title: 5-Aminoimidazole-4-carboxamide ribonucleotide-transformylase and inosine-triphosphate-pyrophosphatase genes variants predict remission rate during methotrexate therapy in patients with juvenile idiopathic arthritis.
abstract: For children with juvenile idiopathic arthritis (JIA) who fail to respond to methotrexate, the delay in identifying the optimal treatment at an early stage of disease can lead to long-term joint damage. Recent studies indicate that relevant variants to predict methotrexate response in JIA are those in 5-aminoimidazole-4-carboxamide ribonucleotide-transformylase (ATIC), inosine-triphosphate-pyrophosphatase (ITPA) and solute-liquid-carrier-19A1 genes. The purpose of the study was, therefore, to explore the role of these candidate genetic factors on methotrexate response in an Italian cohort of children with JIA. Clinical response to methotrexate was evaluated as clinical remission stable for a 6-month period, as ACRPed score and as change in Juvenile Arthritis Disease score. The most relevant SNPs for each gene considered were assayed on patients' DNA. ITPA activity was measured in patients' erythrocytes. Sixty-nine patients with JIA were analyzed: 52.2 % responded to therapy (ACRPed70 score), while 37.7 % reached clinical remission stable for 6 months. ATIC rs2372536 GG genotype was associated with improved clinical remission (adjusted p value = 0.0090). For ITPA, rs1127354 A variant was associated with reduced clinical remission: (adjusted p value = 0.028); this association was present even for patients with wild-type ITPA and low ITPA activity. These preliminary results indicate that genotyping of ATIC rs2372536 and ITPA rs1127354 variants or measuring ITPA activity could be useful to predict methotrexate response in children with JIA after validation by further prospective studies on a larger patient cohort.
authors.affiliation: University of Trieste, Trieste, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pastore
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stocco
authors.forename: Valentina
authors.initials: V
authors.lastname: Moressa
authors.forename: Luigi
authors.initials: L
authors.lastname: Zandonà
authors.forename: Diego
authors.initials: D
authors.lastname: Favretto
authors.forename: Noelia
authors.initials: N
authors.lastname: Malusà
authors.forename: Giuliana
authors.initials: G
authors.lastname: Decorti
authors.forename: Loredana
authors.initials: L
authors.lastname: Lepore
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ventura
mesh_terms: D000293:Adolescent; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001171:Arthritis, Juvenile / Q000188:drug therapy* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics*; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D009097:Multienzyme Complexes / Q000235:genetics*; D009709:Nucleotide Deaminases / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011755:Pyrophosphatases / Q000235:genetics*; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult; D000097630:Inosine Triphosphatase
chemical_list: D018501:Antirheumatic Agents; D019877:Hydroxymethyl and Formyl Transferases; D008727:Methotrexate; D009097:Multienzyme Complexes; D009709:Nucleotide Deaminases; D011755:Pyrophosphatases; C113120:inosine monophosphate synthase; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase