments.