Biology of Sport
eISSN: 2083-1862
ISSN: 0860-021X
Biology of Sport
Current Issue Manuscripts accepted About the journal Editorial board Abstracting and indexing Archive Ethical standards and procedures Contact Instructions for authors Journal's Reviewers Special Information
Editorial System
Submit your Manuscript
SCImago Journal & Country Rank
Search
Editorial Policies
Sarajevo Declaration on Integrity and Visibility of Scholarly Publications

Open access

without publication fees
Share:
Send email
Share:
Original paper

A novel combination of genomic loci in ITGB2, COL5A1 and VEGFA associated with anterior cruciate ligament rupture susceptibility: insights from Australian, Polish, Swedish, and South African cohorts

Senanile B. Dlamini
1, 2
,
Colleen J. Saunders
3
,
Paweł Cieszczyk
4
,
Krzysztof Ficek
5
,
Charlotte K. Häger
6
,
Eva-Lena Stattin
7
,
Kjell G. Nilsson
8
,
Nir Eynon
9
,
Julian A. Feller
10
,
Oren Tirosh
11
,
Christian D. Bope
12, 13, 14
,
Emile R. Chimusa
15, 16
,
Mary-Jessica N. Laguette
1, 2, 17
,
Malcolm Collins
1, 2, 17
,
Alison V. September
1, 2, 17

  1. Division of Physiological Sciences, Department of Human Biology, University of Cape Town, Anatomy Building, Level 5, Anzio Road, Observatory, Cape Town, South Africa
  2. Health through Physical Activity Lifestyle and Sport Research Centre (HPALS), Division of Physiological Sciences, Department of Human Biology, 3rd Floor, Sports Science Institute Building, Boundary Road, Newlands, 7701, South Africa
  3. Division of Emergency Medicine, Department of Family, Community and Emergency Care, University of Cape Town, F51 Old Main Building, Groote Schuur Hospital 7700, Cape Town, South Africa
  4. Faculty of Physical Education, Gdańsk University of Physical Education and Sport, Gdańsk, Poland
  5. Faculty of Physiotherapy, Jerzy Kukuczka Academy of Physical Education in Katowice, Katowice, Poland
  6. Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden
  7. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
  8. Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
  9. Australian Regenerative Medicine Institute (ARMI), Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria, Australia
  10. OrthoSport Victoria Research Unit, Epworth Healthcare, Victoria, Australia
  11. School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, Australia
  12. Department of Mathematics and Computer Science, Faculty of Sciences, University of Kinshasa, Kinshasa, Democratic Republic of Congo
  13. Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
  14. Centre for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway
  15. Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle-upon-Tyne and Wear, United Kingdom
  16. Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
  17. International Federation of Sports Medicine (FIMS) Collaborative Centre of Sports Medicine
Biol Sport. 2026;43:3–20
DOI: https://doi.org/10.5114/biolsport.2026.152346
Online publish date: 2025/07/16
Article file
- 1_04608_Article.pdf  [2.14 MB]
Get citation
 
PlumX metrics:
 
