title: A gain of function polymorphism in the interleukin 6 receptor influences RA susceptibility.
abstract: OBJECTIVE
  To investigate the possible role of a functional polymorphism in the soluble interleukin 6 receptor (sIL-6R) gene in the genetic background of rheumatoid arthritis (RA).
  
  
  METHODS
  An association between disease status and the sIL-6R rs8192284 (A358D) variant was tested in 965 patients with RA and 988 unrelated healthy controls. Odds ratios (ORs) for disease were calculated with asymptotic 95% CI; p values <0.05 were considered statistically significant after adjustment for multiple testing. To determine the relationship between protein levels and IL-6R A358D genotype, the protein levels of sIL-6R in 100 plasma samples from healthy controls were measured using an ELISA and compared across the genotype groups.
  
  
  RESULTS
  The allele frequency of the C allele (alanine) was lower in cases than in controls (38.4% vs 41.7%, p=0.04, OR 0.9, 95% CI 0.8 to 1.0), as were the CC/AC genotypes compared with AA genotype frequencies (61.0% in RA cases vs 67.5% in controls, p=0.004, OR 0.8, 95% CI 0.6 to 0.9). Plasma levels of sIL-6R differed significantly according to genotype in the controls: 17.00 + or - 2.03 ng/ml for A/A, 20.08 + or - 1.83 ng/ml for A/C and 21.57 + or - 2.10 ng/ml for C/C (p=0.0001).
  
  
  CONCLUSIONS
  These data suggest a role for genetically determined lower sIL-6R levels as a risk factor for RA. The proinflammatory role of the IL6 system in established RA has been highlighted by the use of anti-sIL-6R antibodies. However, the findings of this study suggest a protective effect of IL6 on the risk of developing RA.
authors.affiliation: Section of Musculoskeletal Sciences, School of Medicine and Biomedical Sciences, The University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
authors.forename: I
authors.initials: I
authors.lastname: Marinou
authors.forename: K
authors.initials: K
authors.lastname: Walters
authors.forename: J
authors.initials: J
authors.lastname: Winfield
authors.forename: D E
authors.initials: DE
authors.lastname: Bax
authors.forename: A G
authors.initials: AG
authors.lastname: Wilson
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000097:blood / Q000235:genetics*
chemical_list: D019947:Receptors, Interleukin-6