title: Association of the TRAF1/C5 locus with increased mortality, particularly from malignancy or sepsis, in patients with rheumatoid arthritis.
abstract: OBJECTIVE
  Recent genome-wide association studies have identified TRAF1/C5 as a rheumatoid arthritis (RA) susceptibility locus. Tumor necrosis factor receptor-associated factor 1 (TRAF1) has been implicated in the regulation of antiapoptotic pathways, whereas C5 has a well-established role in defense against infection. The purpose of this study was to examine the association of the TRAF1/C5 locus with death in patients with RA.
  
  
  METHODS
  Genomic DNA samples were collected from a prospective cohort of 400 RA patients. TRAF1/C5 rs3761847 was identified using real-time polymerase chain reaction and melting curve analyses. The association of TRAF1/C5 rs3761847 alleles with the risk of death was assessed using Cox proportional hazards regression analyses.
  
  
  RESULTS
  TRAF1/C5 rs3761847 GG homozygote status was associated with an increased risk of death (hazard ratio 3.96 [95% confidence interval 1.24-12.6], P=0.020) as compared with AA homozygote status. The excess mortality was attributed to deaths due to malignancies and sepsis but not cardiovascular disease (CVD). This polymorphism was one of the strongest predictors of death in RA (for TRAF1/C5 GG versus AA, hazard ratio 3.85 [95% confidence interval 1.18-12.59], P=0.026) alongside the erythrocyte sedimentation rate, triglyceride level, prednisolone use, and age.
  
  
  CONCLUSIONS
  The risk of death in RA is increased in TRAF1/C5 rs3761847 GG homozygotes and appears to be independent of RA activity and severity as well as comorbidities relevant to CVD. If this finding is replicated in future studies, TRAF1/C5 genotyping could identify patients at increased risk of death, particularly death due to malignancy or sepsis.
authors.affiliation: Dudley Group of Hospitals National Health Service Trust, Dudley, UK.
authors.forename: Vasileios F
authors.initials: VF
authors.lastname: Panoulas
authors.forename: Jacqueline P
authors.initials: JP
authors.lastname: Smith
authors.forename: Peter
authors.initials: P
authors.lastname: Nightingale
authors.forename: George D
authors.initials: GD
authors.lastname: Kitas
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000401:mortality*; D002423:Cause of Death; D015331:Cohort Studies; D003182:Complement C5 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms / Q000235:genetics / Q000401:mortality*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D018805:Sepsis / Q000235:genetics / Q000401:mortality*; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics*
chemical_list: D003182:Complement C5; D047990:TNF Receptor-Associated Factor 1