Tenascin-C-Matrix Metalloproteinase-3 Phenotype and the Risk of Tendinopathy in High-Performance Athletes: A Case–Control Study

<b>Background/Objectives:</b> Tendon structure is predominantly composed of the extracellular matrix (ECM), and genetic variants in non-collagenous ECM components may influence susceptibility to tendinopathy. We investigated the potential influence of single nucleotide polymorphisms (SNPs) in fibrillin-2 (<i>FBN2</i>), tenascin-C (<i>TNC</i>), and matrix metalloproteinase-3 (<i>MMP3</i>) on the tendon regeneration failure phenotype and impact on the susceptibility to tendinopathy in Brazilian high-performance athletes. <b>Methods:</b> This case-control study was conducted with 397 high-performance athletes from different sports modalities (197 tendinopathy cases and 200 controls), and they were analyzed by validated TaqMan^TM SNP genotyping assays of the SNPs <i>FBN2</i> (rs331079), <i>TNC</i> (rs2104772), and <i>MMP3</i> (rs591058). <b>Results:</b> Out of the 197 tendinopathy cases, 63% suffered from chronic tendon pain and 22% experienced more than three episodes of disease manifestation. The <i>TNC</i>-rs2104772-<i>A</i> allele was significantly associated with tendinopathy (OR: 1.4; 95% CI: 1.1-1.8), while athletes carrying the <i>MMP3</i>-rs591058-<i>T</i> allele were linked to an increased risk of more episodes of disease manifestation (OR: 1.7; 95% CI: 1.1-2.8). The <i>TNC-MMP3</i> tendon regeneration failure phenotype (<i>TNC-A/MMP3-T</i>) was associated with an increased risk of tendinopathy (OR: 1.4; 95% CI: 1.1-2.0) and episodes of disease manifestation (OR: 2.0; 95% CI: 1.2-3.5). Athletes with tendinopathy who had the <i>TNC-A/MMP3-T</i> interaction were more prone to experiencing more than three disease exacerbations (OR: 4.3; 95% CI: 1.8-10.5) compared to <i>TNC-A/TNC-C</i>. <b>Conclusions:</b> This study suggests that rs2104772 and rs591058 SNPs could be involved in the tendon regeneration failure phenotype and may influence the molecular mechanism related to the regulation of the tendon ECM during training workload.