1. Humphrey JD, Dufresne ER, Schwartz MA. Mechanotransduction and extracellular matrix homeostasis. Nat Rev Mol Cell Biol. 2014 Dec; 15(12):802–12. doi: 10.1038/ nrm3896. Epub 2014 Oct 22. PMID: 25355505; PMCID: PMC4513363.
2. Saunders CJ, Dashti MJS, Gamieldien J et al. Semantic interrogation of a multi knowledge domain ontological model of tendinopathy identifies four strong candidate risk genes. Sci. Rep 2016, 25. doi: 10.1038/srep19820.
3. Anton ES, Kreidberg JA, Rakic P. Distinct functions of α3 and α(v) integrin receptors in neuronal migration and laminar organization of the cerebral cortex. Neuron 1999, 22:277–289.
4. Nikonenko I, Toni N, Moosmayer M, Shigeri Y, Muller D, Sargent Jones L. Integrins are involved in synaptogenesis, cell spreading, and adhesion in the postnatal brain. Brain Res. Dev. Brain Res 2003, 140:185–194.
5. Tan SM. The leucocyte beta2 (CD18) integrins: the structure, functional regulation and signalling properties. Biosci. Rep 2012, 32(3):241–269.
6. Caso E, Maestro A, Sabiers CC et al. Whole-exome sequencing analysis in twin sibling males with an anterior cruciate ligament rupture. Injury 2016, 47(3):S41–S50. doi:10.1016/S0020 -1383(16)30605-2.
7. Ma J, Zhao D, Wu Y et al. Cyclic stretch induced gene expression of extracellular matrix and adhesion molecules in human periodontal ligament cells. Arch. Oral Biol 2015, 60(3):447–455.
8. Rahim M, Gibbon A, Collins M, September AV. Chapter fifteen— genetics of musculoskeletal soft tissue injuries: current status, challenges, and future directions. In: Barh D, Ahmetov I, eds. Sports, Exercise, and Nutritional Genomics. Cambridge, MA: Academic Press; 2019:317–339.
9. Dlamini SB, Saunders CJ, Laguette MN, Gibbon A, Gamieldien J, Collins M, September AV. Application of an in silico approach identifies a genetic locus within ITGB2, and its combinations with HSPG2 and FGF9, to be associated with anterior cruciate ligament rupture risk. Eur J Sport Sci 2023, 23:1–11. doi: 10 .1080/17461391.2023.2171906.
10. Alvarez-Romero J, Laguette MN, Seale K et al. Genetic variants within the COL5A1 gene are associated with ligament injuries in physically active populations from Australia, South Africa, and Japan. Eur J Sport Sci 2023, 23(2):284–293. doi: 10.1080/1746 1391.2021.2011426. Epub 2021 Dec 30. PMID: 34821541.
11. Mannion S, Mtintsilana A, Posthumus M et al. Genes encoding proteoglycans are associated with the risk of anterior cruciate ligament ruptures. Br. J. Sports Med 2014, 48(22):1640–1646.
12. Rahim M, Gibbon A, Hobbs H, et al. The association of genes involved in the angiogenesis-associated signaling pathway with risk of anterior cruciate ligament rupture. J Orthop Res 2014, 32:1612–1618.
13. Feldmann DC, Rahim M, Suijkerbuijk MAM, Laguette MN, Cieszczyk P, Ficek K et al. Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury. J Orthop Res 2021, 18. doi: 10.1002/jor.25192. Epub ahead of print. PMID: 34664319.
14. Wang A, Chen M, Wang H, Huang J, Bao Y, Gan X, Liu B, Lu X, Wang L. Cell Adhesion-Related Molecules Play a Key Role in Renal Cancer Progression by Multinetwork Analysis. Biomed Res Int 2019, 16:2325765. doi: 10.1155 /2019/2325765. PMID: 31950034; PMCID: PMC6948336.
15. Yan X, Eynon N, Papadimitriou ID et al. The gene SMART study: method, study design, and preliminary findings. BMC Genomics 2017, 18:821.
16. Suijkerbuijk MAM, Ponzetti M, Rahim M et al. Functional polymorphisms within the inflammatory pathway regulate expression of extracellular matrix components in a genetic risk dependent model for anterior cruciate ligament injuries. J Sci Med Sport 2019, 22:1219–1225.
17. Lulińska-Kuklik E, Leźnicka K, Humińska-Lisowska K et al. The VEGFA gene and anterior cruciate ligament rupture risk in the Caucasian population. Biol Sport 2019, 36:3–8.
18. Flynn RK, Pedersen CL, Birmingham TB, Kirkley A, Jackowski D, Fowler PJ. The familial predisposition toward tearing the anterior cruciate ligament: a case control study. Am J Sports Med. 2005, 33:23–28.
19. Voisin S, Cieszczyk P, Pushkarev VP et al. EPAS1 gene variants are associated with sprint/power athletic performance in two cohorts of European athletes. BMC Genomics 2014, 15:382.
20. Tengman E, Brax Olofsson L, Nilsson KG, Tegner Y, Lundgren L, Häger CK. Anterior cruciate ligament injury after more than 20 years: I. Physical activity level and knee function. Scand J Med Sci Sports. 2014 Dec; 24(6):e491–500. doi: 10 .1111/sms.12212. Epub 2014 Mar 27. PMID: 24673102.
21. Lahiri DK, Nurnberger JI Jr. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991 Oct 11; 19(19):5444. doi: 10.1093/nar/19.19.5444. PMID: 1681511; PMCID: PMC328920.
22. Mokone GG, Gajjar M, September AV, Schwellnus MP, Greenberg J, Noakes TD, Collins M. The guanine-thymine dinucleotide repeat polymorphism within the tenascin-C gene is associated with achilles tendon injuries. Am J Sports Med. 2005 Jul; 33(7):1016–21. doi: 10.1177/0363546504271986. PMID: 15983124.
