VEGFA Promoter Polymorphisms rs699947 and rs35569394 Are Associated With the Risk of Anterior Cruciate Ligament
Manish Shukla1,2, Rahul Gupta2, Vivek Pandey1
1Department of Exercise Physiology, Lakshmibai National Institute of Physical Education, Gwalior, India.
Background:
Associations of genetic variants within certain fibril-forming genes have previously been observed with anterior cruciate ligament (ACL) injuries. Evidence suggests a significant role of angiogenesis-associated cytokines in remodeling the ligament fibril matrix after mechanical loading and maintaining structural and functional integrity of the ligament. Functional polymorphisms within the vascular endothelial growth factor A (VEGFA) gene have emerged as plausible candidates owing to their role in the regulation of angiogenic responses.
Hypothesis:
VEGFA promoter polymorphisms rs699947 and rs35569394 are associated with ACL injury risk among athletes.
Study Design:
Cross-sectional study; Level of evidence, 3.
Methods:
A total of 90 Indian athletes with radiologically confirmed or surgically proven isolated ACL tears and 76 matched-control athletes were selected for the present cross-sectional genetic association study. Oral mouthwash samples were collected from all the case and control athletes and genotyped for VEGFA rs699947 and rs35569394 using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.
Results:
The A allele (rs699947) was significantly overrepresented in the ACL group (C vs A allele: odds ratio [OR], 1.68 [95% CI, 1.08-2.60]; P = .021) (CC vs CA + AA: OR, 2.69 [95% CI, 1.37-5.26]; P = .004). There was a greater frequency of the AA genotype in the ACL group in comparison with the control group (OR, 3.38 [95% CI, 1.23-9.28]; P = .016) when only male athletes were compared. Likewise, there was a greater frequency of the I allele (rs35569394) in the ACL group (D vs I allele: OR, 1.64 [95% CI, 1.06-2.55]; P = .025) (DD vs ID + II: OR, 2.61 [95% CI, 1.31-5.21]; P = .006). The A-I haplotype was overrepresented in the ACL group compared with the control group (OR, 1.68 [95% CI, 1.08-2.60]; χ2 = 5.320; P = .021), and both the polymorphisms were found to be in complete linkage disequilibrium (r 2 = 0.929; logarithm of the odds score = 63.74; D' = 1.0). Female athletes did not show any difference in genotype or allele frequency.
Conclusion:
This is the first study to investigate the association of VEGFA promoter polymorphisms in ACL tears among Indian athletes. Increased frequencies of the A allele (rs699947) and I allele (rs35569394) were observed in the ACL group. These results suggest that sequence variants in the VEGF gene are associated with ACL injury risk among athletes. Further research with long-term follow-ups measuring VEGF expression levels during recovery is warranted to establish its role in ACL injuries and healing.
