VEGFA Promoter Polymorphisms rs699947 and rs35569394 Are Associated With the Risk of Anterior Cruciate Ligament Ruptures Among Indian Athletes: A Cross-sectional Study

Abstract

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.

Genetic Determinants of the Anterior Cruciate Ligament Rupture in Sport: An Up-to-Date Systematic Review

“…Ten studies investigated seven different collagens and ten single nucleotide polymorphisms (SNPs) with regard to the ACLR. Some studies showed the same results with no significant difference in the association of the COL1A1 rs1800012 ( Gibbon et al, 2020 ; Manish Shukla et al, 2020 ; Perini et al, 2022 ; Sivertsen et al, 2019 ; Zhao et al, 2020) and rs1107946 ( Gibbon et al, 2020 ; Perini et al, 2022 ) variant with the risk of ACL ruptures ( p > 0.05). However, when individuals of European ancestry (Swedish, South African, Polish, Norwegian and Finnish; all those participants self-identified as being of white European ancestry) were combined, the rs1800012 TT genotype (TT vs. GT + GG) was significantly over-represented in the control group compared to the ACLR group ( p = 0.040; OR = 2.8), which confirmed a strong link between rs1800012 and the ACL risk ( Gibbon et al, 2020 ).…”

Vascular Endothelial Growth Factor Genetic Variant is Associated with In-Stent Restenosis after Percutaneous Coronary Intervention

“… 45 The frequency of the D/D genotype was higher in patients with breast cancer than in the control group, and the level of VEGF was higher in patients than in the control group in a prior study. 46 Another investigation reported that the frequency of genotype I/I was higher in the case group (patients with anterior cruciate ligament injuries) than in the control group. 46 The VEGF gene can have a protective role against muscle injuries because it seems that the function of the VEGF gene is reduced in individuals with the I/I genotype compared with the D/D genotype.…”

“… 46 Another investigation reported that the frequency of genotype I/I was higher in the case group (patients with anterior cruciate ligament injuries) than in the control group. 46 The VEGF gene can have a protective role against muscle injuries because it seems that the function of the VEGF gene is reduced in individuals with the I/I genotype compared with the D/D genotype. 46 …”

“… 46 The VEGF gene can have a protective role against muscle injuries because it seems that the function of the VEGF gene is reduced in individuals with the I/I genotype compared with the D/D genotype. 46 …”

Genetic Factors Affecting the Vascular Mechanism in Sports: Traditional Review

“…Çalışma sonunda, VEGFA A alleli (rs699947) ile I al-lelinin (rs35569394), ön çapraz bağ yaralanmaları ile ilişkili yapılar olabileceği sonucuna ulaşmışlardır. 37 Sportif performans esnasında vücut hücrelerinin azalan metabolik ihtiyacı, dokuların homeostazında birtakım düzensizlikler oluşturabilmektedir. Bu düzensizlikler, vücudun kollajen yapıları olan yumuşak dokuları önemli bir şekilde etkileyebilmektedir.…”