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Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study

Knevel, R.; Krabben, A.; Brouwer, E.; Posthumus, M. D.; Wilson, A. G.; Lindqvist, Elisabet LU ; Saxne, Tore LU ; de Rooy, D.; Daha, N. and van der Linden, M. P. M., et al. (2012) In Annals of the Rheumatic Diseases 71(10). p.1651-1657
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. Method 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.... (More)
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. Method 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 = 4.0x10(-6), p = 3.8x10(-4), p = 5.0x10(-3), p = 5.0x10(-3) and p = 9.4x10(-3)). Discussion 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. Conclusion Genetic variants in IL-15 are associated with progression of joint destruction in RA. (Less)
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published
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Annals of the Rheumatic Diseases
volume
71
issue
10
pages
1651 - 1657
publisher
British Medical Association
external identifiers
  • wos:000308747900011
  • scopus:84866062778
ISSN
1468-2060
DOI
10.1136/annrheumdis-2011-200724
language
English
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yes
id
5b787231-a6dd-4bd1-9c0d-e134a68b32ea (old id 3135875)
date added to LUP
2012-11-01 16:24:14
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2017-09-10 04:13:55
@article{5b787231-a6dd-4bd1-9c0d-e134a68b32ea,
  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. Method 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 = 4.0x10(-6), p = 3.8x10(-4), p = 5.0x10(-3), p = 5.0x10(-3) and p = 9.4x10(-3)). Discussion 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 &lt; 0.001; rs7665842, p &lt; 0.001; rs4371699, p = 0.01; rs6821171, p = 0.01). These SNPs were also significant after correction for multiple testing. Conclusion Genetic variants in IL-15 are associated with progression of joint destruction in RA.},
  author       = {Knevel, R. and Krabben, A. and Brouwer, E. and Posthumus, M. D. and Wilson, A. G. and Lindqvist, Elisabet and Saxne, Tore and de Rooy, D. and Daha, N. and van der Linden, M. P. M. and Stoeken, G. and van Toorn, L. and Koeleman, B. and Tsonaka, R. and Zhernakoza, A. and Houwing-Duistermaat, J. J. and Toes, R. and Huizinga, T. W. J. and van der Helm-van Mil, A.},
  issn         = {1468-2060},
  language     = {eng},
  number       = {10},
  pages        = {1651--1657},
  publisher    = {British Medical Association},
  series       = {Annals of the Rheumatic Diseases},
  title        = {Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2011-200724},
  volume       = {71},
  year         = {2012},
}