Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.
John C TaylorTim BongartzJonathan MasseyBorbala MifsudAthina SpiliopoulouIan C ScottJianmei WangMichael MorganDarren PlantMarco ColomboPeter OrchardSarah TwiggIain B McInnesDuncan PorterJane E FreestonJackie L NamHeather J CordellJohn D IsaacsJenna L StrathdeeDonna ArnettMaria J H de HairPaul P TakStella AslibekyanRonald F van VollenhovenLeonid PadyukovS Louis BridgesCostantino PitzalisAndrew P CopeSuzanne M M VerstappenPaul EmeryMichael R BarnesFelix AgakovPaul McKeigueTaisei MushirodaMichiaki KuboRichard WeinshilboumRichard B WarrenAnn W MorganJennifer H Barrettnull nullnull nullnull nullPublished in: The pharmacogenomics journal (2018)
Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10-7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.
Keyphrases
- disease activity
- rheumatoid arthritis
- rheumatoid arthritis patients
- genome wide
- juvenile idiopathic arthritis
- end stage renal disease
- systemic lupus erythematosus
- newly diagnosed
- ejection fraction
- chronic kidney disease
- ankylosing spondylitis
- prognostic factors
- dna methylation
- peritoneal dialysis
- randomized controlled trial
- genome wide association study
- high dose
- clinical trial
- combination therapy
- gene expression
- patient reported outcomes
- copy number
- machine learning
- electronic health record
- peripheral blood
- deep learning
- patient reported
- interstitial lung disease
- high density