The research team, led by Amina Marrouh of the Mohammed VI University of Sciences and Health in Casablanca, Morocco, conducted a structured literature search across PubMed, Scopus, Web of Science, and Google Scholar to identify studies investigating genetic polymorphisms associated with tendon and ligament injuries in athletic populations. Eligible studies published in English and involving elite, professional, recreational, or physically active individuals were narratively synthesized. The evidence included 33 candidate genes with 43 polymorphisms, 25 polymorphisms evaluated in haplotype analyses involving these candidate genes as well as three additional genes, and 34 genes identified through genome-wide association studies encompassing 39 variants. These genes are involved in extracellular matrix organization, inflammation, tissue remodeling, angiogenesis, and muscle function, reflecting the multifactorial biological architecture that determines how tendons and ligaments respond to mechanical stress.

Among the structural genes most frequently implicated are the collagens, particularly COL1A1, COL3A1, and COL5A1, which encode the fibrillar proteins that provide tensile strength to tendon and ligament tissues. The COL1A1 Sp1-binding site polymorphism rs1800012 has been consistently associated with susceptibility to injury, with carriers of the minor G allele exhibiting approximately a 1.43-fold lower risk of anterior cruciate ligament rupture compared to T allele carriers in recreational Polish skiers. However, the picture is far from straightforward. A meta-analysis including 933 cases and 1,381 controls confirmed a protective effect of the TT genotype against acute soft tissue injuries, yet another study among elite male Australian Football League players showed that the same TT genotype was significantly associated with a higher number of total ligament injuries per match. These conflicting results underscore the importance of population-specific genetic backgrounds and sport-related mechanical demands in modulating the biological effects of individual variants.

The COL5A1 gene shows more consistent associations, particularly in female athletes. Posthumus and colleagues were the first to identify a genetic risk factor for ACL rupture linked to COL5A1, noting that the CC genotype at rs12722 is more frequent in controls than in individuals with ACL rupture. This finding was further supported by evidence showing that homozygosity for the C-C rs12722-rs13946 haplotype appears protective against ACL injury in professional football players, while the T allele and TT genotype are more frequent among injured players. The COL12A1 gene, encoding collagen type XII alpha 1 chain, demonstrates strong evidence with the AA genotype of rs240736 associated with approximately a 2.4-fold increased risk of injury in women. Importantly, the inferred T plus A pseudo-haplotype combining COL5A1 rs12722 and COL12A1 rs970547 was associated with increased ACL rupture risk in female participants from both South African and Polish cohorts, reinforcing that combined variant effects often exceed the explanatory power of isolated polymorphisms.

Beyond the collagen family, the review highlights the critical role of proteoglycans and glycoproteins in maintaining extracellular matrix integrity. Genes encoding aggrecan (ACAN), decorin (DCN), biglycan (BGN), fibromodulin (FMOD), and tenascin C (TNC) regulate collagen fibril organization and tissue elasticity. The BGN rs1042103 A allele was associated with increased ACL rupture risk, and the C-A and T-A BGN haplotypes influenced susceptibility in female and male groups respectively. The DCN rs516115 A allele was linked to increased hamstring injury risk in football players. Notably, the combined analysis of BGN, COL5A1, and DCN polymorphisms showed that the C-G-C-G allele combination was associated with reduced ACL injury susceptibility, whereas the T-A/G-T-A combination was linked to increased risk, with sex-specific effects observed. These findings demonstrate that genes encoding proteoglycans and glycoproteins exert their influence primarily through multi-locus combinations rather than through individual variant effects.

Matrix metalloproteinases and their inhibitors represent another critical pathway. MMPs degrade extracellular matrix components during tissue remodeling, and their genetic variability has been extensively investigated in relation to Achilles tendinopathy and ACL rupture. Raleigh and colleagues reported that the rs679620 GG, rs591058 CC, and rs650108 AA genotypes of MMP3 were associated with increased risk of Achilles tendinopathy in a South African Caucasian cohort. Haplotype analyses further revealed that the A-T-G combination was linked to reduced risk, whereas interaction between the rs679620 G allele and the COL5A1 rs12722 T allele significantly increased injury susceptibility. A multi-gene haplotype involving MMP10, MMP1, MMP3, and MMP12 was associated with reduced ACL rupture risk, suggesting that combined MMP variants collectively influence ligament integrity. The TIMP2 rs4789932 TT genotype has been associated with Achilles tendon pathology in Caucasian populations, although findings remain limited and inconsistent across different injury phenotypes.

