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We leveraged a collective sample from Sweden, Poland, and Australia to investigate the association of functional polymorphisms in <jats:italic>VEGFA<\/jats:italic> and <jats:italic>KDR<\/jats:italic> with susceptibility to ACL injury risk. Using a case\u2013control genetic association approach, polymorphisms in <jats:italic>VEGFA<\/jats:italic> and <jats:italic>KDR<\/jats:italic> were genotyped and haplotypes inferred from 765 controls, and 912 cases clinically diagnosed with ACL rupture. For <jats:italic>VEGFA<\/jats:italic>, there was a significant overrepresentation of the rs2010963 CC genotype (<jats:italic>p<\/jats:italic>\u2009=\u20090.0001, false discovery rate [FDR]: <jats:italic>p<\/jats:italic>\u2009=\u20090.001, odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.47\u20133.19) in the combined ACL group (18%) compared to the combined control group (11%). The <jats:italic>VEGFA<\/jats:italic> (rs699947 C\/A, rs1570360 G\/A, rs2010963 G\/C) A\u2010A\u2010G haplotype was significantly (<jats:italic>p<\/jats:italic>\u2009=\u20090.010, OR: 0.85, 95% CI: 0.69\u20131.05) underrepresented in the combined ACL group (23%) compared to the combined control group (28%). In addition, the A\u2010G\u2010G construct was significantly (<jats:italic>p<\/jats:italic>\u2009=\u20090.036, OR: 0.81, 95% CI: 0.64\u20131.02) underrepresented in the combined ACL group (12%) compared to the combined CON group (16%). Our findings support the association of the <jats:italic>VEGFA<\/jats:italic> rs2010963 CC genotype with increased risk and (ii) the <jats:italic>VEGFA<\/jats:italic> A\u2010A\u2010G haplotype with a reduced risk, and are in alignment with the a priori hypothesis. Collectively identifying a genetic interval within <jats:italic>VEGFA<\/jats:italic> to be implicated in ACL risk modulation and highlight further the importance of vascular regulation in ligament biology.<\/jats:p>","DOI":"10.1002\/jor.25192","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T09:00:00Z","timestamp":1634806800000},"page":"1604-1612","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Investigation of multiple populations highlight <i>VEGFA<\/i> polymorphisms to modulate anterior cruciate ligament injury"],"prefix":"10.1002","volume":"40","author":[{"given":"Daneil C.","family":"Feldmann","sequence":"first","affiliation":[{"name":"Division of Exercise Science and Sports Medicine, Department of Human Biology University of Cape Town  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masouda","family":"Rahim","sequence":"additional","affiliation":[{"name":"Division of Exercise Science and Sports Medicine, Department of Human Biology University of Cape Town  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2732-9856","authenticated-orcid":false,"given":"Mathijs A. 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