Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases.
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.
1] 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.
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J
Cobb
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
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E
Cule
Rheumatology Unit, UCL Institute of Child Health, London, UK.
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H
Moncrieffe
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.
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A
Hinks
Rheumatology Unit, UCL Institute of Child Health, London, UK.
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S
Ursu
Rheumatology Unit, UCL Institute of Child Health, London, UK.
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F
Patrick
Rheumatology Unit, UCL Institute of Child Health, London, UK.
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L
Kassoumeri
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.
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E
Flynn
Department of Paediatric Immunology, University Medical Centre Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
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M
Bulatović
Department of Paediatric Immunology, University Medical Centre Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
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Wulffraat
Department of Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, The Netherlands.
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B
van Zelst
Department of Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, The Netherlands.
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de Jonge
First Faculty of Medicine and General Faculty Hospital, Charles University in Prague, Praha, Czech Republic.
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Bohm
First Faculty of Medicine and General Faculty Hospital, Charles University in Prague, Praha, Czech Republic.
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P
Dolezalova
Centre for Health Services Research, School of Health Sciences, City University London, London, UK.
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S
Hirani
Centre for Health Services Research, School of Health Sciences, City University London, London, UK.
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S
Newman
Institute of Child Health, Birmingham Children's Hospital, Birmingham, UK.
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P
Whitworth
Institute of Child Health, Birmingham Children's Hospital, Birmingham, UK.
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TR
Southwood
Department of Statistical Sciences, University College London, London, UK.
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M
De Iorio
1] Rheumatology Unit, UCL Institute of Child Health, London, UK [2] Arthritis Research UK Centre for Adolescent Rheumatology, UCL Institute of Child Health, London, UK.
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Wedderburn
1] 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.
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Thomson
D001171:Arthritis, Juvenile / Q000188:drug therapy* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide
D008727:Methotrexate