Inflammatory genes constitute a third major biological axis. The IL6 rs1800795 GG genotype is consistently associated with increased risk of both hamstring injuries and ACL rupture, with odds ratios of 1.68 and 1.74 respectively, whereas the heterozygous GC genotype appears protective. A recent meta-analysis confirmed IL6 rs1800795 as significantly associated with ACL rupture. The IL1B rs16944 TT genotype has been linked to approximately a 3-fold increased risk of non-contact ACL rupture in female participants. Gene-gene interaction analysis involving COL5A1, IL1B, IL6, and IL6R demonstrated that the T-C-G-A allele combination was significantly underrepresented in controls and more frequent in ACL rupture groups, suggesting increased injury susceptibility through combined inflammatory and structural pathways. The CASP8 gene, a key regulator of apoptosis, also shows haplotype-dependent effects, with the ins-G-T combination associated with increased risk while the ins-G-A and del-C haplotypes confer protection against ACL rupture and non-contact injuries.

Genome-wide association studies, although limited in number, have identified novel loci that reinforce the polygenic nature of these conditions. One GWAS in elite athletic cohorts reported 37 SNPs reaching genome-wide significance for injury susceptibility across 32 genes, while a second GWAS in patients with Achilles tendon pathology, ACL rupture, and tendinopathies identified two additional genome-wide significant loci. However, the review emphasizes that these findings should be considered hypothesis-generating with weak evidential support pending replication in independent and sport-specific cohorts. The GWAS-identified genes include CDHR2, CIT, COL22A1, PIEZO2, and NID1, among others, many of which have not been previously implicated in candidate-gene studies. This agnostic scanning approach complements the hypothesis-driven candidate-gene literature by revealing unexpected biological pathways that may contribute to injury susceptibility.

The review authors stress that substantial heterogeneity across populations, sexes, sports disciplines, competitive levels, and injury phenotypes limits the generalizability of current genetic associations. Many reported polymorphisms appear population-specific and are not consistently replicated across independent cohorts. Associations involving COL5A1 and COL12A1 were more consistently observed in female athletes and in South African or Caucasian populations, whereas findings in mixed-sex or other ethnic cohorts were often inconsistent or absent. These discrepancies may reflect differences in genetic background, linkage disequilibrium structure, hormonal influences, biomechanical loading patterns, and sport-specific demands. The review also distinguishes between different injury phenotypes, including tendinopathy, tendon rupture, ACL rupture, hamstring injury, and ankle injury, emphasizing that these represent distinct clinical and biological entities with potentially different genetic determinants.

From a clinical perspective, the review concludes that current genetic evidence should not be used in isolation for risk stratification. The available findings are not sufficiently robust or consistent to support genetic testing as a standalone predictive tool in sports practice. Instead, genetic information may contribute as one component of broader integrative models combining genetic background with biomechanical load, training exposure, previous injury, recovery capacity, and individual physiological characteristics. The authors also raise important ethical considerations, including the privacy of genetic data, the risk of misinterpreting probabilistic associations as deterministic predictions, and the potential for discrimination in athlete profiling. Any future application of genetic markers in sports medicine must adhere to strict ethical and regulatory frameworks, ensuring that genetic data are used solely for health promotion, injury prevention, and evidence-based individualized care rather than for the selection or exclusion of athletes.

Subject of Research: Genetic determinants of tendon and ligament injuries in athletes: a narrative review from single variants to gene-gene interactions

Article Title: Genetic determinants of tendon and ligament injuries in athletes: a narrative review from single variants to gene-gene interactions

Article References: Marrouh, A., El Haddouchi, A., Kartti, S., El Fahime, E., Boutayeb, S., Chagar, Y., Baudot, C., Belyamani, L., Dakka, T., & Eljaoudi, R. (2026). Genetic determinants of tendon and ligament injuries in athletes: a narrative review from single variants to gene-gene interactions. Frontiers in Systems Biology, 6, Article 1858521. https://doi.org/10.3389/fsysb.2026.1858521

Image Credits: AI Generated

DOI: 10.3389/fsysb.2026.1858521

Keywords: Genetic, determinants, tendon, ligament, injuries, athletes, narrative, review, single, variants, gene-gene, interactions