Four-Gene Mucosal Signature Fails to Predict Vedolizumab Response in Ulcerative Colitis

An exploratory search for pre-treatment biomarkers of vedolizumab response in ulcerative colitis has produced a cautionary result: a four-gene mucosal signature that appeared to separate responders from non-responders in its discovery cohort showed no useful predictive performance when tested in independent blood and mucosal samples. Researchers reconstructed a discovery cohort from public transcriptomic data (GSE73661) comprising 24 baseline mucosal samples, including 14 composite responders and 10 non-responders to vedolizumab. Using repeated LASSO variable selection, they identified an exploratory gene set consisting of ZNF689, TPRXL, ZC3H10, and MRPL55.

The selection procedure yielded a mean held-out AUC of 0.611 across 18 complete nested-validation repetitions, a value the authors note does not independently validate the final gene set. When the fixed gene set was projected onto external data, performance fell to chance levels. The AUC for 17 blood samples from GSE191328 was 0.458 (95% CI 0.162–0.755), and the AUC for 27 independent ulcerative colitis mucosal samples from E-MTAB-7845 was 0.534 (95% CI 0.293–0.775).

Both intervals include 0.5, the threshold expected from random guessing. The study also documented the fragility of the apparent signal. The gene set achieved an apparent AUC of 1.000 on the discovery set itself, but 500 full-process bootstrap analyses indicated that gene selection was unstable, meaning different resamples could yield different gene panels.

Among three targeted inflammatory panels examined, interferon-γ showed a directional difference between response groups that was not statistically significant, with a mean GSVA score difference of −0.425 (nominal P = 0.066; adjusted P = 0.197). The authors emphasize that expression scales and clinical endpoints differed across the cohorts, complicating direct comparison. Overall, the findings describe post-selection separation within the discovery cohort only.

They do not establish reproducible predictive performance, tissue specificity, or a definitive four-gene signature, and no reliable pre-treatment biomarker for vedolizumab response currently exists.

Subject of Research: Baseline mucosal transcriptomic biomarkers for predicting vedolizumab response in ulcerative colitis

Article Title: Exploratory baseline mucosal transcriptomics and vedolizumab response in ulcerative colitis

Article References: Zhang, L., Liu, J., Liang, C., Han, Q., Li, D., & Wang, Y. (2026). Exploratory baseline mucosal transcriptomics and vedolizumab response in ulcerative colitis. PLOS One, 21(10), e0361301. https://doi.org/10.1371/journal.pone.0361301

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0361301

Keywords: ulcerative colitis, vedolizumab, biomarkers, transcriptomics, LASSO, gene signature, AUC, validation, mucosal gene expression, interferon-gamma, prediction, inflammatory bowel disease