Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury

Daneil C. Feldmann, Masouda Rahim, Mathijs A.M. Suijkerbuijk, Mary Jessica N. Laguette, Paweł Cieszczyk, Krzysztof Ficek, Kinga Huminska-Lisowska, Charlotte K. Häger, Evalena Stattin, Kjell G. Nilsson, Javier Alvarez-Rumero, Nir Eynon, Julian Feller, Oren Tirosh, Michael Posthumus, Emile R. Chimusa, Malcolm Collins, Alison V. September*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1604-1612
Number of pages9
JournalJournal of Orthopaedic Research
Volume40
Issue number7
DOIs
Publication statusE-pub ahead of print - 18 Oct 2021

Bibliographical note

ACKNOWLEDGMENTS
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.

Publisher Copyright: © 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC

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