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

Daneil C Feldmann¹, Masouda Rahim¹, Mathijs A M Suijkerbuijk², Mary-Jessica N Laguette^{1

3

4}, Paweł Cieszczyk⁵, Krzysztof Ficek⁶, Kinga Huminska-Lisowska⁵, Charlotte K Häger⁷, Evalena Stattin⁸, Kjell G Nilsson⁹, Javier Alvarez-Rumero¹⁰, Nir Eynon¹⁰, Julian Feller¹¹, Oren Tirosh¹², Michael Posthumus^{1

4}, Emile R Chimusa^{13

14}, Malcolm Collins^{1

3

4}, Alison V September^{1

3

4}

Affiliations

¹ Division of Exercise Science and Sports Medicine, Department of Human Biology, University of Cape Town, Cape Town, South Africa.
² Department of Orthopaedic Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
³ UCT Research Centre for Health through Physical Activity, Lifestyle and Sport, Cape Town, South Africa.
⁴ International Federation of Sports Medicine (FIMS) Collaborative Centre of Sports Medicine, Cape Town, South Africa.
⁵ Faculty of Physical Education, Gdańsk University of Physical Education and Sport, Gdańsk, Poland.
⁶ Faculty of Physiotherapy, Jerzy Kukuczka Academy of Physical Education in Katowice, Katowice, Poland.
⁷ Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden.
⁸ Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁹ Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden.
¹⁰ Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia.
¹¹ OrthoSport Victoria, Epworth Healthcare, Melbourne, Victoria, Australia.
¹² School of Health Sciences, Swinburne University of Technology, Melbourne, Victoria, Australia.
¹³ Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
¹⁴ Department of Pathology, Division of Human Genetics, University of Cape Town, Cape Town, South Africa.

PMID: 34664319
DOI: 10.1002/jor.25192

Free article

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

Daneil C Feldmann et al. J Orthop Res. 2022 Jul.

Free article

. 2022 Jul;40(7):1604-1612.

doi: 10.1002/jor.25192. Epub 2021 Oct 18.

Authors

Affiliations

¹ Division of Exercise Science and Sports Medicine, Department of Human Biology, University of Cape Town, Cape Town, South Africa.
² Department of Orthopaedic Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
³ UCT Research Centre for Health through Physical Activity, Lifestyle and Sport, Cape Town, South Africa.
⁴ International Federation of Sports Medicine (FIMS) Collaborative Centre of Sports Medicine, Cape Town, South Africa.
⁵ Faculty of Physical Education, Gdańsk University of Physical Education and Sport, Gdańsk, Poland.
⁶ Faculty of Physiotherapy, Jerzy Kukuczka Academy of Physical Education in Katowice, Katowice, Poland.
⁷ Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden.
⁸ Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁹ Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden.
¹⁰ Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia.
¹¹ OrthoSport Victoria, Epworth Healthcare, Melbourne, Victoria, Australia.
¹² School of Health Sciences, Swinburne University of Technology, Melbourne, Victoria, Australia.
¹³ Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
¹⁴ Department of Pathology, Division of Human Genetics, University of Cape Town, Cape Town, South Africa.

PMID: 34664319
DOI: 10.1002/jor.25192

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.

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

PubMed Disclaimer

References

REFERENCES

1. Stevens CG, Jarbo K, Economopoulos K, Chhabra A. Anatomy and biomechanics of the posterior cruciate ligaments and their surgical implications. In: Fanelli GC, ed. Posterior Cruciate Ligament Injuries: A Practical Guide to Management. 2nd ed. Springer; 2015:19-31.
1. Gurlek AC, Sevinc B, Bayrak E, Erisken C. Synthesis and characterization of polycaprolactone for anterior cruciate ligament regeneration. Mater Sci Eng C Mater Biol Appl. 2017;71:820-826.
1. Mousavizadeh R, Khosravi S, Behzad H, McCormack RG, Duronio V, Scott A. Cyclic strain alters the expression and release of angiogenic factors by human tendon cells. PLOS One. 2014;9:e97356.
1. Nakama LH, King KB, Abrahamsson S, Rempel DM. VEGF, VEGFR-1, and CTGF cell densities in tendon are increased with cyclical loading: an in vivo tendinopathy model. J Orthop Res. 2006;24:393-400.
1. Petersen W, Varoga D, Zantop T, Hassenpflug J, Mentlein R, Pufe T. Cyclic strain influences vascular endothelial growth factor (VEGF) and the hypoxia inducible factor 1 alpha (HIF-la) in tendon fibroblasts. J Orthop Res. 2004;22:847-853.

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

LinkOut - more resources

Full Text Sources
- Ovid Technologies, Inc.
- Wiley
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Miscellaneous