Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1 × 10(-5)): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.

] Arthritis Research UK Centre for Genetics and Genomics Institute of Inflammation and Repair Faculty of Medical and Human Sciences Manchester Academic Health Science Centre The University of Manchester Manchester UK [2] NIHR Manchester Musculoskeletal Biomedical Research Unit Central Manchester National Health Service Foundation Trust Manchester Academic Health Science Centre Manchester UK

] Rheumatology Unit UCL Institute of Child Health London UK [2] Arthritis Research UK Centre for Adolescent Rheumatology UCL Institute of Child Health London UK

1st Faculty of Medicine and General Faculty Hospital Charles University Prague Praha Czech Republic

Arthritis Research UK Centre for Genetics and Genomics Institute of Inflammation and Repair Faculty of Medical and Human Sciences Manchester Academic Health Science Centre The University of Manchester Manchester UK

Centre for Health Services Research School of Health Sciences City University London London UK

Department of Clinical Chemistry Erasmus University Medical Centre Rotterdam The Netherlands

Department of Epidemiology and Biostatistics Imperial College London London UK

Department of Paediatric Immunology University Medical Centre Utrecht Wilhelmina Children's Hospital Utrecht The Netherlands

Department of Statistical Sciences University College London London UK

Institute of Child Health Birmingham Children's Hospital Birmingham UK

Rheumatology Unit UCL Institute of Child Health London UK

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Moorthy LN, Peterson MG, Hassett AL, Lehman TJ. Burden of childhood-onset arthritis. Pediatr Rheumatol Online J. 2010;8:20. PubMed PMC

De K,I, Brinkman DM, Ferster A, Abinun M, Quartier P, Van Der NJ, et al. Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity. Ann Rheum Dis. 2004 Oct;63(10):1318–26. PubMed PMC

Magni-Manzoni S, Rossi F, Pistorio A, Temporini F, Viola S, Beluffi G, et al. Prognostic factors for radiographic progression, radiographic damage, and disability in juvenile idiopathic arthritis. Arthritis Rheum. 2003 Dec;48(12):3509–17. PubMed

Nordal E, Zak M, Aalto K, Berntson L, Fasth A, Herlin T, et al. Ongoing disease activity and changing categories in a long-term nordic cohort study of juvenile idiopathic arthritis. Arthritis Rheum. 2011 Sep;63(9):2809–18. PubMed

Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O’Neil KM, Zeft AS, et al. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 2012 Jun;64(6):2012–21. PubMed PMC

Ruperto N, Murray KJ, Gerloni V, Wulffraat N, de Oliveira SK, Falcini F, et al. A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum. 2004 Jul;50(7):2191–201. PubMed

Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011 Jul;63(7):929–36. PubMed

Ma Q, Lu AY. Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev. 2011 Jun;63(2):437–59. PubMed

Bulatovic M, Heijstek MW, Van Dijkhuizen EH, Wulffraat NM, Pluijm SM, de JR. Prediction of clinical non-response to methotrexate treatment in juvenile idiopathic arthritis. Ann Rheum Dis. 2012 May 10; PubMed

de Rotte MC, Bulatovic M, Heijstek MW, Jansen G, Heil SG, van Schaik RH, et al. ABCB1 and ABCC3 gene polymorphisms are associated with first-year response to methotrexate in juvenile idiopathic arthritis. J Rheumatol. 2012 Oct;39(10):2032–40. PubMed

Dervieux T, Wessels JA, Kremer JM, Padyukov L, Seddighzadeh M, Saevarsdottir S, et al. Patterns of interaction between genetic and nongenetic attributes and methotrexate efficacy in rheumatoid arthritis. Pharmacogenet Genomics. 2012 Jan;22(1):1–9. PubMed

Hinks A, Moncrieffe H, Martin P, Ursu S, Lal S, Kassoumeri L, et al. Association of the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene with response to methotrexate in juvenile idiopathic arthritis. Ann Rheum Dis. 2011 Aug;70(8):1395–400. PubMed PMC

Lee YC, Cui J, Costenbader KH, Shadick NA, Weinblatt ME, Karlson EW. Investigation of candidate polymorphisms and disease activity in rheumatoid arthritis patients on methotrexate. Rheumatology (Oxford) 2009 Jun;48(6):613–7. PubMed PMC

Moncrieffe H, Hinks A, Ursu S, Kassoumeri L, Etheridge A, Hubank M, et al. Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype. Pharmacogenet Genomics. 2010 Nov;20(11):665–76. PubMed PMC

Schmeling H, Biber D, Heins S, Horneff G. Influence of methylenetetrahydrofolate reductase polymorphisms on efficacy and toxicity of methotrexate in patients with juvenile idiopathic arthritis. J Rheumatol. 2005 Sep;32(9):1832–6. PubMed

Wessels JA, van der Kooij SM, le CS, Kievit W, Barerra P, Allaart CF, et al. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum. 2007 Jun;56(6):1765–75. PubMed

Malik F, Ranganathan P. Methotrexate pharmacogenetics in rheumatoid arthritis: a status report. Pharmacogenomics. 2013 Feb;14(3):305–14. PubMed

