The VEGFA and KDR genes are associated with bilateral and multiple chronic Achilles tendon injuries

OBJECTIVES: Pain is the primary symptom of Achilles tendinopathy, with neovascularisation implicated in symptom development despite unclear mechanisms. Neovascularisation and pain are regulated by vascular endothelial growth factor A (VEGFA) and its receptor, KDR. Since VEGFA polymorphisms have previously been associated with Achilles tendinopathy, this study aimed to determine whether VEGFA (rs699947 C>A, rs2010963 G>C) and/or KDR (rs2071559 C>T, rs1870377 A>T) polymorphisms are associated with exercise-related pain at injury onset, multiple and/or bilateral injuries, as well as self-reported pain using multidimensional pain scales. DESIGN: Case-control and cross-sectional genetic association study. METHODS: One hundred and eighty-nine controls without any history of tendon injuries and 181 participants with Achilles tendinopathy were recruited, of which 71 and 91 reported multiple-bilateral and single-unilateral injuries respectively, and genotyped for KDR and VEGFA. Pain was assessed using the VISA-A, short-form McGill Pain and short-form Brief Pain Inventory questionnaires. RESULTS: The KDR C-T and T-A (rs2071559, rs1870377) inferred haplotypes were associated with decreased (cases: 32.8%, controls: 44.3%, p = 0.009) and increased (cases: 22.1%, controls: 12.1%, p = 0.007) risk of multiple-bilateral tendinopathy, respectively. The C-C-T and A-T-A VEGFA (rs699947) and KDR (rs2071559, rs1870377) allele combinations were also associated with decreased (cases: 13.1%, controls: 20.9%, p = 0.018) and increased (cases: 14.0%, controls: 6.2%, p = 0.001) risk of multiple-bilateral tendinopathy, respectively. There were no significant differences in pain scores between the genotype groups. CONCLUSIONS: KDR and VEGF genetic variants are associated with susceptibility to bilateral and/or multiple Achilles tendinopathy, supporting the potential role for angiogenesis signalling pathways in injury risk.