Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: Correlation between gene expression and genotype

Rheumatology Unit, UCL Institute of Child Health, London, UK.
Pharmacogenetics and Genomics (Impact Factor: 3.48). 11/2010; 20(11):665-76. DOI: 10.1097/FPC.0b013e32833f2cd0
Source: PubMed


Little is known about the mechanisms of efficacy of methotrexate (MTX) in childhood arthritis, or genetic influences upon response to MTX. The aims of this study were to use gene expression profiling to identify novel pathways/genes altered by MTX and then investigate these genes for genotype associations with response to MTX treatment.
Gene expression profiling before and after MTX treatment was performed on 11 children with juvenile idiopathic arthritis (JIA) treated with MTX, in whom response at 6 months of treatment was defined. Genes showing the most differential gene expression after the treatment were selected for single nucleotide polymorphism (SNP) genotyping. Genotype frequencies were compared between nonresponders and responders (ACR-Ped70). An independent cohort was available for validation.
Gene expression profiling before and after MTX treatment revealed 1222 differentially expressed probes sets (fold change >1.7, P<0.05) and 1065 when restricted to full responder cases only. Six highly differentially expressed genes were analyzed for genetic association in response to MTX. Three SNPs in the SLC16A7 gene showed significant association with MTX response. One SNP showed validated association in an independent cohort.
This study is the first, to our knowledge, to evaluate gene expression profiles in children with JIA before and after MTX, and to analyze genetic variation in differentially expressed genes. We have identified a gene, which may contribute to genetic variability in MTX response in JIA, and established as proof of principle that genes that are differentially expressed at mRNA level after drug administration may also be good candidates for genetic analysis.

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Available from: Lucy R Wedderburn
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    • "In another approach, SNP genotyping of genes found to be differentially expressed in a gene expression profiling study, of a UK cohort of JIA patients before and after treatment with MTX, identified three SNPs in the solute carrier family 16 member 7 (SLC16A7) gene associated with response to MTX. Validation of these SNPs in a validation cohort revealed significant association of one of the SNPs with non-response to MTX [33]. "
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    ABSTRACT: Use of biomarkers in clinical practice has proved extremely valuable and is a rapidly expanding field. However, despite the huge potential of biomarkers, for juvenile idiopathic arthritis (JIA) there are currently no validated paediatric biomarkers available to help with setting up a more tailored approach on which drug choice could be based, to achieve remission early in the course of disease. Early remission reduces burden of disease, limits side effects from toxic and unnecessary medication, and, most importantly, enhances quality of life. Several studies have suggested promising biomarkers: these may be a protein, cellular component, mRNA, or genetic component, for example a single nucleotide polymorphism (SNP). Here we describe recent developments in the use of biomarkers for JIA and their potential to assist in management of disease by predicting disease phenotype, severity, progression, and response to treatment, and determining when patients have reached stable remission and can safely discontinue treatment.
    Full-text · Article · Mar 2014 · Current Rheumatology Reports
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    • "As parents are key facilitators in their child’s medication regime [8], it is also important to gain an insight into parents’ views of MTX and whether any difficulties their child experiences in taking MTX affects their willingness to allow their child to try other medications that may be prescribed in the future. The Sport Aiding Medical Research for Kids (SPARKS) Childhood Arthritis Response to Medication Study (CHARMS) [9,10] aims to define the factors that influence the response of children with JIA to methotrexate. As part of the study we investigated the difficulties arising from the use of MTX for JIA. "
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    ABSTRACT: Background Children who take methotrexate for juvenile idiopathic arthritis may experience side effects, including nausea and vomiting, leading to anticipatory nausea in some children, and fear of injections or blood tests. The aim of this study was to examine the prevalence and extent of these difficulties and their impact on quality of life. Methods Participants were mothers of children with JIA who were currently taking methotrexate (MTX). Mothers completed a questionnaire about MTX that was developed for the study, two questions from the treatment subscale of the Pediatric Quality of Life Inventory (PedsQL) Rheumatology scale to assess needle-related problems and the Child Health Questionnaire 50-item parent version (CHQ-PF50) to assess health-related quality of life (HRQoL). Results 171 mothers participated in the study. More than half of children were reported to have experienced one or more of: nausea or vomiting after taking MTX, anticipatory nausea, fear of blood tests or fear of injections. There was no significant difference in reported rates of sickness or needle-related problems between MTX responders (ACR70 or above), partial responders (ACR30 or ACR50) and non-responders. In multivariate analyses, variables that were significant independent predictors of one or more MTX-related difficulties included younger age, taking MTX subcutaneously and having a larger number of currently active joints. Feeling sick after taking MTX was a significant independent predictor of poorer scores on the physical summary scale of the CHQ-PF50. Anxiety about injections and feeling sick after taking MTX were significant independent predictors of poorer scores on the psychosocial summary scale. Conclusions Difficulties in taking MTX are experienced by a significant proportion of children with JIA and these may have an adverse impact on HRQoL. Approaches to help minimize these difficulties are required.
    Full-text · Article · May 2013 · Pediatric Rheumatology
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    ABSTRACT: Despite major advancements in therapeutics, variability in drug response remains a challenge in both adults and children diagnosed with rheumatic disease. The genetic contribution to interindividual variability has emerged as a promising avenue of exploration; however, challenges remain in making this knowledge relevant in the clinical realm. New genetic associations in patients with rheumatic disease have been reported for disease modifying antirheumatic drugs, antimetabolites and biologic drugs. However, many of these findings are in need of replication, and few have taken into account the concept of ontogeny, specific to pediatrics. In the current era in which we practice, genetic variation will undoubtedly contribute to variability in therapeutic response and may be a factor that will ultimately impact individualized care. However, preliminary studies have shown that there are many hurdles that need to be overcome as we explore pharmacogenomic associations specifically in the field of pediatric rheumatology.
    No preview · Article · Jun 2012 · Current opinion in rheumatology
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