Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis

Background and aims: Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor α (anti-TNFα) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis. Methods: Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data. Results: For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity. Conclusion: Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis. ClinicalTrials.gov number, NCT00639821.

[1]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[2]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[3]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[4]  Q. Yao,et al.  Human Stanniocalcin-1 Blocks TNF-&agr;–Induced Monolayer Permeability in Human Coronary Artery Endothelial Cells , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[5]  R. W. Davis,et al.  Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  R. Homer,et al.  IL-11 Receptor α in the Pathogenesis of IL-13-Induced Inflammation and Remodeling1 , 2005, The Journal of Immunology.

[7]  Ronald W. Davis,et al.  Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray , 1995, Science.

[8]  A. Öst,et al.  A reproducible grading scale for histological assessment of inflammation in ulcerative colitis , 2000, Gut.

[9]  R. Tibshirani,et al.  Diagnosis of multiple cancer types by shrunken centroids of gene expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[11]  Paul Rutgeerts,et al.  Infliximab for induction and maintenance therapy for ulcerative colitis. , 2005, The New England journal of medicine.

[12]  R. Puri,et al.  IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis , 2006, Nature Medicine.

[13]  S. Hanauer,et al.  Update on the etiology, pathogenesis and diagnosis of ulcerative colitis , 2004, Nature Clinical Practice Gastroenterology &Hepatology.

[14]  M. Bronner,et al.  The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia. , 2000, The American journal of pathology.

[15]  R. Puri,et al.  The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway. , 2001, Blood.

[16]  G. Morgan,et al.  Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. , 2003, Immunity.

[17]  R. Puri,et al.  IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. , 2006, Nature medicine.

[18]  R. Tibshirani,et al.  Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. , 2004, The New England journal of medicine.

[19]  M. Pfaffl,et al.  A new mathematical model for relative quantification in real-time RT-PCR. , 2001, Nucleic acids research.

[20]  M. Baccarani,et al.  Evaluation of five staging systems in 470 patients with multiple myeloma. , 1995 .

[21]  A. Donnet-Hughes,et al.  Osteoprotegerin production by human intestinal epithelial cells: a potential regulator of mucosal immune responses. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[22]  R. Homer,et al.  IL-11 receptor alpha in the pathogenesis of IL-13-induced inflammation and remodeling. , 2005, Journal of immunology.