title: Genetic Variations in Pattern Recognition Receptor Loci Are Associated with Anti-TNF Response in Patients with Rheumatoid Arthritis.
abstract: OBJECTIVE
  To determine whether genetic variation within genes related to the Toll-like receptor, inflammasome and interferon-γ pathways contributes to the differences in treatment response to tumour necrosis factor inhibitors (anti-TNF) in patients with rheumatoid arthritis (RA).
  
  
  METHODS
  In a retrospective case-case study, we assessed 23 functional single nucleotide polymorphisms (SNPs) in 15 genes. We included 538 anti-TNF naïve Danish RA patients from the nationwide DANBIO database. Multivariable logistic regression analyses were performed to detect associations (p-value<0.05) between genotypes and European League Against Rheumatism (EULAR) treatment responses. False Discovery Rate corrections for multiple testing (q-value) and stratified analyses were performed to investigate association with individual therapies and IgM-rheumatoid factor (RF) status.
  
  
  RESULTS
  Six of twenty successfully genotyped polymorphisms were nominally associated with EULAR treatment response. Three of these were in weak to moderate linkage disequilibrium with polymorphisms previously reported associated with anti-TNF treatment response. TLR5(rs5744174) variant allele carriers (odds ratio(OR) = 1.7(1.1-2.5),p = 0.010,q = 0.46) and TLR1(rs4833095) homozygous variant carriers (OR = 2.8(1.1-7.4),p = 0.037,q = 0.46) had higher odds for a positive treatment response. NLRP3(rs10754558) variant allele carriers (odds ratio(OR) = 0.6(0.4-1.0),p = 0.045,q = 0.46) were more likely to have a negative treatment response. The association in TLR5(rs5744174) remained significant after correction for multiple comparisons among patients negative for RF (OR = 6.2(2.4-16.3),p = 0.0002,q = 0.024). No other association withstood correction for multiple testing. Post hoc analyses showed that change in Patient Global score on a visual analogue scale (VAS) and change in pain VAS were the main factors responsible for the association.
  
  
  CONCLUSIONS
  We reproduced previously reported associations between genetic variation in the TLR10/1/6 gene cluster, TLR5, and NLRP3 loci and response to anti-TNF treatment in RA. Changes in VAS pain and patient global scores were the main contributors to the association found for TLR5. Furthermore, we identified other candidate genes that require replication in independent cohorts.
authors.affiliation: Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark; Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark; Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark, Odense, Denmark; OPEN (Odense Patient data Explorative Network), Odense University Hospital, Odense, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Sode
authors.affiliation: National Research Centre for the Working Environment, Copenhagen, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
authors.affiliation: Department of Medicine, Viborg Regional Hospital, Viborg, Denmark; Biomedicine, University of Aarhus, Aarhus, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Bank
authors.affiliation: Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark; Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Paal Skytt
authors.initials: PS
authors.lastname: Andersen
authors.affiliation: The DANBIO Registry, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Merete Lund
authors.initials: ML
authors.lastname: Hetland
authors.affiliation: Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Locht
authors.affiliation: Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark; Clinical Biochemistry, Clinical Institute, University of Southern Denmark, Odense, Denmark.
authors.forename: Niels H H
authors.initials: NH
authors.lastname: Heegaard
authors.affiliation: Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark, Odense, Denmark; Department of Medicine, Viborg Regional Hospital, Viborg, Denmark; Molecular Diagnostic and Clinical Research Unit, Hospital of Southern Jutland, Aabenraa, Denmark; OPEN (Odense Patient data Explorative Network), Odense University Hospital, Odense, Denmark.
authors.forename: Vibeke
authors.initials: V
authors.lastname: Andersen
mesh_terms: D000068879:Adalimumab / Q000627:therapeutic use; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics*; D000068800:Etanercept / Q000627:therapeutic use; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D056426:Genetic Loci; D006801:Humans; D058847:Inflammasomes / Q000235:genetics; D000069285:Infliximab / Q000627:therapeutic use; D007371:Interferon-gamma / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D000070576:NLR Proteins; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D051193:Toll-Like Receptors / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018501:Antirheumatic Agents; D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; D000070576:NLR Proteins; C427903:NLRP1 protein, human; D051193:Toll-Like Receptors; D007371:Interferon-gamma; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept