# The Role of COL1A1, COL5A1, ACTN3, MMP3, and GDF5 Gene Variants in Common Sports Injuries: Systematic Review of ACL Rupture, Achilles Tendinopathy, and Stress Fractures **Authors:** Shahd Abboud, Elizabeth Akam, David John Hunter, Sarabjit Mastana PMC · DOI: 10.3390/genes17020212 · Genes · 2026-02-09 ## TL;DR This study reviews how specific gene variants may increase the risk of common sports injuries like ACL rupture and Achilles tendinopathy, suggesting a genetic component in injury susceptibility. ## Contribution A systematic review identifying genetic variants in COL1A1, COL5A1, ACTN3, MMP3, and GDF5 associated with musculoskeletal sports injuries. ## Key findings - COL1A1 rs1800012 may protect against ACL rupture. - COL5A1 rs1272 and rs13946 increase risk for ACL rupture and Achilles tendinopathy. - ACTN3 R577X XX genotype is linked to higher muscle injury risk. ## Abstract Background: Anterior cruciate ligament (ACL) rupture, Achilles tendinopathy, and stress fracture are common sports injuries with significant long-term effects on performance and health. Despite similar exposure, injury susceptibility varies among athletes, suggesting a genetic component. Variants in COL1A1, COL5A1, ACTN3, MMP3, and GDF5 genes influence collagen integrity, muscle performance, and extracellular matrix remodelling, making them potential risk factors. Objective: To systematically review associations between five selected genes and musculoskeletal injury risk. Methods: Following PRISMA 2020 guidelines, PubMed, EMBASE, SPORTDiscus, and Web of Science were searched for studies examining these genes in relation to sports injuries. Data were extracted using Covidence and assessed for quality via the Newcastle–Ottawa Scale (NOS). Results: Twenty-six studies (n > 7000) were included. COL1A1 rs1800012 showed a protective effect against ACL rupture; COL5A1 rs1272 and rs13946 increased risk for ACL rupture and Achilles tendinopathy. MMP3 variants (rs679620, 5A/6A) showed variable associations, particularly in combination with COL5A1. ACTN3 R577X was linked to higher muscle and soft tissue injury risk in XX genotype carriers. Evidence for GDF5 rs143383 was limited but suggested a possible association with stress fractures. Conclusions: Genetic variants in COL1A1, COL5A1, MMP3, ACTN3, and GDF5 may influence susceptibility to ACL rupture, Achilles tendinopathy, and stress fractures. Larger, multi-ethnic studies are needed to validate these findings and inform personalised injury prevention strategies. ## Linked entities - **Genes:** COL1A1 (collagen type I alpha 1 chain) [NCBI Gene 1277], COL5A1 (collagen type V alpha 1 chain) [NCBI Gene 1289], ACTN3 (actinin alpha 3) [NCBI Gene 89], MMP3 (matrix metallopeptidase 3) [NCBI Gene 4314], GDF5 (growth differentiation factor 5) [NCBI Gene 8200] ## Full-text entities - **Genes:** NID1 (nidogen 1) [NCBI Gene 4811] {aka NID}, COL12A1 (collagen type XII alpha 1 chain) [NCBI Gene 1303] {aka BA209D8.1, BTHLM2, COL12A1L, DJ234P15.1, EDSMYP, UCMD2}, COL5A1 (collagen type V alpha 1 chain) [NCBI Gene 1289] {aka EDSC, EDSCL1, FMDMF}, SP1 (Sp1 transcription factor) [NCBI Gene 6667], COLGALT1 (collagen beta(1-O)galactosyltransferase 1) [NCBI Gene 79709] {aka BSVD3, ColGalT 1, GLT25D1}, COL1A1 (collagen type I alpha 1 chain) [NCBI Gene 1277] {aka CAFYD, EDSARTH1, EDSC, OI1, OI2, OI3}, COL3A1 (collagen type III alpha 1 chain) [NCBI Gene 1281] {aka EDS4A, EDSVASC, PMGEDSV}, TIMP2 (TIMP metallopeptidase inhibitor 2) [NCBI Gene 7077] {aka CSC-21K, DDC8}, BCL2A1 (BCL2 related protein A1) [NCBI Gene 597] {aka ACC-1, ACC-2, ACC1, ACC2, BCL2L5, BFL1}, PAEP (progestagen associated endometrial protein) [NCBI Gene 5047] {aka GD, GdA, GdF, GdS, PAEG, PEP}, COL1A2 (collagen type I alpha 2 chain) [NCBI Gene 1278] {aka EDSARTH2, EDSCV, OI4}, ACTN3 (actinin alpha 3) [NCBI Gene 89] {aka ACTN3D}, NOS2 (nitric oxide synthase 2) [NCBI Gene 4843] {aka HEP-NOS, INOS, NOS, NOS2A}, GDF5 (growth differentiation factor 5) [NCBI Gene 8200] {aka BDA1C, BMP-14, BMP14, CDMP1, DUPANS, LAP-4}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, MIR608 (microRNA 608) [NCBI Gene 693193] {aka MIRN608, hsa-mir-608}, MMP3 (matrix metallopeptidase 3) [NCBI Gene 4314] {aka CHDS6, MMP-3, SL-1, STMY, STMY1, STR1}, KDR (kinase insert domain receptor) [NCBI Gene 3791] {aka CD309, FLK1, VEGFR, VEGFR2} - **Diseases:** muscle injuries (MESH:D009135), V collagen (MESH:D003095), joint laxity (MESH:D007593), musculoskeletal injuries (MESH:D009140), joint injuries (MESH:D000092464), and Soft Tissue Injuries (MESH:D017695), Stress Fracture (MESH:D015775), tendon and muscle injuries (MESH:D013708), CL rupture (MESH:D002971), AT (MESH:D052256), bone injuries (MESH:D001847), microtrauma (MESH:D000070617), acute failure (MESH:D058186), ligament sprain (MESH:D013180), fatigue (MESH:D005221), non- (MESH:C580335), -impact injuries (MESH:D004834), osteoarthritis (MESH:D010003), fracture (MESH:D050723), Injury (MESH:D014947), inflammation (MESH:D007249), ACL rupture (MESH:D000070598), weakness (MESH:D018908), Tendon rupture (MESH:D012421), Impairments in proprioception (MESH:D020886), Sports Injuries (MESH:D001265) - **Species:** Homo sapiens (human, species) [taxon 9606] - **Mutations:** rs412777, rs42524, rs17602729, rs1800012, rs970547, rs1134170, rs4919510, rs2621215, rs3196378, rs1107946, rs13945, Rs143383, rs10735810, rs16399, rs679620, C/T, GG/AA, rs650108, rs680, rs1800255, 6A-G, rs35796750, rs591058, rs71746744, T-C, rs12722, R577X, rs1272, rs3025058 ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12940354/full.md ## Figures 1 figure with captions in the complete paper: https://tomesphere.com/paper/PMC12940354/full.md ## References 62 references — full list in the complete paper: https://tomesphere.com/paper/PMC12940354/full.md --- Source: https://tomesphere.com/paper/PMC12940354