VEGFA and KDR gene variants as potential markers of endurance performance and sports-related injuries: A systematic review

The traits that enable the achievement of outstanding sports performance and differentiate individual predispositions for participating in specific disciplines, resulting from anatomical structure and physiological characteristics of the human body, are shaped by environmental and genetic factors as well as their interactions (Baker, 2011). Professional athletes are increasingly undergoing genetic testing to gain deeper insights into their physical and metabolic traits, while coaches utilize these analyses to design tailored training programs. In recent years, there has been a growing number of services offering genetic profiling for sports purposes, which are available not only to professional athletes but also to individuals who engage in recreational sports (Patel & Varley, 2019; Pickering et al., 2019; Roth, 2012).

Single nucleotide polymorphism (SNP) and insertion-deletion polymorphism (indels) are commonly used to identify traits influencing athletic performance. SNPs involve the substitution of a single nucleotide in the DNA sequence at a specific location in the genome, while indels include addition or removal of nucleotide sequence ranging from single nucleotide to several base pairs. Both types of genetic variants are widely spread throughout the human genome and have been investigated in relation to muscle strength and power, endurance, energy metabolism, recovery, and injury susceptibility (Lin et al., 2017, Ysabel et al., 2018).

Angiogenesis is a process essential for maintaining homeostasis in the body, enabling the reconstruction of blood vessels. It plays a crucial role in embryonic development, wound healing, and tissue regeneration (Shibuya, 2011). Vascular endothelial growth factor (VEGF) is one of the primary regulators of angiogenesis, stimulating endothelial cell proliferation and migration while increasing vascular permeability (Ferreira et al., 2024).

VEGF is a homodimeric protein that exists in several isoforms, generated through alternative splicing. Five main isoforms have been identified: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E. Among them, VEGF-A plays the most significant role in regulating angiogenesis in humans. It acts as a ligand binding to and activating VEGF receptors (VEGFR-1 and VEGFR-2), initiating a signaling cascade that promotes angiogenesis, increases vascular permeability, facilitates cell migration, and expression of genes associated with vascular remodeling. The interaction between VEGF-A and the VEGFR-2 receptor activates the PLCγ-PKC-MAPK signaling pathway, which is critical for initiating endothelial cell proliferation (Karamysheva, 2008; Takahashi & Shibuya, 2005).

It has been shown that VEGF plays a crucial role in the post-injury regeneration of tendons and ligaments. The process of rebuilding damaged blood vessels ensures adequate oxygenation, nutrient supply, removal of waste products, and delivery of signaling molecules involved in the healing process (Liu et al., 2021).

The formation of new blood vessels and the repair of damaged ones are essential for maintaining proper oxygenation of the body, particularly in organs with high metabolic demands. In physically active individuals, the oxygen requirement of skeletal muscles increases significantly. Consequently, regulatory mechanisms that control oxygen delivery, including angiogenesis and vascular adaptation, can influence muscle performance, endurance, and overall physical efficiency (Bloor, 2005; Kissane & Egginton, 2019).

The genes responsible for the synthesis of VEGF-A and its receptor VEGFR-2 exhibit high genetic variability. SNPs within these genes can influence their expression levels, thereby affecting the amount of protein produced as well as potential changes in its structure and function (Komar, 2007; Shastry, 2009).

Due to the roles that the VEGFA and KDR genes play in tendon and ligament regeneration, as well as in ensuring proper oxygenation of organs, including skeletal muscles, variants of these genes are potential candidate biomarkers. These markers can help determine susceptibility to soft tissue injuries within the skeletal system as well as assess predisposition to physical exertion among athletes and physically active individuals (Balberova et al., 2022; Bonsignore et al., 2010).

This systematic review aims to examine the impact of SNPs within the VEGFA and KDR genes on susceptibility to tendon and ligament injuries, as well as on physical performance in athletes and highly physically active individuals. Additionally, it seeks to evaluate their potential as genetic markers in sports.

