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A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis

Knevel, Rachel; de Rooy, Diederik P. C.; Saxne, Tore LU ; Lindqvist, Elisabet LU ; Leijsma, Martha K.; Daha, Nina A.; Koeleman, Bobby P. C.; Tsonaka, Roula; Houwing-Duistermaat, Jeanine J. and Schonkeren, Joris J. M., et al. (2014) In Arthritis Research and Therapy 16(3).
Abstract
Introduction: 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 kappa 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... (More)
Introduction: 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 kappa 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. (Less)
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Arthritis Research and Therapy
volume
16
issue
3
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BioMed Central
external identifiers
  • wos:000347078700003
  • scopus:84901389239
ISSN
1478-6362
DOI
10.1186/ar4558
language
English
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yes
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c0509b7b-adf5-4f18-84a2-de99cbdc9e98 (old id 5091503)
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@article{c0509b7b-adf5-4f18-84a2-de99cbdc9e98,
  abstract     = {Introduction: 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 kappa 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 &lt;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.},
  articleno    = {R108},
  author       = {Knevel, Rachel and de Rooy, Diederik P. C. and Saxne, Tore and Lindqvist, Elisabet and Leijsma, Martha K. and Daha, Nina A. and Koeleman, Bobby P. C. and Tsonaka, Roula and Houwing-Duistermaat, Jeanine J. and Schonkeren, Joris J. M. and Toes, Rene E. M. and Huizinga, Tom W. J. and Brouwer, Elisabeth and Wilson, Anthony G. and van der Helm-van Mil, Annette H. M.},
  issn         = {1478-6362},
  language     = {eng},
  number       = {3},
  publisher    = {BioMed Central},
  series       = {Arthritis Research and Therapy},
  title        = {A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis},
  url          = {http://dx.doi.org/10.1186/ar4558},
  volume       = {16},
  year         = {2014},
}