Investigation of multiple populations highlight <em>VEGFA</em> polymorphisms to modulate anterior cruciate ligament injury

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

Affiliations

¹Division of Exercise Science and Sports Medicine, Department of Human Biology, University of Cape Town, Cape Town, South Africa

²Department of Orthopaedic Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

³UCT Research Centre for Health through Physical Activity, Lifestyle and Sport, Cape Town, South Africa

⁴International Federation of Sports Medicine (FIMS) Collaborative Centre of Sports Medicine, Cape Town, South Africa

⁵Faculty of Physical Education, Gdańsk University of Physical Education and Sport, Gdańsk, Poland

⁶Faculty of Physiotherapy, Jerzy Kukuczka Academy of Physical Education in Katowice, Katowice, Poland

⁷Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden

⁸Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

⁹Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden

¹⁰Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia

¹¹OrthoSport Victoria, Epworth Healthcare, Melbourne, Victoria, Australia

¹²School of Health Sciences, Swinburne University of Technology, Melbourne, Victoria, Australia

¹³Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

¹⁴Department of Pathology, Division of Human Genetics, University of Cape Town, Cape Town, South Africa

Abstract and keywords

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.

Keywords: ACL; angiogenesis; genetic association studies; ligament healing

Links

DOI: 10.1002/jor.25192

PubMed: 34664319

WoS: 000708263800001

History

Received: 2021-05-20

Revised: 2021-09-07

Accepted: 2021-09-30

Cited Works (1)

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