The articles for this study were selected by searching the following databases: PubMed, Scopus, World of Science, and EBSCO host. The search was completed on 9 January 2025. The following keywords according to MeSH were used: “VEGF,” “VEGFR,” “vascular endothelial factor,” “polymorphism,” “SNP,” “variant,” “gene,” “injury,” and “physical performance” combined using the Boolean operators AND and OR.

The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review protocol was registered in the PROSPERO database under the ID number CRD420250653479.

The inclusion criteria involved original research articles published in English after the year 2000. Only case-control studies conducted on human participants were considered, specifically those analyzing the association of SNPs within the VEGFA and KDR genes with predisposition to the type of physical effort undertaken and the susceptibility to tendon and ligament injuries in athletes and physically active individuals.

Studies published before the year 2000, systematic reviews, and meta-analyses were excluded from this review. Additionally, animal studies, clinical trials, cancer research, and case studies were not considered. Research that did not include SNP analyses or did not involve athletes or physically active participants was also excluded (Table 1).

The search process was conducted by a single investigator, who screened each record by analyzing the title, followed by the abstract, and finally the full text.

Initially, duplicate records and studies identified as systematic reviews or meta-analyses were removed. Titles were screened to determine whether they included SNP analyses within the VEGFA and KDR genes and whether they examined the association between genetic variants and susceptibility to injuries or physical performance. Subsequently, book chapters, dissertations, and conference materials were excluded. Studies were further excluded if only the abstract was available, if they were published in a language other than English, or if they involved animal research, clinical trials, or case studies (Figure 1).

Figure 1

Studies selection flow diagram (PRISMA flow diagram for systematic reviews)

The Joanna Briggs Institute (JBI) checklist for case-control studies was utilized to assess the quality of the selected articles. The final articles were scored based on the JBI checklist, with a minimum acceptable score of 60% required for inclusion in this systematic review.

The following data were extracted from the selected studies, as reported: population details (sample size, ethnicity, and athletic status); genetic variants analyzed in the VEGFA and KDR genes; endurance performance and susceptibility to tendon/ligament injuries; and key findings reported by the authors, specifically allele/genotype associations, odds ratios (ORs), confidence intervals (CIs), and p-values.

This systematic review aimed to provide further insights into the role of VEGFA and KDR polymorphisms in aerobic performance and susceptibility to ACL injury as well as to evaluate polymorphism within these genes as potential genetic markers in sports science and to contextualize VEGFA and KDR variants as potential susceptibility modifiers rather than deterministic predictors. Both genes are involved in the regulation of angiogenesis, encoding proteins that participate in a signaling pathway in which VEGF-A binds to its primary receptor, VEGFR-2, and initiates intracellular cascade that promotes endothelial cell proliferation and expansion of capillary network. This process ultimately contributes to the formation of new blood vessels and the repair of damaged capillaries. Proper regulation of this pathway ensures adequate oxygen delivery to skeletal muscles, which in athletes is associated with improved tolerance to prolonged physical exertion. Adequate tissue oxygenation is essential for the repair of microdamage within ligaments resulting from repetitive mechanical load during training or following injury. Particularly important during the phases of collagen synthesis and tissue remodeling, crucial for maintaining structural integrity of ligament tissue (Kissane & Egginton, 2019; Rahim et al., 2022).

In the analyzed studies concerning the VEGFA rs699947, Cięszczyk et al. (2017) and Feldmann et al. (2022) did not find significant differences in allele and genotype frequencies that could contribute to an increased risk of ACL injury in athletes. However, the presence of the A allele associated with a higher risk of ACL rupture was identified by Shukla et al. (2020). The VEGFA rs699947 polymorphism is located within the promoter region of the VEGFA gene and may influence its transcriptional activity, thereby modulating VEGF-A expression levels (Stevens et al., 2003). Altered expression of VEGF-A may affect the regulation of angiogenesis and extracellular matrix remodeling, processes that are crucial for both inflammatory joint diseases and ligament integrity (Rivron et al., 2012). The association of the A allele with increased susceptibility to rheumatoid arthritis (RA) and ACL rupture may be connected to mechanisms involving dysregulated vascular responses and soft tissue remodeling due to altered VEGF protein levels (Chen et al., 2012; Shukla et al., 2020).

