title: Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) does not always respond to available treatments, including tumour necrosis factor (TNF) antagonists. A study was undertaken to investigate whether genetic variation within genes, encoding proteins in the p38 signalling network, contributes to the variable response to TNF antagonists.
  
  
  METHODS
  1102 UK Caucasian patients with RA receiving anti-TNF therapy (infliximab, adalimumab and etanercept) were genotyped for 38 pairwise-tagging single nucleotide polymorphisms (SNPs) spanning 12 candidate genes from the p38 network. Regression analyses were performed to test association between genotype and treatment response at 6 months using both absolute change in DAS28 (Disease Activity Score across 28 joints) and European League Against Rheumatism (EULAR) improvement criteria. Stratified analyses were performed to investigate association with individual therapies.
  
  
  RESULTS
  Seven SNPs, in five genes, were associated with improvement in DAS28 at 6 months at a nominal 0.1 significance level, jointly explaining 3% of variance in outcome in a model adjusting for other predictors. These encoded proteins both upstream (MKK6) and downstream (MAPKAPK2, MSK1, MSK2) of p38, and MAPK14, the p38-α isoform of p38 MAPK. One SNP (rs2716191 in MAP2K6) was associated with EULAR response at the 0.1 level. SNPs generally showed greater correlation with response to infliximab and adalimumab, but not to etanercept.
  
  
  CONCLUSIONS
  More SNPs than would be expected by chance, mapping to the p38 signalling network, showed association with the anti-TNF response as a whole, and particularly with the response to infliximab and adalimumab. Validation of these findings in independent cohorts is warranted.
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), University of Leeds, Leeds, UK.
authors.forename: Lydia R
authors.initials: LR
authors.lastname: Coulthard
authors.forename: John C
authors.initials: JC
authors.lastname: Taylor
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
authors.forename: James I
authors.initials: JI
authors.lastname: Robinson
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: Kimme
authors.initials: K
authors.lastname: Hyrich
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrett
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.forename: Michael F
authors.initials: MF
authors.lastname: McDermott
mesh_terms: D000068879:Adalimumab; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D015331:Cohort Studies; D000068800:Etanercept; D005260:Female; D005838:Genotype; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D000069285:Infliximab; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D048051:p38 Mitogen-Activated Protein Kinases; D000068879:Adalimumab; D000068800:Etanercept