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The binding of RANKL (Receptor Activator for Nuclear Factor \u03ba 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 <jats:italic>OPG, RANK, RANKL<\/jats:italic> and <jats:italic>TRAF6<\/jats:italic> are associated with the rate of joint destruction in RA.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>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 <jats:italic>OPG, RANK, RANKL<\/jats:italic> and <jats:italic>TRAF6,<\/jats:italic> 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.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>We found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in <jats:italic>OPG<\/jats:italic> and four SNPs in <jats:italic>RANK<\/jats:italic> were associated with progression of joint destruction with <jats:italic>P<\/jats:italic>-value &lt;0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of <jats:italic>OPG<\/jats:italic>-rs1485305 expressed higher rates of joint destruction compared to patients without these risk variants (<jats:italic>P<\/jats:italic>\u2009=\u20092.35x10<jats:sup>\u22124<\/jats:sup>). This variant was also significant after Bonferroni correction.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>These results indicate that a genetic variant in <jats:italic>OPG<\/jats:italic> is associated with a more severe rate of joint destruction in RA.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/ar4558","type":"journal-article","created":{"date-parts":[[2014,5,7]],"date-time":"2014-05-07T09:02:45Z","timestamp":1399453365000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis"],"prefix":"10.1186","volume":"16","author":[{"given":"Rachel","family":"Knevel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diederik PC","family":"de Rooy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tore","family":"Saxne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabet","family":"Lindqvist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martha K","family":"Leijsma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina A","family":"Daha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bobby PC","family":"Koeleman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roula","family":"Tsonaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeanine J","family":"Houwing-Duistermaat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joris JM","family":"Schonkeren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rene EM","family":"Toes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom WJ","family":"Huizinga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Brouwer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony G","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annette HM","family":"van der Helm-van Mil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2014,5,7]]},"reference":[{"key":"4190_CR1","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1093\/rheumatology\/31.8.519","volume":"31","author":"DM van der Heijde","year":"1992","unstructured":"van der Heijde DM, van Riel PL, van Leeuwen MA, van 't Hof MA, van Rijswijk MH, van de Putte LB: Prognostic factors for radiographic damage and physical disability in early rheumatoid arthritis. 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