Evidence for a second ankylosing spondylitis-associated RUNX3 regulatory polymorphism

• Published in: Rheumatic & musculoskeletal diseases open 2018-01, Vol.4 (1), p.e000628-e000628
• Main Authors: Vecellio, Matteo, Cortes, Adrian, Roberts, Amity R, Ellis, Jonathan, Cohen, Carla Jayne, Knight, Julian C, Brown, Matthew A, Bowness, Paul, Wordsworth, Bryan Paul
• Format: Article
• Language: English
• Subjects: Arthritis; Bioinformatics; Consortia; Deoxyribonucleic acid; Disease; DNA; Epigenetics; Gene expression; Genomes; Genomics; Lymphocytes; Pathogenesis; Spondyloarthritis; Studies; Transcription factors
• ISSN: 2056-5933; 2056-5933
• DOI: 10.1136/rmdopen-2017-000628

ObjectivesTo explore the functions of RUNX3 single nucleotide polymorphisms (SNPs) associated with ankylosing spondylitis (AS).MethodsIndividual 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.ResultsWe confirmed the independent association of AS with rs4265380, which was robust (P=4.7×10−6) to conditioning on another nearby AS-associated RUNX3 SNP (rs4648889). A RUNX3 haplotype incorporating both SNPs was strongly associated with AS (OR 6.2; 95% CI 3.1 to 13.2, P=1.4×10−8). In a large UK cohort, rs4265380 is associated with leucocyte counts (including monocytes). RUNX3 expression is lower in AS peripheral blood mononuclear cells than healthy controls (P