title: Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis.
abstract: OBJECTIVE
  Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the possible biological pathways associated with the treatment response to TNFα inhibitors.
  
  
  METHODS
  TNFα-naive patients with RA, who had available DNA and initiated TNFα inhibitor therapy between 1999 and 2008, were identified in the DANBIO registry and genotyped using the Illumina HumanHap550K Duo array. The associations between SNPs and changes in the absolute and the relative Disease Activity Score, and European League Against Rheumatism good versus no response after 14 weeks of treatment were tested. SNP data were combined with two independent cohorts in a meta-analysis. A gene-set enrichment analysis (GSEA) was carried out to identify the biological pathways associated with the treatment response.
  
  
  RESULTS
  After genotyping and quality control, 486 450 SNPs were analyzed in 196 Danish patients with moderate to severe RA treated with infliximab (n=142), etanercept (n=12), and adalimumab (n=42). None of the previously identified SNPs were confirmed in our dataset or in meta-analyses of available studies. Other potential SNPs were identified, but none achieved genome-wide significance. A GSEA identified the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways to have a potential influence on the treatment response.
  
  
  CONCLUSIONS
  In a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis, we found no SNPs associated with treatment response to TNFα inhibitors. A GSEA suggested that the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response.
authors.affiliation: DANBIO Registry and Department of Rheumatology, Hvidovre and Glostrup Hospitals, Glostrup, Denmark. krintel@sophine.dk
authors.forename: Sophine B
authors.initials: SB
authors.lastname: Krintel
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palermo
authors.forename: Julia S
authors.initials: JS
authors.lastname: Johansen
authors.forename: Søren
authors.initials: S
authors.lastname: Germer
authors.forename: Laurent
authors.initials: L
authors.lastname: Essioux
authors.forename: Ryma
authors.initials: R
authors.lastname: Benayed
authors.forename: Laura
authors.initials: L
authors.lastname: Badi
authors.forename: Mikkel
authors.initials: M
authors.lastname: Ostergaard
authors.forename: Merete L
authors.initials: ML
authors.lastname: Hetland
mesh_terms: D000068879:Adalimumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics; D054316:Biomarkers, Pharmacological; D000068800:Etanercept; D055106:Genome-Wide Association Study; D007074:Immunoglobulin G / Q000627:therapeutic use; D000069285:Infliximab; D020641:Polymorphism, Single Nucleotide; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D054316:Biomarkers, Pharmacological; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept