rs2104772 — TNC

Tendon Resilience and the Extracellular Matrix Scaffold

Your tendons are more than passive cables transmitting force from muscle to bone. They're dynamic, living tissues that constantly sense mechanical stress and adapt their internal structure. At the heart of this adaptation is tenascin C¹¹ tenascin C
a large hexameric glycoprotein that acts as a molecular shock absorber, expressed at myotendinous junctions and upregulated during tissue repair and mechanical loading. The TNC gene encodes this protein, and the rs2104772 variant determines how well your tendons can withstand the repetitive high-force contractions that define elite athletic performance.

The rs2104772 polymorphism sits in exon 17 of the TNC gene, within a fibronectin type III domain²² fibronectin type III domain
one of multiple modular protein domains that give tenascin C its characteristic elasticity. This single-nucleotide change swaps isoleucine for leucine at position 1677 of the protein. While both are hydrophobic amino acids, this substitution affects protein folding and function. Studies show the T variant associates with lower tenascin C protein content³³ Studies show the T variant associates with lower tenascin C protein content
Butt et al. found reduced TNC expression in T/T carriers, which impairs molecular elasticity and compromises the extracellular matrix's ability to buffer mechanical stress.

The Mechanism

Tenascin C is a mechano-regulated protein. When you load a tendon—sprinting, jumping, cutting—mechanical stress activates the Rho/ROCK signaling cascade⁴⁴ Rho/ROCK signaling cascade
a molecular pathway that translates physical force into chemical signals, upregulating TNC gene expression. The resulting tenascin C molecules assemble into hexameric structures that can stretch to several times their resting length, protecting collagen fibers from damage during high-strain events.

The rs2104772 variant disrupts this protective system. The T-to-A substitution (creating the Ile1677Leu change) sits in a functionally critical region. Carriers of the T allele produce less tenascin C protein overall, and what they do produce has reduced elasticity. This means less cushioning for the collagen scaffold during eccentric loading—the phase of muscle contraction when tendons experience peak tensile stress, like when your hamstring decelerates your leg during the late swing phase of sprinting, or when your Achilles absorbs impact during the push-off phase of running.

The functional consequences extend beyond tendon mechanics. Tenascin C regulates cell-matrix interactions and plays a central role in the muscle damage-repair cycle. A Swiss endurance training study⁵⁵ A Swiss endurance training study
Valdivieso et al., PLOS One 2017 found that T/T individuals showed a 15% decrease in capillary-to-fiber ratio after six weeks of cycling training, while A-allele carriers increased capillary density as expected. The T/T genotype was also associated with 3.1-fold reduced vimentin protein after training—a marker of impaired vascular remodeling. This suggests the variant affects not just tendon structure but the broader tissue adaptation response to mechanical loading.

The Evidence

The association between rs2104772 and tendon injury is well-replicated across multiple athletic populations and injury types:

Achilles tendinopathy: A case-control study of Croatian elite athletes⁶⁶ A case-control study of Croatian elite athletes
Jerić et al., Genes 2025 genotyped 63 tendinopathy cases and 92 controls. The T/T genotype was significantly overrepresented in cases (42.9% vs 22.8%, p=0.0089), with an odds ratio of 2.54 (95% CI: 1.26–5.09). Each copy of the T allele increased risk by 68% (OR=1.68, 95% CI: 1.06–2.66), while the A allele was protective (OR=0.60).

Hamstring injury in soccer: A prospective study of 107 elite male soccer players⁷⁷ A prospective study of 107 elite male soccer players
Larruskain et al., Med Sci Sports Exerc 2018 tracked 129 hamstring injuries over six seasons. In a multivariable Cox model, each T allele increased hamstring injury hazard by 65% (HR=1.65, 95% CI: 1.17–2.32). The genetic model showed acceptable discrimination in the discovery phase (C-index=0.74) but failed to validate prospectively (C-index=0.52), suggesting genetic variants contribute to etiology but lack standalone predictive value.

ACL rupture (sex-specific): Whole-exome sequencing of Achilles and ACL cases⁸⁸ Whole-exome sequencing of Achilles and ACL cases
Ficek et al., PLOS One 2018 found the A/A genotype significantly associated with ACL ruptures in female athletes (p=0.035, OR=2.3, 95% CI: 1.1–5.5), though this finding was not replicated in Polish Caucasian participants, suggesting population-specific effects.

Exercise-induced angiogenesis: A Swiss training study⁹⁹ A Swiss training study
Valdivieso et al., PLOS One 2017 enrolled 61 untrained males for six weeks of endurance cycling. T/T homozygotes (18% of the cohort) showed impaired capillary remodeling: training decreased their capillary-to-fiber ratio by 15%, while A-allele carriers increased it as expected. The T/T genotype also blunted vimentin upregulation, a marker of vascular adaptation.

The mechanism is biologically plausible. Tenascin C is expressed in regenerating myofibers and at the myotendinous junction—the most vulnerable site for hamstring and Achilles injuries. It provides strength and elasticity to withstand mechanical forces and regulates the tissue's response to mechanical loading. Lower TNC expression reduces the extracellular matrix's shock-absorbing capacity, increasing strain on collagen fibers during high-force eccentric contractions.

Practical Actions

If you carry the T allele—especially if you're T/T—your tendons have reduced built-in protection against mechanical stress. This doesn't mean you're destined for injury, but it does mean you need to be strategic about load management, tissue quality, and recovery.

Progressive loading is non-negotiable. Tendon adaptation is slow—much slower than muscle adaptation. A muscle can gain strength in 4-6 weeks; a tendon needs 12-16 weeks to meaningfully increase stiffness and collagen cross-linking. Eccentric and heavy slow resistance protocols both work¹⁰¹⁰ Eccentric and heavy slow resistance protocols both work, but the key is gradual progression. Increase volume or intensity by no more than 10% per week. Avoid sudden spikes in training load—these are the scenarios where your reduced tenascin C expression leaves collagen fibers vulnerable.

Collagen peptide supplementation has emerging evidence. 15 grams of hydrolyzed collagen¹¹¹¹ 15 grams of hydrolyzed collagen
containing glycine, proline, and hydroxyproline taken 60 minutes before exercise increases circulating amino acids (glycine up 376 mmol/L, proline up 162 mmol/L) and provides the building blocks for collagen synthesis. A study in female soccer players¹²¹² A study in female soccer players
Shaw et al., Front Physiol 2023 found collagen supplementation augmented patellar tendon stiffness changes during training. Take it with 50 mg vitamin C—vitamin C acts as a cofactor¹³¹³ vitamin C acts as a cofactor
hydroxylating proline and lysine residues in the collagen synthesis pathway.

Monitor for early warning signs. Tendinopathy typically progresses through stages: reactive tendinopathy (acute overload), tendon dysrepair (failed healing), and degenerative tendinopathy (irreversible structural changes). Catch it early. If you notice morning stiffness that warms up, localized tenderness along the Achilles or hamstring tendon, or pain during loading that eases with rest, reduce training volume immediately and consult a sports physiotherapist. Progressive tendon-loading exercises¹⁴¹⁴ Progressive tendon-loading exercises are more effective than rest alone, but they need to be dosed correctly.

Prioritize recovery between high-eccentric sessions. Eccentric exercise—downhill running, plyometrics, Nordic hamstring curls, heavy negatives—causes greater muscle and tendon damage than concentric work, especially in T/T individuals. The Swiss angiogenesis study¹⁵¹⁵ Swiss angiogenesis study showed T/T carriers had impaired vascular remodeling, meaning slower nutrient delivery and waste removal. Allow 48-72 hours between high-eccentric sessions. Use isometric holds (e.g., Spanish squats for Achilles, isometric hamstring bridges) on recovery days—these build tendon tolerance without excessive strain.

Interactions

TNC rs2104772 doesn't act in isolation. The Croatian study identified a T-T-T haplotype¹⁶¹⁶ The Croatian study identified a T-T-T haplotype combining TNC rs2104772-T, COL27A1 rs946053-T, and COL5A1 rs12722-T that was significantly predisposing for tendinopathy, while the G-A-C haplotype was protective. The biological logic is clear: COL5A1 encodes type V collagen, which regulates collagen fibril assembly and diameter, while COL27A1 contributes to cartilage and tendon structure. If you carry risk alleles in multiple collagen-pathway genes, the combined effect on extracellular matrix integrity is greater than any single variant.

There's also evidence for interaction with MMP3 rs679620¹⁷¹⁷ interaction with MMP3 rs679620. MMP3 encodes matrix metalloproteinase-3, an enzyme that degrades extracellular matrix proteins during tissue remodeling. The G allele of MMP3 rs679620 and the T allele of TNC rs2104772 significantly interacted to raise Achilles tendinopathy risk (p=0.006). This makes mechanistic sense: reduced tenascin C (from TNC T/T) combined with elevated MMP3 activity (from MMP3 G/G) creates a scenario where the extracellular matrix is simultaneously less resilient and more actively degraded.

Finally, consider the hamstring injury genetic model¹⁸¹⁸ hamstring injury genetic model that included TNC rs2104772 alongside MMP3 rs679620, IL-6 rs1800795, NOS3 rs1799983, and HIF-1α rs11549465. These genes regulate inflammation (IL-6), nitric oxide signaling (NOS3), and hypoxic adaptation (HIF-1α). The multivariable model had a C-index of 0.74 in the discovery cohort, suggesting genetic variants collectively explain a meaningful fraction of hamstring injury risk. While the model didn't validate prospectively for prediction, it underscores that tendon injury is a complex trait influenced by ECM structure, inflammation, vascular health, and metabolic stress response.