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All known human genes were assessed through the model to identify potential new risk genes for anterior cruciate ligament (ACL) ruptures and Achilles tendinopathy (AT). Genes were prioritised and explored in a case\u2013control study comparing participants with ACL ruptures (ACL\u2010R), including a sub\u2010group with non\u2010contact mechanism injuries (ACL\u2010NON), to uninjured control individuals (CON). After gene filtering, 3376 genes, including 411 genes identified through previous whole exome sequencing, were found to be potentially linked to AT and ACL ruptures. Four variants were prioritised: <jats:italic>HSPG2<\/jats:italic>:rs2291826A\/G, <jats:italic>HSPG2:<\/jats:italic>rs2291827G\/A, <jats:italic>ITGB2<\/jats:italic>:rs2230528C\/T and <jats:italic>FGF9:<\/jats:italic>rs2274296C\/T. The rs2230528 CC genotype was over\u2010represented in the CON group compared to ACL\u2010R (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and ACL\u2010NON (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and the TT genotype and T allele were over\u2010represented in the ACL\u2010R group and ACL\u2010NON compared to CON (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) group. Several significant differences in distributions were noted for the gene\u2010gene interactions: (<jats:italic>HSPG2<\/jats:italic>:rs2291826, rs2291827 and <jats:italic>ITGB2:<\/jats:italic>rs2230528) and (<jats:italic>ITGB2:<\/jats:italic>rs2230528 and <jats:italic>FGF9<\/jats:italic>:rs2297429). This study substantiates the efficiency of using a prior knowledge\u2010driven <jats:italic>in silico<\/jats:italic> approach to identify candidate genes linked to tendon and ACL injuries. Our biomedical knowledge graph identified and, with further testing, highlighted novel associations of the <jats:italic>ITGB2<\/jats:italic> gene which has not been explored in a genetic case control association study, with ACL rupture risk. We thus recommend a multistep approach including bioinformatics in conjunction with next generation sequencing technology to improve the discovery potential of genomics technologies in musculoskeletal soft tissue injuries.<\/jats:p>","DOI":"10.1080\/17461391.2023.2171906","type":"journal-article","created":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T06:40:20Z","timestamp":1674283220000},"page":"2098-2108","update-policy":"https:\/\/doi.org\/10.1080\/tandf_crossmark_01","source":"Crossref","is-referenced-by-count":5,"title":["Application of an <i>in silico<\/i> approach identifies a genetic locus within <i>ITGB2,<\/i> and its interactions with <i>HSPG2 and FGF9,<\/i> to be associated with anterior cruciate ligament rupture risk"],"prefix":"10.1002","volume":"23","author":[{"given":"Senanile B.","family":"Dlamini","sequence":"first","affiliation":[{"name":"Division of Physiological Sciences Department of Human Biology University of Cape Town Cape Town South 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