Nevertheless, a study published by Rahim et al. (2014), which investigated the association between this polymorphism and ACL rupture risk, reported an increased frequency of the CC genotype in individuals diagnosed with ACL rupture. Similar findings were later reported by the same research team in 2022, following a study conducted on patients with surgically confirmed ACL rupture (Rahim et al., 2022).

The localization of the VEGFA rs2010963 (G/C) polymorphism within the 5′ UTR may influence mRNA stability or translational efficiency, thereby affecting VEGF-A expression and protein levels, a key factor in angiogenesis (Metzger et al., 2015). Studies suggest that the C allele of this polymorphism is associated with increased VEGF-A production, which may lead to an intensification of the angiogenic process (Ma et al., 2018). These results are consistent with previous research by Ahmetov et al. (2008), where the C allele was linked to increased maximal oxygen uptake (VO₂max) and power output (Wmax), key determinants of aerobic performance. Increased VEGF-A availability may promote skeletal muscle capillarization, enhancing oxygen diffusion capacity and supporting endurance-related adaptations to training (Bloor, 2005).

When evaluating tendon and ligament injury risk, our findings indicate a significant association between the VEGFA rs2010963 CC genotype and increased ACL injury risk, consistent with the Lulińska-Kuklik et al. (2018) and Feldmann et al. (2022) studies. Additionally, the A–A–G haplotype (rs699947, rs1570360, rs2010963) in VEGFA appeared to have a protective role against ACL rupture. Notably, gene–gene interactions between VEGFA (rs699947 A/C, rs2010963 G/C) and KDR (rs2071559 G/A and rs1870377 T/A), particularly the A–G–A–A combination, were observed less frequently in ACL-injured individuals, suggesting a potential protective genetic interplay that may contribute to ligament resilience. Haplotype analyses and gene–gene interaction approaches may better capture the combined influence of multiple variants located within the same genomic region and provide a more comprehensive understanding of their functional effect than single-locus analyses, which focus on individual genetic effects. In the case of VEGFA, haplotype structure involves regulatory regions affecting mRNA stability and gene expression levels. Furthermore, gene–gene interaction analyses between VEGFA and KDR variants provide additional insight into the functional complexity of the VEGF signaling pathway. The analyzed variants are located in the promoter region, 5′ UTR, and coding sequence, and therefore may influence both gene expression and protein structure. Consequently, these variants may affect the efficiency of VEGF–VEGFR-2 signaling and the regulation of angiogenesis. Individual polymorphisms within the VEGFA and KDR genes should be interpreted as components of broader biological networks regulating angiogenesis, vascular adaptation, and tissue remodeling. Moreover, recent research in sports genomics increasingly emphasizes polygenic and multifactorial models rather than single-SNP associations. Athletic performance and injury susceptibility are complex traits influenced by the combined influence of multiple genetic variants and their interactions with environmental factors such as training load, biomechanics, and recovery strategies (Juginović et al., 2025).

The VEGFA rs35569394 polymorphism is an 18-bp indel variant located in the promoter region of the VEGFA gene and may influence changes in gene expression levels. This variant was associated with a higher ACL injury risk in I allele carriers in the study conducted by Shukla et al (2020). Additionally, the C–D haplotype (rs699947 and rs35569394) may have protective characteristics against ACL injury risk.

