Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury.
ACL
angiogenesis
genetic association studies
ligament healing
Journal
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
ISSN: 1554-527X
Titre abrégé: J Orthop Res
Pays: United States
ID NLM: 8404726
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
07
09
2021
received:
20
05
2021
accepted:
30
09
2021
pubmed:
20
10
2021
medline:
24
6
2022
entrez:
19
10
2021
Statut:
ppublish
Résumé
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.
Substances chimiques
VEGFA protein, human
0
Vascular Endothelial Growth Factor A
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1604-1612Informations de copyright
© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.
Références
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.
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.
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.
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.
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.
Beye JA, Hart DA, Bray RC, McDougall JJ, Salo PT. Injury-induced changes in mRNA levels differ widely between anterior cruciate ligament and medial collateral ligament. Am J Sports Med. 2008;36:1337-1346.
Bray RC, Leonard CA, Salo PT. Correlation of healing capacity with vascular response in the anterior cruciate and medial collateral ligaments of the rabbit. J Orthop Res. 2003;21:1118-1123.
Pufe T, Petersen W, Tillmann B, Mentlein R. The angiogenic peptide vascular endothelial growth factor is expressed in foetal and ruptured tendons. Virchows Arch. 2001;439:579-585.
Yoshikawa T, Tohyama H, Enomoto H, Matsumoto H, Toyama Y, Yasuda K. Expression of vascular endothelial growth factor and angiogenesis in patellar tendon grafts in the early phase after anterior cruciate ligament reconstruction. Knee Surg Sports Traumatol Arthrosc. 2006;14:804-810.
Rahim M, Lacerda M, Collins M, Posthumus M, September AV. Risk modelling further implicates the angiogenesis pathway in anterior cruciate ligament ruptures. Eur J Sport Sci. 2021:1-8.
Ferrara N, Gerber H, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669-676.
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.
Rahim M, Mannion S, Klug B, et al. Modulators of the extracellular matrix and risk of anterior cruciate ligament ruptures. J Sci Med Sport. 2017;20:152-158.
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.
Rahim M, El Khoury LY, Raleigh SM, et al. Human genetic variation, sport and exercise medicine, and achilles tendinopathy: role for angiogenesis-associated genes. OMICS. 2016;20:520-527.
Salles JI, Duarte ME, Guimarães JM, et al. Vascular endothelial growth factor receptor-2 polymorphisms have protective effect against the development of tendinopathy in volleyball athletes. PLOS One. 2016;11:e0167717.
Gibson W. Genetic association studies for complex traits: relevance for the sports medicine practitioner. Br J Sport Med. 2009;43:314-316.
Lambrechts D, Storkebaum E, Morimoto M, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet. 2003;34:383-394.
Wang Y, Zheng Y, Zhang W, et al. Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol. 2007;50:760-767.
Shahbazi M, Fryer AA, Pravica V, et al. Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J Am Soc Nephrol. 2002;13:260-264.
Hansen TF, Sørensen FB, Spindler KL, et al. Microvessel density and the association with single nucleotide polymorphisms of the vascular endothelial growth factor receptor 2 in patients with colorectal cancer. Virchows Arch. 2010;456:251-260.
Awata T, Inoue K, Kurihara S, et al. A common polymorphism in the 5'-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes. 2002;51:1635-1639.
Dong DM, Yao M, Liu B, Sun CY, Jiang YQ, Wang YS. Association between the -1306C/T polymorphism of matrix metalloproteinase-2 gene and lumbar disc disease in Chinese young adults. Eur Spine J. 2007;16:1958-1961.
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.
Yan X, Eynon N, Papadimitriou ID, et al. The gene SMART study: method, study design, and preliminary findings. BMC Genomics. 2017;18:821.
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.
Markström JL, Grip H, Schelin L, Häger CK. Dynamic knee control and movement strategies in athletes and non-athletes in side hops: implications for knee injury. Scand J Med Sci Sports. 2019;29:1181-1189.
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.
Lahiri DK, Nurnberger JJI. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991;19:5444.
Mokone GG, Schwellnus MP, Noakes TD, Collins M. The COL5A1 gene and Achilles tendon pathology. Scand J Med Sci Sports. 2006;16:19-26.
Warnes G, Gorjanc G, Leisch F, Man M. Population genetics, 2013. Version 1.3.8.1.
Gonzalez R, Armengol L, Guino E, et al. SNP-based whole genome association studies. 2014. Version 1.9-2.
Sinnwell J, Schaid D. Statistical analysis of haplotypes with traits and covariates when linkage is ambiguous. 2015. Version 1.7.1.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B. 1995;57:289-300.
Hauser RA, Dolan EE. Ligament injury and healing: an overview of current clinical concepts. Journal of Prolotherapy. 2011;3:836-846.
Yoshikawa T, Tohyama H, Katsura T, et al. Effects of local administration of vascular endothelial growth factor on mechanical characteristics of the semitendinosus tendon graft after anterior cruciate ligament reconstruction in sheep. Am J Sports Med. 2006;34:1918-1925.
Huisman ES, Andersson G, Scott A, Reno CR, Hart DA, Thornton GM. Regional molecular and cellular differences in the female rabbit Achilles tendon complex: potential implications for understanding responses to loading. J Anat. 2014;224:538-547.
Fenwick SA, Hazleman BL, Riley GP. The vasculature and its role in the damaged and healing tendon. Arthritis Res. 2002;4:252-260.
Funahashi Y, Shawber CJ, Sharma A, Kanamaru E, Choi YK, Kitajewski J. Notch modualtes VEGF action in endothelial cells by inducing Matrix Metalloprotease activity. Vasc Cell. 2011;3:2.
Nell E-M, van der Merwe L, Cook J, Handley CJ, Collins M, September AV. The apoptosis pathway and the genetic predisposition to Achilles tendinopathy. J Orthop Res. 2012;30:1719-1724.
Willard K, Laguette MN, Alves de Souza Rios L, et al. Altered expression of proteoglycan, collagen and growth factor genesin a TGF-β1 stimulated genetic risk model for musculoskeletal softtissue injuries. J Sci Med Sport. 2020;23:695-700.