title: Tumor necrosis factor-α promoter -308/238 polymorphism association with less severe disease in ankylosing spondylitis is unrelated to serum TNF-α and does not predict TNF inhibitor response.
abstract: OBJECTIVE
  Despite the clinical efficacy of tumor necrosis factor inhibitors (TNFi), the manner in which TNF-α contributes to disease in patients with ankylosing spondylitis (AS) remains unresolved. We investigated the relationship between TNF-α gene promoter region polymorphism, serum TNF-α levels, and clinical phenotype.
  
  
  METHODS
  We did a cross-sectional and longitudinal cohort study in TNFi-naive patients with AS (n = 335). Clinical data and biological samples were collected during a research visit with genotyping for TNF-α -238 A/G and -308 A/G performed by Taqman RT-PCR and TNF levels determined by sandwich ELISA. Longitudinal TNF levels were monitored in unselected patients (n = 61).
  
  
  RESULTS
  TNF-α -308 GA/AA genotype was present in 14% and TNF-α -238 GA/AA genotype in 1% of patients. TNF-α -308 GA/AA genotype was associated with a reduced risk of uveitis and better spinal function, while TNF-α -238 GA/AA genotype was associated with later age of onset and lower erythrocyte sedimentation rate (ESR). Serum TNF-α level was lower in patients with AS (151 pg/ml) than in controls (263 pg/ml), because more patients with AS had undetectable serum TNF-α (66 vs 25%, p < 0.001). TNFi treatment did not influence serum TNF-α. There was no effect of TNF-α -308/-238 or HLA-B27 genotype on serum TNF-α or subsequent initiation of TNFi.
  
  
  CONCLUSIONS
  TNF-α -238 or -308 GA/AA genotypes in patients with AS are associated with signs of less severe disease. Serum TNF-α is, however, undetectable in two-thirds of patients with AS and is not influenced by TNF-α promoter genotype or TNFi therapy. These data suggest a more significant role for TNF-α at local sites of inflammation in AS than through systemic effects.
authors.affiliation: From the Bone and Joint Research Group, Department of Clinical Medicine, University of Tromsø, Tromsø, Norway.J.C. Nossent, MD, PhD, Professor of Medicine; S. Sagen-Johnsen, PhD, bioengineer; G. Bakland, MD, PhD, Bone and Joint Research Group, Department of Clinical Medicine, University of Tromsø.Dr. J.C. Nossent is currently at Sir Charles Gairdner Hospital, Perth, Australia. Dr. S. Sagen-Johnsen is currently at University in Aas, Norway. Dr. G. Bakland is at University Hospital North Norway, Tromsø. hans.nossent@uit.no.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Nossent
authors.affiliation: From the Bone and Joint Research Group, Department of Clinical Medicine, University of Tromsø, Tromsø, Norway.J.C. Nossent, MD, PhD, Professor of Medicine; S. Sagen-Johnsen, PhD, bioengineer; G. Bakland, MD, PhD, Bone and Joint Research Group, Department of Clinical Medicine, University of Tromsø.Dr. J.C. Nossent is currently at Sir Charles Gairdner Hospital, Perth, Australia. Dr. S. Sagen-Johnsen is currently at University in Aas, Norway. Dr. G. Bakland is at University Hospital North Norway, Tromsø.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Sagen-Johnsen
authors.affiliation: From the Bone and Joint Research Group, Department of Clinical Medicine, University of Tromsø, Tromsø, Norway.J.C. Nossent, MD, PhD, Professor of Medicine; S. Sagen-Johnsen, PhD, bioengineer; G. Bakland, MD, PhD, Bone and Joint Research Group, Department of Clinical Medicine, University of Tromsø.Dr. J.C. Nossent is currently at Sir Charles Gairdner Hospital, Perth, Australia. Dr. S. Sagen-Johnsen is currently at University in Aas, Norway. Dr. G. Bakland is at University Hospital North Norway, Tromsø.
authors.forename: Gunnstein
authors.initials: G
authors.lastname: Bakland
mesh_terms: D000328:Adult; D000483:Alleles; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D015415:Biomarkers; D001799:Blood Sedimentation; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012720:Severity of Illness Index; D013167:Spondylitis, Ankylosing / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics*
chemical_list: D018501:Antirheumatic Agents; D015415:Biomarkers; D014409:Tumor Necrosis Factor-alpha
keywords: ANKYLOSING SPONDYLITIS; PROMOTER REGION; SERUM TUMOR NECROSIS FACTOR; TUMOR NECROSIS FACTOR