Polymorphisms in VEGFA and KDR encoding proteins have been associated with anterior cruciate ligament (ACL) injury risk. We leveraged a collective sample from Sweden, Poland, and Australia to investigate the association of functional polymorphisms in VEGFA and KDR with susceptibility to ACL injury risk. Using a case–control genetic association approach, polymorphisms in VEGFA and KDR were genotyped and haplotypes inferred from 765 controls, and 912 cases clinically diagnosed with ACL rupture. For VEGFA, there was a significant overrepresentation of the rs2010963 CC genotype (p = 0.0001, false discovery rate [FDR]: p = 0.001, odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.47–3.19) in the combined ACL group (18%) compared to the combined control group (11%). The VEGFA (rs699947 C/A, rs1570360 G/A, rs2010963 G/C) A-A-G haplotype was significantly (p = 0.010, OR: 0.85, 95% CI: 0.69–1.05) underrepresented in the combined ACL group (23%) compared to the combined control group (28%). In addition, the A-G-G construct was significantly (p = 0.036, OR: 0.81, 95% CI: 0.64–1.02) underrepresented in the combined ACL group (12%) compared to the combined CON group (16%). Our findings support the association of the VEGFA rs2010963 CC genotype with increased risk and (ii) the VEGFA A-A-G haplotype with a reduced risk, and are in alignment with the a priori hypothesis. Collectively identifying a genetic interval within VEGFA to be implicated in ACL risk modulation and highlight further the importance of vascular regulation in ligament biology.
K.G.N. is a consultant for Zimmer. Additionally, he received grants from both Zimmer and Link. Also, he is a speaker for Zimmer, Smith&Nephew and DePuy. No further declarations for any of the other authors. This study was funded in part by funds from the National Research Foundation (NRF) of South Africa (Grant: CPRR160426163211) and the University of Cape Town, South Africa. In Sweden, financial support was obtained from the Swedish research Council (Grants Nos. K2011-69X-21877-01-6, K2014-99X-21876-04-4), Västerbotten County Council (Grant No. ALF VLL548501 and Strategic funding VLL-358901; Project No.7002795). For Poland, the study was supported by the National Science Centre of Poland (No. UMO-2016/21/B/NZ7/01068). In Australia, funding was received from the Perpetual Trustees Grant and the Epworth Research Institute Grant. M.A.M.S and M.R were financially supported by the European Union funded project RUBICON H2020-MSCA-RISE-2015–690850, in addition MR was funded by the Harry Crossley Postdoctoral fellowship. D.C.F was funded by the NRF South African Doctoral Scholarship, and in part by the University of Cape Town.
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