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

Abstract

Objectives-Little is known about 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 treatment were selected for SNP genotyping. Genotype frequencies were compared between non-responders 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 analysed for genetic association to 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 analyse 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 which are differentially expressed at mRNA level after drug administration may also be good candidates for genetic analysis.

Pharmacogenomics in pediatric rheumatology

“…this study revealed one of the two ATIC SNPs trending toward significance (P ¼ 0.07), but there were no proxies (r 2 > 0.8) available for testing the ITPA SNP in the US cohort [24 && ]. Lastly, recent work has reported changes in gene expression after MTX initiation in 11 JIA patients well characterized as best responders or nonresponders to the drug [25]. Three SNPs in solute carrier family 16, member 7 (SLC16A7) showed significant association with MTX response, and one (the minor A allele of the SNP rs3763980) was validated in an independent cohort as being associated with an increased risk of nonresponse to MTX in JIA [25].…”

Genetic Polymorphisms in Low-Dose Methotrexate Transporters: Current Relevance as Methotrexate Therapeutic Outcome Biomarkers

“…At present, the functional relationship of SLC16A7 expression and MTX mechanisms remains unclear. This variant of SLC16A7 results in a substitution of an A with a T and leads to an amino acid change from threonine to a serine at position 445 [18]. This polymorphism occurs in a predicted region encoding for a cytoplasmic domain, with implications in phosphorylation and signaling and, therefore, is potentially functional [18].…”

Therapeutic advancements in juvenile idiopathic arthritis

“…Genes in the purine synthesis portion of the folate pathway have been investigated, based on the biologic plausibility that enzyme variability may directly affect the formation of adenosine and thus the anti-inflammatory properties of MTX [24,25]. Single nucleotide polymorphisms (SNPs) in MTX transporter genes can also affect intracellular drug levels and alterations in response and efficacy [26,27]. A predictive response model was developed based on the presence of an elevation in the erythrocyte sedimentation rate (ESR) and SNPs in methionine synthase reductase (MTRR), ATP-binding cassette, sub-family B, member 1 (ABCB1), ATP-binding cassette, subfamily C, member 1 (ABCC1), and the proton-coupled folate transporter (PCFT).…”