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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Moncrieffe
Halima
H
Rheumatology Unit, UCL Institute of Child Health, London, UK.
Hinks
Anne
A
Ursu
Simona
S
Kassoumeri
Laura
L
Etheridge
Angela
A
Hubank
Mike
M
Martin
Paul
P
Weiler
Tracey
T
Glass
David N
DN
Thompson
Susan D
SD
Thomson
Wendy
W
Wedderburn
Lucy R
LR
D018501:Antirheumatic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001171:Arthritis, Juvenile / Q000188:drug therapy / Q000235:genetics*; D015331:Cohort Studies; D015870:Gene Expression; D020869:Gene Expression Profiling; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008727:Methotrexate / Q000493:pharmacokinetics / Q000627:therapeutic use*; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism
D018501:Antirheumatic Agents; D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; C490427:SLC16A7 protein, human; D008727:Methotrexate
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