The KDR rs1870377 (T/A) polymorphism is a missense variant located in the coding sequence of the gene, resulting in a histidine to glutamine substitution (His472Gln). This amino acid change may influence the conformation of the VEGFR-2 receptor and potentially affect the efficiency of downstream signaling within the VEGF pathway. The A allele occurred more frequently in endurance athletes, supporting its role in vascular adaptation and slow-twitch muscle fiber composition in research conducted by Ahmetov et al. (2009). This suggests that variations in VEGFA and KDR genes may influence aerobic performance through enhanced angiogenesis, oxygen delivery, and muscle fiber composition.

Interestingly, no significant associations were found for KDR gene variants rs1870377 and rs2071559 in ACL injury susceptibility. This contrasts with their more consistently reported role in endurance-related phenotypes, suggesting that the influence of KDR polymorphisms may vary depending on the studied phenotype, indicating that while KDR polymorphisms may influence endurance performance, their role in ligament injury risk remains inconclusive. However, in 2014, Rahim et al. linked GA genotype of KDR rs2071559 polymorphism with lower risk of ACL injury in non-athlete participants (Rahim et al., 2014). Moreover, in the following study, the rs2071559 GG genotype was associated with a 2.8-fold increased risk of ACL rupture (Rahim et al., 2018). These findings suggest that, although significant associations have not yet been demonstrated in athletic populations, KDR variants may still contribute to ACL injury susceptibility in the general population and therefore should not be excluded from consideration as potential genetic markers. The current evidence regarding the role of KDR variants in ACL injury susceptibility in athletes remains limited. To date, studies conducted in athletic populations have investigated only two polymorphisms within the KDR gene (rs1870377 and rs2071559), which restricts the ability to draw broader conclusions about the involvement of this gene in ligament injury risk. Moreover, studies conducted in general populations have reported inconsistent findings regarding the functional significance of these variants.

Beyond their relevance to athletic traits, several of the analyzed variants have also been investigated in the context of human diseases. For example, the VEGFA rs699947 polymorphism has been associated with susceptibility to RA, with studies conducted by Hussain et al. and Paradowska-Gorycka et al. linking the A allele to an increased risk of RA development (Hussain et al., 2023; Paradowska-Gorycka et al., 2016), highlighting the broader biological relevance of VEGF signaling in inflammatory and connective tissue disorders. Moreover, enhanced angiogenesis can influence various physiological and pathological processes, including tissue regeneration and tumor development (Melincovici et al., 2018). In line with this, indel VEGFA variant, rs35569394, has been associated with bladder cancer development, a disease in which tumor growth, progression, and metastasis are strongly dependent on angiogenic activity (El Azzouzi et al., 2023).

Research on the impact of VEGFA and KDR gene polymorphisms on physical performance and susceptibility to tendon and ligament injuries in athletes remains limited. Therefore, VEGFA and KDR variants should be interpreted as susceptibility modifiers rather than as deterministic predictors of performance or injury risk. However, the available evidence suggests that certain VEGFA variants may be associated with susceptibility to ACL injuries. Furthermore, the VEGFA and KDR variants may serve as potential biomarkers for evaluating predispositions to endurance sports. These findings may contribute to the development of genetic profiling strategies in sport, supporting individualized approaches to training optimizations, injury prevention, and recovery strategies in physically active individuals and professional athletes.

This research was funded by the Ministry of Science and Higher Education in 2025/2026 as part of the University Research Project of the University of Physical Education in Warsaw UPB Nr 12 – The influence of genetic conditions on sports performance – performance profiling based on candidate genetic variants.

Study design – K. Jabłońska-Paszko, K. Krawczak-Wójcik; Data collection – K. Jabłońska-Paszko; Data interpretation – K. Jabłońska-Paszko, K. Krawczak-Wójcik, E. Maculewicz; Manuscript preparation – K. Jabłońska-Paszko, E. Maculewicz; Literature search – K. Jabłońska-Paszko; Funding acquision – E. Maculewicz.

Authors state no conflict of interest.