Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype.
Summary of "Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype."
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.
aRheumatology Unit bMolecular Haematology and Cancer Biology Units, UCL Institute of Child Health, London, UK cArthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre dDivision of Rheumatology, Cincinnati Children's Hospital Med
This article was published in the following journal.
Name: Pharmacogenetics and genomics
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20827233
- DOI: http://dx.doi.org/10.1097/FPC.0b013e32833f2cd0
Medical and Biotech [MESH] Definitions
Macrophage Activation Syndrome
A serious complication of childhood systemic inflammatory disorders that is thought to be caused by excessive activation and proliferation of T-LYMPHOCYTES and MACROPHAGES. It is seen predominantly in children with systemic onset JUVENILE IDIOPATHIC ARTHRITIS.
Human immune-response, D-related antigen encoded by the D locus on chromosome 6 and found on lymphoid cells. It is strongly associated with rheumatoid arthritis and juvenile diabetes.
Human immune-response, D-related antigen encoded by the D-locus on chromosome 6 and found on lymphoid cells. It is associated with Kaposi sarcoma in AIDS and juvenile rheumatoid arthritis.
An idiopathic vascular disorder characterized by bilateral Raynaud phenomenon, the abrupt onset of digital paleness or CYANOSIS in response to cold exposure or stress.
Arthritis, Juvenile Rheumatoid
Rheumatoid arthritis of children occurring in three major subtypes defined by the symptoms present during the first six months following onset: systemic-onset (Still's Disease, Juvenile-Onset), polyarticular-onset, and pauciarticular-onset. Adult-onset cases of Still's disease (STILL'S DISEASE, ADULT-ONSET) are also known. Only one subtype of juvenile rheumatoid arthritis (polyarticular-onset, rheumatoid factor-positive) clinically resembles adult rheumatoid arthritis and is considered its childhood equivalent.
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