Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases.
Joanna CobbE CuleH MoncrieffeA HinksS UrsuF PatrickL KassoumeriE FlynnM BulatovićN WulffraatB van ZelstR de JongeM BohmP DolezalovaS HiraniS NewmanP WhitworthT R SouthwoodM De Iorionull nullnull nullnull nullL R WedderburnW ThomsonPublished in: The pharmacogenomics journal (2014)
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.
Keyphrases
- juvenile idiopathic arthritis
- genome wide
- dna methylation
- phase ii
- clinical trial
- disease activity
- cystic fibrosis
- high dose
- electronic health record
- copy number
- single cell
- open label
- systemic lupus erythematosus
- deep learning
- rheumatoid arthritis
- combination therapy
- young adults
- cross sectional
- machine learning
- double blind
- genome wide identification