Wang J, Bansal AT, Martin M, Germer S, Benayed R, Essioux L, et al. Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis. Pharmacogenomics J. 2013 Jun;13(3):235–41. PubMed

Adib N, Hyrich K, Thornton J, Lunt M, Davidson J, Gardner-Medwin J, et al. Association between duration of symptoms and severity of disease at first presentation to paediatric rheumatology: results from the Childhood Arthritis Prospective Study. Rheumatology (Oxford) 2008 Jul;47(7):991–5. PubMed PMC

Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004 Feb;31(2):390–2. PubMed

Nugent J, Ruperto N, Grainger J, Machado C, Sawhney S, Baildam E, et al. The British version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ) Clin Exp Rheumatol. 2001 Jul;19(4 Suppl 23):S163–S167. PubMed

Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 1997 Jul;40(7):1202–9. PubMed

Patterson N, Price AL, Reich D. Population structure and eigenanalysis. PLoS Genet. 2006 Dec;2(12):e190. PubMed PMC

Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006 Aug;38(8):904–9. PubMed

Price AL, Weale ME, Patterson N, Myers SR, Need AC, Shianna KV, et al. Long-range LD can confound genome scans in admixed populations. Am J Hum Genet. 2008 Jul;83(1):132–5. PubMed PMC

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007 Sep;81(3):559–75. PubMed PMC

Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010 Sep 15;26(18):2336–7. PubMed PMC

Delaneau O, Marchini J, Zagury JF. A linear complexity phasing method for thousands of genomes. Nat Methods. 2012 Feb;9(2):179–81. PubMed

Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009 Jun;5(6):e1000529. PubMed PMC

Martin P, Barton A, Eyre S. ASSIMILATOR: a new tool to inform selection of associated genetic variants for functional studies. Bioinformatics. 2011 Jan 1;27(1):144–6. PubMed PMC

Ellis JA, Munro JE, Chavez RA, Gordon L, Joo JE, Akikusa JD, et al. Genome-scale case-control analysis of CD4+ T-cell DNA methylation in juvenile idiopathic arthritis reveals potential targets involved in disease. Clin Epigenetics. 2012;4(1):20. PubMed PMC

Veyrieras JB, Kudaravalli S, Kim SY, Dermitzakis ET, Gilad Y, Stephens M, et al. High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet. 2008 Oct;4(10):e1000214. PubMed PMC

Beresford MW. Juvenile idiopathic arthritis: new insights into classification, measures of outcome, and pharmacotherapy. Paediatr Drugs. 2011 Jun 1;13(3):161–73. PubMed

Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ, DeWitt EM, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken) 2011 Apr;63(4):465–82. PubMed PMC

Ott CJ, Blackledge NP, Kerschner JL, Leir SH, Crawford GE, Cotton CU, et al. Intronic enhancers coordinate epithelial-specific looping of the active CFTR locus. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19934–9. PubMed PMC

Conseil G, Deeley RG, Cole SP. Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters. Pharmacogenet Genomics. 2005 Aug;15(8):523–33. PubMed

Ellinghaus D, Ellinghaus E, Nair RP, Stuart PE, Esko T, Metspalu A, et al. Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am J Hum Genet. 2012 Apr 6;90(4):636–47. PubMed PMC

Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010 Dec;42(12):1118–25. PubMed PMC

Imielinski M, Baldassano RN, Griffiths A, Russell RK, Annese V, Dubinsky M, et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet. 2009 Dec;41(12):1335–40. PubMed PMC

Patsopoulos NA, Esposito F, Reischl J, Lehr S, Bauer D, Heubach J, et al. Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann Neurol. 2011 Dec;70(6):897–912. PubMed PMC

Li X, Thyssen G, Beliakoff J, Sun Z. The novel PIAS-like protein hZimp10 enhances Smad transcriptional activity. J Biol Chem. 2006 Aug 18;281(33):23748–56. PubMed

Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007 Jul 13;317(5835):256–60. PubMed

Nistala K, Wedderburn LR. Th17 and regulatory T cells: rebalancing pro- and anti-inflammatory forces in autoimmune arthritis. Rheumatology (Oxford) 2009 Jun;48(6):602–6. PubMed

Pessah M, Prunier C, Marais J, Ferrand N, Mazars A, Lallemand F, et al. c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6198–203. PubMed PMC

Wolff S, Harper PA, Wong JM, Mostert V, Wang Y, Abel J. Cell-specific regulation of human aryl hydrocarbon receptor expression by transforming growth factor-beta(1) Mol Pharmacol. 2001 Apr;59(4):716–24. PubMed

Comabella M, Craig DW, Morcillo-Suarez C, Rio J, Navarro A, Fernandez M, et al. Genome-wide scan of 500,000 single-nucleotide polymorphisms among responders and nonresponders to interferon beta therapy in multiple sclerosis. Arch Neurol. 2009 Aug;66(8):972–8. PubMed

Daly AK. Genome-wide association studies in pharmacogenomics. Nat Rev Genet. 2010 Apr;11(4):241–6. PubMed