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Exploratory transcriptomic analysis suggests candidate genes associated with loss of response to ustekinumab in

Jiayi Lin1, Tingting Xie1, Jiahao Zhong1

  • 1The Second Affiliated Hospital, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China.

Frontiers in Genetics
|June 8, 2026
PubMed
Abstract

Insights

Loss of response to ustekinumab in Crohn's disease may involve pro-inflammatory pathways and a pro-fibrotic microenvironment. Genes like FFAR2, ITGA2B, SOCS3, and KCNJ15 show differential expression in non-responders.

Area of Science:

  • Gastroenterology
  • Immunology
  • Genomics

Background:

  • Ustekinumab is effective for Crohn's disease but some patients lose response.
  • Understanding the genetic basis of ustekinumab non-response is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate differential gene expression in Crohn's disease patients experiencing loss of response to ustekinumab.
  • To identify potential biomarkers and pathways associated with treatment failure.

Main Methods:

  • Prospective RNA sequencing of peripheral blood mononuclear cells from ustekinumab responders and non-responders.
  • Differential gene expression analysis (DESeq2), pathway analysis (GO, KEGG), WGCNA, and PPI network analysis.
  • Validation of candidate genes using qPCR and clinical factor analysis.

Main Results:

  • 510 differentially expressed genes were identified between responders and non-responders.
  • A gene module associated with non-response and stricturing behavior was enriched in platelet activation and neutrophil extracellular trap formation pathways.
  • FFAR2, ITGA2B, SOCS3, and KCNJ15 showed statistically significant differential expression.

Conclusions:

  • Loss of response may be linked to pro-inflammatory pathways and a pro-fibrotic microenvironment, independent of ustekinumab's mechanism.
  • FFAR2, ITGA2B, SOCS3, and KCNJ15 are potential candidate genes for ustekinumab loss of response in Crohn's disease.
Keywords:
Crohn’s diseaseRNA-seqloss of responsetranscriptomicustekinumab

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