Identification of candidate genes for rituximab response in rheumatoid arthritis patients by microarray expression profiling in blood cells

作     者：Julia, Antonio Barcelo, Mireia Erra, Alba Palacio, Carles Marsal, Sara 

作者机构：Hosp Valle De Hebron Inst Recerca Grp Recerca Reumatol Barcelona Spain Hosp Univ Vall dHebron Barcelona Spain 

出 版 物：《PHARMACOGENOMICS》 (药物基因组学)

年 卷 期：2009年第10卷第10期

页      面：1697-1708页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：Roche Pharma  Spain 

主　　题：biological agents biomarkers gene expression microarray response to therapy rheumatoid arthritis rituximab 

摘      要：Aims: Transient CD20(+) B-cell depletion with rituximab is an effective treatment for rheumatoid arthritis (RA). However, there is a subgroup of patients that do not show significant clinical response to rituximab and for these patients, other modes of treatment are preferred. Finding biomarkers for drug response in RA has immense potential for improving treatment and lowering healthcare costs for treating RA patients by facilitating the optimization of their pharmacotherapy. In the present study, we report on gene expression profiles of three different blood cell types in rituximab responders and nonresponder RA patients identifying new candidate genes associated with rituximab response. Materials & methods: Transcriptional profiles of whole-blood, CD4(+) T cells and B cells were analyzed from nine female patients (mean age 53 +/- 11 years) with active RA disease (DAS28 5.1), starting rituximab therapy using Illumina (CA, USA) gene-expression microarrays. Whole-blood RNA was extracted using the PAXgene (TM) system (PreAnalytix, Hombrechtikon, Switzerland) whilst the lymphocyte RNA was obtained following cell isolation using negative selection. Flow cytometry analysis was performed to determine whole blood subpopulations, as well as the lymphocyte isolation purity. A whole-genome expression profiling was performed on the RNA samples prepared from the three blood cell populations using the Illumina Human 6 Beadchip array system version 1 (Illumina). From the group of statistically significant genes showing differential expression in rituximab responders compared with nonresponder RA patients, we selected a group of candidate genes that were subsequently validated in the same RNA samples using TaqMan (R) real-time PCR assays. Results: Several genes were identified whose level of expression is associated significantly with the response to rituximab in all three blood cell types evaluated (multiple-test corrected p-value 0.05). Real-time PCR-validated genes include