title: Association of variants in IL2RA with progression of joint destruction in rheumatoid arthritis.
abstract: OBJECTIVE
  Heritability studies have suggested an important role of genetic predisposition in the progression of joint destruction in rheumatoid arthritis (RA); the heritability is estimated at 45-58%. Several single-nucleotide polymorphisms (SNPs) have been identified as being associated with RA susceptibility. Our objective was to study the association of several of these loci with progression of joint destruction.
  
  
  METHODS
  We studied 1,750 RA patients in 4 independent data sets with 4,732 radiographs scored using the modified Sharp/van der Heijde method. Thirteen susceptibility SNPs that were not previously associated with joint destruction were tested in 596 Dutch RA patients. Subsequently, significant SNPs were studied in data sets of RA patients from North America and Iceland. Data were summarized in inverse-weighted variance meta-analyses. Further, the association with circulating protein levels was studied and the associated region was fine-mapped.
  
  
  RESULTS
  In stage 1, 3 loci (AFF3, IL2RA, and BLK) were significantly associated with the rate of joint destruction and were further analyzed in the additional data sets. In the combined meta-analyses, the minor (C) allele of IL2RA (rs2104286) was associated with less progression of joint destruction (P = 7.2 × 10(-4) ). Furthermore, the IL2RA (rs2104286) protective genotype was associated with lower (0.85-fold [95% confidence interval 0.77-0.93], P = 1.4 × 10(-3) ) circulating levels of soluble interleukin-2 receptor α (sIL-2Rα). Additionally, lower sIL-2Rα levels were associated with a lower rate of joint destruction (P = 3.4 × 10(-3) ). The association of IL2RA with the rate of joint destruction was further localized to a 40-kb region encompassing the IL2RA intron 1 and the 5' region of IL2RA and RBM17.
  
  
  CONCLUSIONS
  The present genetic and serologic data suggest that inherited altered genetic constitution at the IL2RA locus may predispose to a less destructive course of RA.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands. r.knevel@lumc.nl
authors.forename: R
authors.initials: R
authors.lastname: Knevel
authors.forename: D P C
authors.initials: DP
authors.lastname: de Rooy
authors.forename: A
authors.initials: A
authors.lastname: Zhernakova
authors.forename: G
authors.initials: G
authors.lastname: Gröndal
authors.forename: A
authors.initials: A
authors.lastname: Krabben
authors.forename: K
authors.initials: K
authors.lastname: Steinsson
authors.forename: C
authors.initials: C
authors.lastname: Wijmenga
authors.forename: G
authors.initials: G
authors.lastname: Cavet
authors.forename: R E M
authors.initials: RE
authors.lastname: Toes
authors.forename: T W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: P K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: A H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D033023:Foot Joints / Q000000981:diagnostic imaging; D020022:Genetic Predisposition to Disease; D050823:Hand Joints / Q000000981:diagnostic imaging; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011859:Radiography
chemical_list: C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit