Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases

Cobb, Joanna; Cule, Erika; Moncrieffe, Halima; Hinks, Anne; Ursu, Simona; Patrick, Fiona; Kassoumeri, Laura; Flynn, Edward; Bulatović, Maja; Wulffraat, Nico; Zelst, Bertrand van; Jonge, Robert de; Böhm, M.; Doležalová, Pavla; Hirani, Shashivadan P.; Newman, Stanton; Whitworth, Polly; Southwood, T. R. E.; Iorio, Maria De; Wedderburn, Lucy R.; Thomson, Wendy

doi:10.1038/tpj.2014.3

Cited by 50 publications

(41 citation statements)

References 44 publications

(46 reference statements)

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“…The * 15 allele was tested for association with MTX response because it was associated with slow clearance and high exposure after high‐dose MTX in leukemia patients , but the hypothesized association with a good response was not observed in JIA patients. Interestingly, the SLCO1B1 gene was not identified as a region of interest in the only published genome‐wide association study of MTX response in JIA patients , but this study did not test for individual SLCO1B1 alleles.…”

Section: Discussionmentioning

confidence: 97%

Association of SLCO1B1 *14 Allele with Poor Response to Methotrexate in Juvenile Idiopathic Arthritis Patients

Ramsey

Moncrieffe

Smith

et al. 2019

ACR Open Rheumatology

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ObjectiveVariants in the SLCO1B1 gene, encoding a hepatic methotrexate (MTX) transporter, affect clearance of high‐dose MTX. We tested whether in the *14 and *15 alleles of SLCO1B1 influenced the response to low‐dose MTX in juvenile idiopathic arthritis (JIA) patients.MethodsThe study included 310 JIA patients genotyped for three single nucleotide polymorphisms (SNPs) in SLCO1B1 (rs4149056, rs2306283, and rs11045819). A patient's SLCO1B1 diplotype was determined by combining the SNPs into the *1a, *1b, *4, *5, *14, and *15 alleles. Number of active joints at follow‐up (visit closest to 6 months of treatment and prior to starting a tumor necrosis factor inhibitor) was used as the dependent variable in a negative binomial regression model that included active joint count at baseline as a covariate.ResultsThe SLCO1B1*14 allele was associated with less response to MTX (P = 0.024) and the *15 allele was not associated with response to MTX (P = 0.392).Conclusion SLCO1B1 alleles may be associated with poor response to MTX in JIA patients. The *14 allele has been associated with fast clearance (low exposure) after high‐dose MTX in patients with leukemia. Thus, the SLCO1B1 gene may be informative for precision dosing of MTX in JIA patients. Patients carrying the *14 allele may require a higher dose than noncarriers to achieve a similar response to MTX.

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Section: Discussionmentioning

confidence: 97%

Association of SLCO1B1 *14 Allele with Poor Response to Methotrexate in Juvenile Idiopathic Arthritis Patients

Ramsey

Moncrieffe

Smith

et al. 2019

ACR Open Rheumatology

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“…Non-targeted whole genome analysis was conducted in 694 JIA patients to identify genetic polymorphisms associated with response to MTX and identified a number of genes [92]. The strongest association was observed with a gene that encodes the alpha chain of a low-voltage calcium channel important in neuronal signaling (CACNA1I).…”

Section: Genetic Biomarkersmentioning

confidence: 99%

Disease modifying anti-rheumatic drugs in juvenile idiopathic arthritis: striving for individualized therapy

Funk

Becker

2016

Expert Review of Precision Medicine and Drug Development

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Disease-Modifying Anti-Rheumatic Drug (DMARD) use in the treatment of juvenile idiopathic arthritis (JIA) has experienced a dramatic evolution since the early introduction of methotrexate in the 1970's. This renaissance has been primarily driven by innovation in drug discovery and development that has resulted in the approval of a number of protein-based therapeutics targeting disease-specific pathways. Despite the expansion in the number of drugs available in the treatment of JIA, interindividual variation in therapeutic response and drug-associated toxicities continue to be a major concern and has driven efforts towards individualized therapy. Recent advances in pediatric drug development and innovative approaches to identifying a priori predictors of drug response hold the promise for an individualized approach to therapy that will yield the highest efficacy and safety potential for each JIA patient.

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“…Non-response to methotrexate has also been associated with one SNP within the SLC19A1 region 66 . At a genome wide level in a study analysing almost 700 JIA cases 69 , several genetic regions were implicated as associating with response to methotrexate in JIA but await validation in replication cohorts.…”

Section: Biomarkers To Aid the Prediction Of Treatment Response In Jiamentioning

confidence: 99%

Predicting disease outcomes in juvenile idiopathic arthritis: challenges, evidence, and new directions

Shoop-Worrall

Davies

et al. 2019

The Lancet Child & Adolescent Health

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Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases

Cited by 50 publications

References 44 publications

Association of SLCO1B1 *14 Allele with Poor Response to Methotrexate in Juvenile Idiopathic Arthritis Patients

Association of SLCO1B1 *14 Allele with Poor Response to Methotrexate in Juvenile Idiopathic Arthritis Patients

Disease modifying anti-rheumatic drugs in juvenile idiopathic arthritis: striving for individualized therapy

Predicting disease outcomes in juvenile idiopathic arthritis: challenges, evidence, and new directions

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