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Differentiating Functional Roles of Gene Expression from Immune and Non-immune Cells in Mouse Colitis by Bone Marrow Transplantation

Differentiating Functional Roles of Gene Expression from Immune and Non-immune Cells in Mouse Colitis by Bone Marrow Transplantation

Published on: October 1, 2012

Gene expression changes associated with resistance to intravenous corticosteroid therapy in children with severe

Boyko Kabakchiev¹, Dan Turner, Jeffrey Hyams

¹Mount Sinai Hospital, Toronto, Ontario, Canada. kabakchiev@lunenfeld.ca

|October 14, 2010

Insights

Gene expression in whole blood can predict corticosteroid treatment response in pediatric ulcerative colitis (UC). Elevated inflammatory gene expression indicates resistance, aiding early clinical management decisions.

Area of Science:

Molecular biology
Genomics
Inflammation research

Background:

Microarray analysis of RNA expression provides insight into inflammatory pathways.
Identifying early indicators of treatment response in severe ulcerative colitis (UC) is crucial.

Purpose of the Study:

To determine if genes expressed in whole blood early after initiating intravenous corticosteroid therapy can be associated with treatment response in pediatric UC patients.
To explore gene expression profiles for classifying corticosteroid resistance.

Main Methods:

Analysis of RNA expression from whole blood samples of 40 pediatric UC patients (20 responders, 20 non-responders) on day 3 of intravenous corticosteroid therapy.
Utilized Affymetrix Human Gene 1.0 ST arrays for transcriptome quantification.
Employed local-pooled error method for differential gene expression discovery and false discovery rate correction.

Main Results:

Identified 41 statistically significant differentially expressed genes between responders and non-responders.
Observed overexpression of CEACAM1 and MMP8 in non-responsive patients.
A cluster of 10 genes demonstrated an 80% sensitivity and 80% specificity in classifying patients, with ABCC4 (MRP4) identified as a novel candidate gene for corticosteroid resistance.

Conclusions:

Elevated expression of inflammatory pathway genes correlates with resistance to intravenous corticosteroid therapy in early-stage pediatric UC.
Gene expression profiling shows potential for classifying corticosteroid resistance and informing clinical management decisions in severe UC.

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Abstract

Background And Aims:

Microarray analysis of RNA expression allows gross examination of pathways operative in inflammation. We aimed to determine whether genes expressed in whole blood early following initiation of intravenous corticosteroid treatment can be associated with response.

Methods:

From a prospectively accrued cohort of 128 pediatric patients hospitalized for intravenous corticosteroid treatment of severe UC, we selected for analysis 20 corticosteroid responsive (hospital discharge or PUCAI ≤45 by day 5) and 20 corticosteroid resistant patients (need for second line medical therapy or colectomy, or PUCAI >45 by day 5). Total RNA was extracted from blood samples collected on day 3 of intravenous corticosteroid therapy. The eluted transcriptomes were quantified on Affymetrix Human Gene 1.0 ST arrays. The data was analysed by the local-pooled error method for discovery of differential gene expression and false discovery rate correction was applied to adjust for multiple comparisons.

Results:

A total of 41 genes differentially expressed between responders and non-responders were detected with statistical significance. Two of these genes, CEACAM1 and MMP8, possibly inhibited by methylprednisolone through IL8, were both found to be over-expressed in non-responsive patients. ABCC4 (MRP4) as a member of the multi-drug resistance superfamily was a novel candidate gene for corticosteroid resistance. The expression pattern of a cluster of 10 genes selected from the 41 significant hits were able to classify the patients with 80% sensitivity and 80% specificity.

Conclusions:

Elevated expression of several genes involved in inflammatory pathways was associated with resistance to intravenous corticosteroid therapy early in the course of treatment. Gene expression profiles may be useful to classify resistance to intravenous corticosteroids in children with severe UC and assist with clinical management decisions.

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