{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T23:40:00Z","timestamp":1793835600791,"version":"4.6.1"},"reference-count":36,"publisher":"BMJ","issue":"1","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2018,1,16]]},"published-print":{"date-parts":[[2018,2]]},"abstract":"<jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To explore the functions of <jats:italic>RUNX3<\/jats:italic> single nucleotide polymorphisms (SNPs) associated with ankylosing spondylitis (AS).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Individual SNP associations were evaluated in 4230 UK cases. Their effects on transcription factor (TF) binding, transcription regulation, chromatin modifications, gene expression and gene interactions were tested by database interrogation, luciferase reporter assays, electrophoretic mobility gel shifts, chromatin immunoprecipitation and real-time PCR.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We confirmed the independent association of AS with <jats:italic>rs4265380<\/jats:italic>, which was robust (P=4.7\u00d710<jats:sup>\u22126<\/jats:sup>) to conditioning on another nearby AS-associated <jats:italic>RUNX3<\/jats:italic> SNP (<jats:italic>rs4648889<\/jats:italic>). A <jats:italic>RUNX3<\/jats:italic> haplotype incorporating both SNPs was strongly associated with AS (OR 6.2; 95%\u2009CI 3.1 to 13.2, P=1.4\u00d710<jats:sup>\u22128<\/jats:sup>). In a large UK cohort, <jats:italic>rs4265380<\/jats:italic> is associated with leucocyte counts (including monocytes). <jats:italic>RUNX3<\/jats:italic> expression is lower in AS peripheral blood mononuclear cells than healthy controls (P&lt;0.002), independent of <jats:italic>rs4265380<\/jats:italic> genotype. Enhancer function for this <jats:italic>RUNX3<\/jats:italic> region was suggested by increased luciferase activity (approximately tenfold; P=0.005) for reporter constructs containing <jats:italic>rs4265380<\/jats:italic>. In monocytes, there was differential allelic binding of nuclear protein extracts to a 50\u2009bp DNA probe containing <jats:italic>rs4265380<\/jats:italic> that was strongly augmented by lipopolysaccharide activation. TF binding also included the histone modifier p300. There was enrichment for histone modifications associated with active enhancer elements (H3K27Ac and H3K79Me2) that may be allele dependent. Hi-C database interrogation showed chromosome interactions of RUNX3 bait with the nearby RP4-799D16.1 lincRNA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The association of AS with this <jats:italic>RUNX3<\/jats:italic> regulatory region involves at least two SNPs apparently operating in different cell types. Monocytes may be potential therapeutic targets in AS.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/rmdopen-2017-000628","type":"journal-article","created":{"date-parts":[[2018,2,12]],"date-time":"2018-02-12T11:09:55Z","timestamp":1518433795000},"page":"e000628","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Evidence for a second ankylosing spondylitis-associated <i>RUNX3<\/i> regulatory polymorphism"],"prefix":"10.1136","volume":"4","author":[{"given":"Matteo","family":"Vecellio","sequence":"first","affiliation":[{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK"},{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research Oxford Musculoskeletal Biomedical Research Unit, Oxford, UK, Oxford, UK"},{"name":"Nuffield Department of Orthopaedics, Rheumatology and 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UK, Oxford, UK"},{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Ellis","sequence":"additional","affiliation":[{"name":"Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology at Translational Research Institute, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla Jayne","family":"Cohen","sequence":"additional","affiliation":[{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK"},{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research Oxford 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