Genetic Variability in VEGFA Gene Influences the Effectiveness of Tennis Elbow Therapy with PRP: A Two-Year Prospective Cohort Study

Abstract

Vascular endothelial growth factor (VEGF) is implicated in both the etiology of tendinopathy and its healing process. Polymorphic variants of the VEGFA gene exhibit varied expression, which can influence the phenotype and treatment effectiveness. The aim of the present study was to analyze the influence of VEGFA gene variants on the effectiveness of tennis elbow therapy using platelet-rich plasma (PRP), measured through common patient-reported outcome measures (PROMs). A cohort of 107 patients (132 elbows) with tennis elbow was prospectively analyzed, with a two-year follow-up (at weeks 2, 4, 8, 12, 24, 52, and 104 after PRP injection). PROMs values were compared between variants of five VEGFA gene polymorphisms (rs699947 A>C, rs2010963 C>G, rs1413711 C>T, rs3024998 C>T and rs3025021 C>T) at each follow-up point. Patients with genotypes GG (rs2010963) and CC (rs3024998) had better response to PRP therapy (significantly fewer symptoms and limitations in the upper limb compared to carriers of alleles C and T, respectively). Polymorphisms influenced also selected hematological parameters. VEGFA gene polymorphisms (rs2010963 and rs3024998) appear to be significant treatment modifiers for tendinopathy, and their genotyping may serve as an effective tool for personalized patient selection for PRP therapy.

Keywords: VEGFA; genetic polymorphism; platelet-rich plasma; tendinopathy; tennis elbow; vascular endothelial growth factor.

Figure 1

Involvement of VEGF in the physiology and pathology of tendons after injury. Based on [1,2,3,4,5,6,7,8,9,10,11]. Tendinopathy is a multifactorial condition (A). Its subclinical form usually arises from chronic or acute tendon overload, while overlapping predisposing factors (biological, coexisting diseases, or certain medications) can exacerbate the patient’s condition. Damage to tendon structures leads to hypoxia (B), during which there is an increased secretion of hypoxia-inducible factor-1 (HIF-1). HIF-1, mechanical tendon overload, neuronal signals, and some pro-inflammatory cytokines are the main factors that increase VEGFA expression. VEGFA can promote events leading to both healing and the manifestation of the clinical form of tendinopathy (C). In the early stages of the tendon injury response, VEGFA participates in the restoration of microcirculation by stimulating endothelial cell division. It also intensifies the proliferation of pericytes, tenocytes, and fibroblasts. Angiogenesis also promotes the chemotaxis of monocytes and granulocytes and increases the availability of other growth factors. Both of these processes, along with increased proliferation of tenocytes and fibroblasts, are observed during both tendon healing and tendinopathy. During tendinopathy, a remodeling of the extracellular matrix (ECM) is also observed, involving the loss of type 1 collagen and its replacement with type 3 collagen. VEGFA promotes these processes by influencing the expression of matrix metalloproteinases (MMP) and inhibiting the expression of tissue inhibitors of metalloproteinases (TIMP) in endothelial cells and fibroblasts, leading to the destruction of type 1 collagen. On the other hand, VEGFA also participates in restoring the initial proportions of collagen during the healing process, stimulating the expression of COL1A1 (encoding type 1 collagen chains) in tenocytes and reducing the expression of COL3A1 (encoding type 3 collagen chains). The pathological neovascularization observed in tendinopathy is the result of the prolonged influence of VEGFA on the damaged tendon, disrupting its biomechanical properties.

Figure 2

Haplotype analysis of VEGFA gene polymorphisms in the study group (A) and CEU (U.S. Utah residents with ancestry from northern and western Europe) population (B).

Figure 3

Medians (±QD) of PROMs values in respect to genotype variants of the VEGFA gene rs2010963 polymorphism (recessive/dominant model). Legend: QD, quartile deviation; PROM, patient-reported outcome measure; VAS, visual analog scale; QDASH, quick version of disabilities of the arm, shoulder and hand score; PRTEE, patient-rated tennis elbow evaluation; *, differences remaining significant (p < 0.050) after removing diabetics from the analysis.

Figure 4

White blood cells (WBC) and mean platelet volume (MPV) values in individuals with particular genotypes of VEGFA gene polymorphisms (additive model): (A) for rs2010963; (B) for rs3024998.

Figure 5

Flowchart of the study selection.

Figure 6

Location of the studied polymorphisms on chromosome 6 (the figure was created on the basis of data from LDmatrix Tool [39]).