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

J Cobb; E Cule; H Moncrieffe; A Hinks; S Ursu; F Patrick; L Kassoumeri; E Flynn; M Bulatović; N Wulffraat; B van Zelst; R de Jonge; M Bohm; P Dolezalova; S Hirani; S Newman; P Whitworth; T R Southwood; M De Iorio; Childhood Arthritis Response to Medication Study (CHARMS); Childhood Arthritis Prospective Study (CAPS); BSPAR study group; L R Wedderburn; W Thomson

doi:10.1038/tpj.2014.3

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

Pharmacogenomics J. 2014 Aug;14(4):356-64. doi: 10.1038/tpj.2014.3. Epub 2014 Apr 8.

Authors

J Cobb¹, E Cule², H Moncrieffe³, A Hinks⁴, S Ursu³, F Patrick³, L Kassoumeri³, E Flynn⁴, M Bulatović⁵, N Wulffraat⁵, B van Zelst⁶, R de Jonge⁶, M Bohm⁷, P Dolezalova⁷, S Hirani⁸, S Newman⁸, P Whitworth⁹, T R Southwood⁹, M De Iorio¹⁰; Childhood Arthritis Response to Medication Study (CHARMS); Childhood Arthritis Prospective Study (CAPS); BSPAR study group; L R Wedderburn¹¹, W Thomson¹

Collaborators

Eileen Baildam, Nick Bishop, Lynsey Brown, Joanne Buckley, Alice Chieng, Roberto Carrasco, Joanna Cobb, Lucy Cook, Joyce Davidson, Annette Duggan, Michael Eltringham, Helen Foster, Elizabeth Friel, Mark Friswell, Janet Gardner-Medwin, Paul Gilbert, Vikki Gould, Kelly Hadfield, Kimme Hyrich, Julie Jones, Sham Lal, Mark Lay, Gabrielle Lloyd, Olivia Lloyd, Carol Lydon, Natasha Makengo, Ann McGovern, Alexandra Meijer, Nicola Mills-Wierda, Theresa Moorcroft, Vicki Price, Liang Qiao, Kay Riding, Jane Sim, Tauny Southwood, Wendy Thomson, Maureen Todd, Susan Tremble, Katharine Venter, Debbie Wade, Peter Ward, Sharon Watson, Gwen Webster, Lucy R Wedderburn, Jadranka Zelenovic, Katrin Buerkle, Joanna Cobb, Catherine Cotter, Angela Etheridge, Paul Gilbert, Anne Hinks, Shashi Hirani, Laura Kassoumeri, Sham Lal, Laura Melville, Halima Moncrieffe, Kathleen Mulligan, Stanton Newman, Fiona Patrick, Tauny Southwood, Wendy Thomson, Simona Ursu, Lucy R Wedderburn, Pamela Whitworth, Patricia Woo, Mario Abinum, A Bell, Alan W Craft, Esther Crawley, Joel David, Helen Foster, Janet Gardener-Medwin, Jane Griffin, A Hall, M Hal, Ariane L Herrick, P Hollingworth, Lennox Holt, Stan Jones, Gillian Pountain, Clive Ryder, Tauny Southwood, I Stewart, Helen Venning, Lucy R Wedderburn, Patricia Woo, Sue Wyatt

Affiliations

¹ 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.
² Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
³ Rheumatology Unit, UCL Institute of Child Health, London, UK.
⁴ 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.
⁵ Department of Paediatric Immunology, University Medical Centre Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
⁶ Department of Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, The Netherlands.
⁷ First Faculty of Medicine and General Faculty Hospital, Charles University in Prague, Praha, Czech Republic.
⁸ Centre for Health Services Research, School of Health Sciences, City University London, London, UK.
⁹ Institute of Child Health, Birmingham Children's Hospital, Birmingham, UK.
¹⁰ Department of Statistical Sciences, University College London, London, UK.
¹¹ 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.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Arthritis, Juvenile / drug therapy*
Arthritis, Juvenile / genetics
Child
Child, Preschool
Cohort Studies
Female
Humans
Male
Methotrexate / therapeutic use*
Polymorphism, Single Nucleotide

Substances

Methotrexate

Abstract

Publication types

MeSH terms

Substances

Grants and funding