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The role of intron 4\u2010exon 5 variants within the \u03b11 chain of type V collagen (<jats:italic>COL5A1<\/jats:italic>) gene and genes of the transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2) family, <jats:italic>TGFBR3<\/jats:italic> and <jats:italic>TGFBI<\/jats:italic>, was investigated on the risk of anterior cruciate ligament (ACL) ruptures. A case\u2010control genetic association study was performed on 210 control (CON) and 249 participants with surgically diagnosed ruptures (ACL), of which 147 reported a noncontact mechanism of injury (NON). Whole\u2010exome sequencing data were used to prioritize variants of potential functional relevance. Genotyping for <jats:italic>COL5A1<\/jats:italic> (rs3922912 G&gt;A, rs4841926 C&gt;T, and rs3124299 C&gt;T), <jats:italic>TGFBR3<\/jats:italic> (rs1805113 G&gt;A and rs1805117 T&gt;C), and <jats:italic>TGFBI<\/jats:italic> (rs1442 G&gt;C) was performed using Taqman SNP genotyping assays. Significant overrepresentation of the G allele of <jats:italic>TGFBR3<\/jats:italic> rs1805113 was observed in CON vs ACL (<jats:italic>P<\/jats:italic>\u2009=\u2009.014) and NON groups (<jats:italic>P<\/jats:italic>\u2009=\u2009.021). Similar results were obtained in a female with the G allele (CON vs ACL: <jats:italic>P<\/jats:italic>\u2009=\u2009.029; CON vs NON: <jats:italic>P<\/jats:italic>\u2009=\u2009.016). The <jats:italic>TGFBI<\/jats:italic> rs1442 CC genotype was overrepresented in the female ACL vs CON (<jats:italic>P<\/jats:italic>\u2009=\u2009.013). Associations of inferred allele combinations were observed in line with the above results. <jats:italic>COL5A1<\/jats:italic> intron 4\u2010exon 5 genomic interval was not associated with the risk of ACL ruptures. Instead, this novel study is the first to use this approach to identify variants within the TGF\u2010\u03b2 signaling pathway to be implicated in the risk of ACL ruptures. A genetic susceptibility interval was identified to be explored in the context of extracellular matrix remodeling.<\/jats:p>","DOI":"10.1002\/jor.24585","type":"journal-article","created":{"date-parts":[[2020,1,10]],"date-time":"2020-01-10T12:45:20Z","timestamp":1578660320000},"page":"1856-1865","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Exploring new genetic variants within <i>COL5A1<\/i> intron 4\u2010exon 5 region and TGF\u2010\u03b2 family with risk of anterior cruciate ligament ruptures"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9979-117X","authenticated-orcid":false,"given":"Mary\u2010Jessica N.","family":"Laguette","sequence":"first","affiliation":[{"name":"Division of Exercise Science and Sports Medicine (ESSM) University of Cape Town Cape Town South Africa"},{"name":"International Federation of Sports Medicine (FIMS) Collaborative Centre of Sports Medicine, 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