23. Zhang Y. I-TASSER server for protein 3D structure prediction. BMC bioinformatics 2008, 9:40. https://doi.org/10.1186 /1471-2105-9-40 PMID: 18215316.
24. Berendsen HJC, van der Spoel D, van Drunen R. GROMACS: A message-passing parallel molecular dynamics implementation. Comp Phys Comm 1995, 91:43–56.
25. Lindahl E, Hess B, van der Spoel D. GROMACS 3.0: A package for molecular simulation and trajectory analysis. J Mol Mod 2001, 7:306–17.
26. Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ. GROMACS: fast, flexible, and free. J Comput Chem 2005, 26(16):1701–18. https://doi.org/10 .1002/jcc.20291 PMID: 16211538.
27. Pronk S, Pa´ ll S, Schulz R, Larsson P, Bjelkmar P, Apostolov R et al. GROMACS 4.5: a high-throughput and highly parallel open-source molecular simulation toolkit. Bioinformatics 2013, 29(7):845–54. https://doi.org/10 .1093/bioinformatics/btt055 PMID: 23407358.
28. Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO et al. Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins 2010, 78(8):1950–8. https://doi.org/10.1002/prot.22711 PMID: 20408171.
29. Kuleshov MV, Jones MR, Rouillard AD et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016 Jul 8; 44(W1):W90-7. doi: 10.1093/nar/gkw377. Epub 2016 May 3. PMID: 27141961; PMCID: PMC4987924.
30. Xie Z, Bailey A, Kuleshov MV, Clarke DJB et al. Gene Set Knowledge Discovery with Enrichr. Curr Protoc. 2021 Mar; 1(3):e90. doi: 10.1002/cpz1.90. PMID: 33780170; PMCID: PMC8152575.
31. Warde-Farley D, Donaldson SL, Comes O et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res 2010, 1(38): W214–220 PubMed Abstract (PDF).
32. R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing. (2010) Retrieved from www.r–project.org.
33. Warnes G, Genetics: A package for population genetics. R Package (version 1.3.6) (2011). Retrieved from http:// cran.r-project.org/package = genetics.
34. González JR, Armengol L, Solé X et al. SNPassoc: An R package to perform whole genome association studies. Bioinformatics 2007, 23(5):644–645.
35. Sinnwell J & Schaid D. Haplo.stats: A package for statistical analysis of haplotypes with traits and covariates when linkage phase is ambiguous. R package (version 1.5.4). (2011) Retrieved from http://cran.rproject.org /package = haplo.stats
36. Burnham KP & Anderson DR. Multimodel Inference: Understanding AIC and BIC in Model Selection. Sociol Methods Res 2004, 33:261–304.
37. Benjamini Y & Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 1995, 57(1):289–300.
38. Collins M, Posthumus M, Schwellnus MP. The COL1A1 gene and acute soft tissue ruptures. Br J Sports Med 2010, 44(14):1063–4. doi: 10.1136/bjsm .2008.056184. Epub 2009 Feb 4. PMID: 19193665.
39. Brown KL, Seale KB, El Khoury LY, Posthumus M, Ribbans WJ, Raleigh SM, Collins M, September AV. Polymorphisms within the COL5A1 gene and regulators of the extracellular matrix modify the risk of Achilles tendon pathology in a British case-control study. J Sports Sci 2017, 35(15):1475–1483. doi: 10.1080 /02640414.2016.1221524. Epub 2016 Aug 19. PMID: 27541197.
40. Ren G, Roberts AI, Shi Y. Adhesion molecules: key players in Mesenchymal stem cell-mediated immunosuppression. Cell Adh Migr 2011, 5(1):20–2. doi: 10.4161/cam.5.1.13491. Epub 2011 Jan 1. PMID: 20935502; PMCID: PMC3038091.
41. Shihab HA, Gough J, Cooper DN et al. Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models. Hum. Mutat 2013, 34(1):57–65.
42. Kelly SM & Price NC. The use of circular dichroism in the investigation of protein structure and function. Curr Protein Pept Sci 2000, 1(4):349–84. doi: 10.2174 /1389203003381315. PMID: 12369905.
43. de Wit E, Delport W, Rugamika CE, Meintjes A et al. Genome-wide analysis of the structure of the South African Coloured Population in the Western Cape. Hum Genet. 2010 Aug; 128(2):145–53. doi: 10.1007/s00439-010-0836-1. Epub 2010 May 20. PMID: 20490549.
44. Campbell MC, Tishkoff SA. African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping. Annu Rev Genomics Hum Genet. 2008; 9:403–33. doi: 10.1146/annurev.genom .9.081307.164258. PMID: 18593304; PMCID: PMC2953791.
45. Novembre J, Johnson T, Bryc K, Kutalik Z et al. Genes mirror geography within Europe. Nature. 2008 Nov 6; 456(7218):98–101. doi: 10.1038 /nature07331. Epub 2008 Aug 31. Erratum in: Nature. 2008 Nov 13; 456(7219):274. PMID: 18758442; PMCID: PMC2735096.
Copyright: Institute of Sport. This is an Open Access article distributed under the terms of the Creative Commons CC BY License (https://creativecommons.org/licenses/by/4.0/). This license enables reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
  
Termedia
About us Contact
Copyright notice Privacy policy Advertising policy Contact us
Quick links
Journals Books eBooks Events
© 2025 Termedia Sp. z o.o.
Developed by Bentus.