Plasma Proteomics for Risk Prediction and Therapeutic Target Discovery in Crohn's Disease and Ulcerative Colitis

Area of Science:

• Gastroenterology
• Proteomics
• Genetics

Background:

• Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), poses a significant health burden.
• Identifying reliable biomarkers for early detection and risk stratification in IBD is crucial.

Purpose of the Study:

• To identify plasma proteins associated with incident CD and UC.
• To develop and validate predictive models for CD and UC risk using proteomic data.
• To uncover novel protein-based therapeutic targets for IBD.

Main Methods:

• Utilized large-scale proteomic profiling on plasma samples from UK Biobank participants (development and internal replication sets) and an external validation set.
• Employed two-sample Mendelian randomization (MR) to assess causal associations of identified proteins with CD and UC.
• Developed and validated proteomic-based risk prediction models, comparing their performance against traditional clinical models.

Main Results:

• Identified 49 and 34 proteins significantly associated with incident CD and UC risk, respectively, with findings replicated across datasets.
• MR analysis revealed causal roles for specific proteins in CD (TIMP1, TNFRSF10A, LTBR) and UC (CCL20, OSM, NOS2, CD300E).
• Proteomic models significantly enhanced CD and UC risk prediction (external validation C-indices: 0.94 for CD, 0.82 for UC) compared to clinical models alone.

Conclusions:

• Novel plasma proteins associated with CD and UC, supported by genetic evidence, represent potential therapeutic targets.
• Plasma proteomics substantially improves risk prediction for incident CD and UC.
• Findings open new avenues for IBD drug discovery and personalized risk assessment.