title: Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study.
abstract: BACKGROUND
  Interleukin (IL)-15 levels are increased in serum, synovium and bone marrow of patients with rheumatoid arthritis (RA). IL-15 influences both the innate and the adaptive immune response; its major role is activation and proliferation of T cells. There are also emerging data that IL-15 affects osteoclastogenesis. The authors investigated the association of genetic variants in IL15 with the rate of joint destruction in RA.
  
  
  METHODS
  1418 patients with 4885 x-ray sets of both hands and feet of four independent data sets were studied. First, explorative analyses were performed on 600 patients with early RA enrolled in the Leiden Early Arthritis Clinic. Twenty-five single-nucleotide polymorphisms (SNPs) tagging IL-15 were tested. Second, SNPs with significant associations in the explorative phase were genotyped in data sets from Groningen, Sheffield and Lund. In each data set, the relative increase of the progression rate per year in the presence of a genotype was assessed. Subsequently, data were summarised in an inverse weighting meta-analysis.
  
  
  RESULTS
  Five SNPs were significantly associated with rate of joint destruction in phase 1 and typed in the other data sets. Patients homozygous for rs7667746, rs7665842, rs2322182, rs6821171 and rs4371699 had respectively 0.94-, 1.04-, 1.09-, 1.09- and 1.09-fold rate of joint destruction compared to other patients (p=4.0×10(-6), p=3.8×10(-4), p=5.0×10(-3), p=5.0×10(-3) and p=9.4×10(-3)).
  
  
  CONCLUSIONS
  Independent replication was not obtained, possibly due to insufficient power. Meta-analyses of all data sets combined resulted in significant results for four SNPs (rs7667746, p<0.001; rs7665842, p<0.001; rs4371699, p=0.01; rs6821171, p=0.01). These SNPs were also significant after correction for multiple testing.
  
  
  CONCLUSIONS
  Genetic variants in IL-15 are associated with progression of joint destruction in RA.
authors.affiliation: Correspondence to Rachel Knevel, Leiden University Medical Center, Department of Rheumatology, Leiden 2333ZA, Netherlands. r.knevel@lumc.nl
authors.forename: R
authors.initials: R
authors.lastname: Knevel
authors.forename: A
authors.initials: A
authors.lastname: Krabben
authors.forename: E
authors.initials: E
authors.lastname: Brouwer
authors.forename: M D
authors.initials: MD
authors.lastname: Posthumus
authors.forename: A G
authors.initials: AG
authors.lastname: Wilson
authors.forename: E
authors.initials: E
authors.lastname: Lindqvist
authors.forename: T
authors.initials: T
authors.lastname: Saxne
authors.forename: D
authors.initials: D
authors.lastname: de Rooy
authors.forename: N
authors.initials: N
authors.lastname: Daha
authors.forename: M P M
authors.initials: MP
authors.lastname: van der Linden
authors.forename: G
authors.initials: G
authors.lastname: Stoeken
authors.forename: L
authors.initials: L
authors.lastname: van Toorn
authors.forename: B
authors.initials: B
authors.lastname: Koeleman
authors.forename: R
authors.initials: R
authors.lastname: Tsonaka
authors.forename: A
authors.initials: A
authors.lastname: Zhernakoza
authors.forename: J J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: R
authors.initials: R
authors.lastname: Toes
authors.forename: T W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: A
authors.initials: A
authors.lastname: van der Helm-van Mil
mesh_terms: D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005528:Foot / Q000000981:diagnostic imaging / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006225:Hand / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011859:Radiography
chemical_list: C569274:IL15 protein, human; D019409:Interleukin-15