title: Anti-TNF treatment response in rheumatoid arthritis patients is associated with genetic variation in the NLRP3-inflammasome.
abstract: OBJECTIVE
  Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-α blocking treatment (anti-TNF), but about one third do not respond. The objective of this study was to replicate and extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-κB- and pattern recognition receptor signalling pathways.
  
  
  METHODS
  Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data. Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3-6 months using the European League Against Rheumatism (EULAR) response criterion. American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes. Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status. False discovery rate (FDR) controlling was used to adjust for multiple testing.
  
  
  RESULTS
  Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response = 0.64 (95% confidence interval: 0.44-0.95), p = 0.025, q = 0.95) and INFG(rs2430561) (OR = 0.40 (0.21-0.76), p = 0.005, q = 0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36-0.98), p = 0.040, q = 0.76). Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR = 0.24 (0.10-0.56), p = 0.001, q = 0.04).
  
  
  CONCLUSIONS
  In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported. The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers. Furthermore, we find that a functional polymorphism in the interferon-γ gene is associated with anti-TNF response. All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products.
authors: Clinical Biochemistry, Immunology & Genetics, Statens Serum Institut, Copenhagen, Denmark; Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark; Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
authors: Jacob
authors: J
authors: Sode
authors: National Research Centre for the Working Environment, Copenhagen, Denmark.
authors: Ulla
authors: U
authors: Vogel
authors: Department of Medicine, Viborg Regional Hospital, Viborg, Denmark; Biomedicine, University of Aarhus, Aarhus, Denmark.
authors: Steffen
authors: S
authors: Bank
authors: Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
authors: Paal Skytt
authors: PS
authors: Andersen
authors: Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark.
authors: Marianne Kragh
authors: MK
authors: Thomsen
authors: The DANBIO Registry, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Glostrup Hospital, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Merete Lund
authors: ML
authors: Hetland
authors: Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.
authors: Henning
authors: H
authors: Locht
authors: Clinical Biochemistry, Immunology & Genetics, Statens Serum Institut, Copenhagen, Denmark.
authors: Niels H H
authors: NH
authors: Heegaard
authors: Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; Department of Medicine, Viborg Regional Hospital, Viborg, Denmark; Organ Center, Hospital of Southern Jutland, Aabenraa, Denmark; OPEN (Odense Patient data Explorative Network), Odense University Hospital, Odense, Denmark.
authors: Vibeke
authors: V
authors: Andersen
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D018501:Antirheumatic Agents; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D014409:Tumor Necrosis Factor-alpha