{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:42:00Z","timestamp":1780472520130,"version":"3.54.1"},"reference-count":29,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2010,12,28]],"date-time":"2010-12-28T00:00:00Z","timestamp":1293494400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2011,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The response to and toxicity of methotrexate (MTX) are unpredictable in patients with juvenile idiopathic arthritis (JIA). Intracellular polyglutamation of MTX, assessed by measuring concentrations of MTX polyglutamates (MTXGlu), has been demonstrated to be a promising predictor of drug response. Therefore, this study was aimed at investigating the genetic predictors of MTXGlu variability and associations between MTXGlu and drug response in JIA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The study was designed as a single\u2010center cross\u2010sectional analysis of patients with JIA who were receiving stable doses of MTX at a tertiary care children's hospital. After informed consent was obtained from the 104 patients with JIA, blood was withdrawn during routine MTX\u2010screening laboratory testing. Clinical data were collected by chart review. Genotyping for 34 single\u2010nucleotide polymorphisms (SNPs) in 18 genes within the MTX metabolic pathway was performed. An ion\u2010pair chromatographic procedure with mass spectrometric detection was used to measure MTXGlu<jats:sub>1\u20137<\/jats:sub>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Analysis and genotyping of MTXGlu was completed in the 104 patients. K\u2010means clustering resulted in 3 distinct patterns of MTX polyglutamation. Cluster 1 had low red blood cell (RBC) MTXGlu concentrations, cluster 2 had moderately high RBC MTXGlu<jats:sub>1 + 2<\/jats:sub> concentrations, and cluster 3 had high concentrations of MTXGlu, specifically MTXGlu<jats:sub>3\u20135<\/jats:sub>. SNPs in the purine and pyrimidine synthesis pathways, as well as the adenosine pathway, were significantly associated with cluster subtype. The cluster with high concentrations of MTXGlu<jats:sub>3\u20135<\/jats:sub> was associated with elevated liver enzyme levels on liver function tests (LFTs), and there were higher concentrations of MTXGlu<jats:sub>3\u20135<\/jats:sub> in children who reported gastrointestinal side effects and had abnormal findings on LFTs. No association was noted between MTXGlu and active arthritis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>MTXGlu remains a potentially useful tool for determining outcomes in patients with JIA being treated with MTX. The genetic predictors of MTXGlu variability may also contribute to a better understanding of the intracellular biotransformation of MTX in these patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.30080","type":"journal-article","created":{"date-parts":[[2010,10,15]],"date-time":"2010-10-15T16:58:25Z","timestamp":1287161905000},"page":"276-285","source":"Crossref","is-referenced-by-count":62,"title":["The effect of genotype on methotrexate polyglutamate variability in juvenile idiopathic arthritis and association with drug response"],"prefix":"10.1002","volume":"63","author":[{"given":"Mara L.","family":"Becker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Gaedigk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"van Haandel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Lasky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Hoeltzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongying","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Stobaugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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