{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:25:23Z","timestamp":1760189123411},"reference-count":44,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2010,6,7]],"date-time":"2010-06-07T00:00:00Z","timestamp":1275868800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2010,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>We previously observed the association of the co\u2010occurrence of the <jats:italic>HLA\u2013DRB1<\/jats:italic> shared epitope (SE) and <jats:italic>RANKL<\/jats:italic> single\u2010nucleotide polymorphisms (SNPs) with younger age at the onset of rheumatoid arthritis (RA) in 182 rheumatoid factor (RF)\u2013positive European American patients with early\u2010onset RA. The aim of this study was to fine\u2010map the 48\u2010kb <jats:italic>RANKL<\/jats:italic> region in the extended cohort of 210 European American RF\u2010positive patients with early RA, to seek replication of RA\u2010associated SNPs in additional RA cohorts of 501 European Americans and 298 African Americans, and to explore the functional consequences of RA\u2010associated SNPs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>SNP genotyping was conducted using pyrosequencing or TaqMan polymerase chain reaction (PCR) assays. Associations of rs7984870 with RANKL expression in plasma, peripheral blood mononuclear cells, and isolated T cells were quantified using enzyme\u2010linked immunosorbent assay and reverse transcription\u2013PCR. Site\u2010directed mutagenesis of rs7984870 within the 2\u2010kb <jats:italic>RANKL<\/jats:italic> promoter was performed to drive the luciferase reporter gene in osteoblast and stromal cell lines. Interaction of DNA and protein was determined by electrophoretic mobility shift assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A single promoter SNP, rs7984870, was consistently significantly associated with earlier age at the onset of RA in 3 independent seropositive (RF or anti\u2013cyclic citrullinated peptide antibody) RA cohorts but not in seronegative RA patients. The C risk allele of rs7984870 conferred 2\u2010fold higher plasma RANKL levels in RF\u2010positive patients with RA, significantly elevated <jats:italic>RANKL<\/jats:italic> messenger RNA expression in activated normal T cells, and increased promoter activity after stimulation in vitro via differential binding to the transcription factor SOX5.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The <jats:italic>RANKL<\/jats:italic> promoter allele that increased transcription levels upon stimulation might promote interaction between activated T cells and dendritic cells, predisposing to a younger age at the onset of RA in seropositive European American and African American patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.27589","type":"journal-article","created":{"date-parts":[[2010,6,7]],"date-time":"2010-06-07T15:48:02Z","timestamp":1275925682000},"page":"2864-2875","source":"Crossref","is-referenced-by-count":28,"title":["A functional <i>RANKL<\/i> polymorphism associated with younger age at onset of rheumatoid arthritis"],"prefix":"10.1002","volume":"62","author":[{"given":"Wenfeng","family":"Tan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lezlie A.","family":"Derber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy A.","family":"Shadick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doyt L.","family":"Conn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwin A.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivian H.","family":"Gersuk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerald T.","family":"Nepom","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larry W.","family":"Moreland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel E.","family":"Furst","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan D.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beth L.","family":"Jonas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V. 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