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However, the underlying association mechanisms were largely unknown. From the perspective of protein phosphorylation, gene expression regulation, and bone cell activity, this study aims to illustrate association mechanisms for representative <jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>s of interest.<\/jats:p><jats:p>We utilized public databases and bioinformatics tool to identify <jats:styled-content style=\"fixed-case\">OP<\/jats:styled-content>\u2010associated <jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>s which potentially influence protein phosphorylation (phos<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>s). Associations with hip\/spine <jats:styled-content style=\"fixed-case\">BMD<\/jats:styled-content>, as well as fracture risk, in human populations for one significant phos<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>, that is, rs227584 (major\/minor allele: C\/A, <jats:styled-content style=\"fixed-case\">EAS<\/jats:styled-content> population) located in <jats:italic>C17orf53<\/jats:italic> gene, were suggested in prior meta\u2010analyses. Specifically, carriers of allele C had significant higher <jats:styled-content style=\"fixed-case\">BMD<\/jats:styled-content> and lower risk of low\u2010trauma fractures than carriers of A. We pursued to test the molecular and cellular functions of rs227584 in bone through osteoblastic cell culture and multiple assays.<\/jats:p><jats:p>We identified five phos<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>s significant for <jats:styled-content style=\"fixed-case\">OP<\/jats:styled-content> (<jats:italic>P\u00a0<\/jats:italic>&lt;\u00a00.01). The osteoblastic cells, which was transfected with wild\u2010type <jats:italic>C17orf53<\/jats:italic> (allele C at rs227584, P126), demonstrated specific interaction with <jats:italic><jats:styled-content style=\"fixed-case\">NEK<\/jats:styled-content>2<\/jats:italic> kinase, increased expression levels of osteoblastic genes significantly (<jats:italic><jats:styled-content style=\"fixed-case\">OPN<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> OCN<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> COL<\/jats:styled-content>1A1<\/jats:italic>,<jats:italic> P\u00a0<\/jats:italic>&lt;\u00a00.05), and promoted osteoblast growth and <jats:italic><jats:styled-content style=\"fixed-case\">ALP<\/jats:styled-content><\/jats:italic> activity, in contrast to those transfected with mutant <jats:italic>C17orf53<\/jats:italic> (allele A at rs227584, T126).<\/jats:p><jats:p>In the light of the consistent evidences between the present functional study in human bone cells and the prior association studies in human populations, we conclude that the <jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content> rs227584, via altering protein\u2010kinase interaction, regulates osteoblastic gene expression, influences osteoblast growth and activity, hence to affect <jats:styled-content style=\"fixed-case\">BMD<\/jats:styled-content> and fracture risk in humans.<\/jats:p>","DOI":"10.1111\/jcmm.13991","type":"journal-article","created":{"date-parts":[[2018,10,29]],"date-time":"2018-10-29T02:58:48Z","timestamp":1540781928000},"page":"898-907","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Why <scp>SNP<\/scp> rs227584 is associated with human <scp>BMD<\/scp> and fracture risk? A molecular and cellular study in bone cells"],"prefix":"10.1111","volume":"23","author":[{"given":"Xu","family":"Zhou","sequence":"first","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics School of Public Health Soochow University Suzhou Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases School of Public Health Soochow University Suzhou Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying\u2010Hua","family":"Qiu","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics School of Public Health Soochow University Suzhou Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases School of Public Health Soochow University Suzhou Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei","family":"He","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics School of Public Health Soochow University Suzhou Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases School of Public Health Soochow University Suzhou Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics School of Public Health Soochow University Suzhou Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases School of Public Health Soochow University Suzhou Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long\u2010Fei","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics School of Public Health Soochow University Suzhou Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases School of Public Health Soochow University Suzhou Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Lu","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics School of Public Health Soochow University Suzhou Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases School of Public Health Soochow University Suzhou Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu\u2010Feng","family":"Lei","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics School of Public Health Soochow University Suzhou Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases School of Public Health Soochow University Suzhou Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7553-5358","authenticated-orcid":false,"given":"Fei\u2010Yan","family":"Deng","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics School of Public Health Soochow University Suzhou Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases School of Public Health Soochow University Suzhou Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,10,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)08761-5"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-016-3712-7"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0070-2153(06)76004-5"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.8.12.1229"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10212"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M900273-MCP200"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0188805"},{"issue":"3","key":"e_1_2_7_9_1","first-page":"S489","article-title":"Chalepin: a compound from Ruta angustifolia L. 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