1. Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury
- Author
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Emile R. Chimusa, Paweł Cięszczyk, Kinga Humińska-Lisowska, Julian A. Feller, Javier Alvarez-Rumero, Eva-Lena Stattin, Alison V. September, Mathijs A.M. Suijkerbuijk, Daneil Caroline Feldmann, Malcolm Collins, Krzysztof Ficek, Masouda Rahim, Nir Eynon, Michael Posthumus, Kjell G. Nilsson, Charlotte K. Häger, Mary-Jessica Nancy Laguette, Oren Tirosh, Orthopedics and Sports Medicine, and Radiology & Nuclear Medicine
- Subjects
Oncology ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,endocrine system ,Genotype ,Anterior cruciate ligament ,Polymorphism, Single Nucleotide ,Gene Frequency ,Internal medicine ,medicine ,Humans ,Orthopedics and Sports Medicine ,Genetic association ,business.industry ,Anterior Cruciate Ligament Injuries ,Haplotype ,Odds ratio ,medicine.disease ,ACL injury ,Confidence interval ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,Haplotypes ,Case-Control Studies ,business - 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.
- Published
- 2022