title: A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis.
abstract: BACKGROUND
  Progression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor κ B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA.
  
  
  METHODS
  1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied.
  
  
  RESULTS
  We found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value <0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of OPG-rs1485305 expressed higher rates of joint destruction compared to patients without these risk variants (P = 2.35x10-4). This variant was also significant after Bonferroni correction.
  
  
  CONCLUSIONS
  These results indicate that a genetic variant in OPG is associated with a more severe rate of joint destruction in RA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Knevel
authors.forename: Diederik P C
authors.initials: DP
authors.lastname: de Rooy
authors.forename: Tore
authors.initials: T
authors.lastname: Saxne
authors.forename: Elisabet
authors.initials: E
authors.lastname: Lindqvist
authors.forename: Martha K
authors.initials: MK
authors.lastname: Leijsma
authors.forename: Nina A
authors.initials: NA
authors.lastname: Daha
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: Roula
authors.initials: R
authors.lastname: Tsonaka
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Joris J M
authors.initials: JJ
authors.lastname: Schonkeren
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brouwer
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: Annette H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007592:Joint Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D053244:Osteoprotegerin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053245:RANK Ligand / Q000235:genetics; D011859:Radiography; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics; D012307:Risk Factors; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D048029:TNF Receptor-Associated Factor 6; C505686:TNFRSF11A protein, human