{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:36:27Z","timestamp":1760060187815,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: The increased risk of developing tendinopathies in athlete populations has led to investigations of several genes associated with tendon properties, suggesting that some individuals have a greater genetic predisposition for developing tendinopathies. The main purpose of this study was to investigate how the functional polymorphisms within the COL5A1, COL27A1 and TNC genes impact the risk of developing tendinopathies in high-level Croatian athletes. Methods: For this case\u2013control genetic study, we recruited 63 high-level athletes with a diagnosis of tendinopathies and 92 healthy asymptomatic individuals as controls. All individuals were genotyped for three single-nucleotide polymorphisms (SNPs) within the COL5A1, COL27A1 and TNC genes using the pyrosequencing method. Results:\u00a0TNC rs2104772 TT (p = 0.0089) and the T-T-T haplotype (p = 0.0234), constructed from rs12722, rs946053 and rs2104772, were significantly overrepresented in cases versus controls, implicating a predisposition for tendinopathies. COL27A1 rs946053 GG (p = 0.0118) and the G-A-C haplotype (p = 0.0424), constructed from rs12722, rs946053 and rs2104772, were significantly overrepresented in controls, implicating a protective role. Conclusions: These results further support associations between functional polymorphisms within the COL27A1 and TNC genes and the risk of tendinopathies in high-level athletes. Further research is needed to replicate these results in various populations and larger cohorts.<\/jats:p>","DOI":"10.3390\/genes16080935","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T10:58:26Z","timestamp":1754564306000},"page":"935","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Association of the COL27A1 rs946053 and TNC rs2104772s with Tendinopathies: A Case\u2013Control Study in High-Level Croatian Athletes"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4541-4659","authenticated-orcid":false,"given":"Goran","family":"Vrgo\u010d","sequence":"first","affiliation":[{"name":"Faculty of Kinesiology, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Orthopaedic Surgery, University Hospital \u201cSveti Duh\u201d, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sa\u0161a","family":"Jankovi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Kinesiology, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Orthopaedic Surgery, University Hospital \u201cSveti Duh\u201d, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damir","family":"Knjaz","sequence":"additional","affiliation":[{"name":"Faculty of Kinesiology, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4807-8913","authenticated-orcid":false,"given":"Ivana","family":"Duvnjak Ore\u0161kovi\u0107","sequence":"additional","affiliation":[{"name":"Genos Ltd., 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordan","family":"Lauc","sequence":"additional","affiliation":[{"name":"Genos Ltd., 10000 Zagreb, Croatia"},{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"\u0160imuni\u0107-Bri\u0161ki","sequence":"additional","affiliation":[{"name":"Genos Ltd., 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kim, S.K., Roos, T.R., Roos, A.K., Kleimeyer, J.P., Ahmed, M.A., Goodlin, G.T., Fredericson, M., Ioannidis, J.P.A., Avins, A.L., and Dragoo, J.L. (2017). Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0170422"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.csm.2007.10.007","article-title":"International Olympic Committee Consensus Statement: Molecular Basis of Connective Tissue and Muscle Injuries in Sport","volume":"27","author":"Ljungqvist","year":"2008","journal-title":"Clin. Sports Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1177\/1071100712460223","article-title":"Achilles tendon rupture in women","volume":"34","author":"Vosseller","year":"2013","journal-title":"Foot Ankle Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1177\/1938640009355191","article-title":"Achilles tendon rupture: A review of etiology, population, anatomy, risk factors, and injury prevention","volume":"3","author":"Hess","year":"2010","journal-title":"Foot Ankle Spec."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1097\/01.jsm.0000165347.55638.23","article-title":"Cumulative Incidence of Achilles Tendon Rupture and Tendinopathy in Male Former Elite Athletes","volume":"15","author":"Kujala","year":"2005","journal-title":"Clin. J. Sport Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1136\/bjsports-2011-090342","article-title":"Incidence of midportion Achilles tendinopathy in the general population","volume":"45","author":"Weir","year":"2011","journal-title":"Br. J. Sports Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"56","DOI":"10.2174\/1574888X09666140710112535","article-title":"Unravelling the Genetic Susceptibility to Develop Ligament and Tendon Injuries","volume":"10","author":"Longo","year":"2015","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1097\/00042752-199407000-00004","article-title":"Assessing Causation in Sport Injury: A Multifactorial Model","volume":"4","author":"Meeuwisse","year":"1994","journal-title":"Clin. J. Sport Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1093\/rheumatology\/keg448","article-title":"The pathogenesis of tendinopathy. A molecular perspective","volume":"43","author":"Riley","year":"2004","journal-title":"Rheumatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1016\/S0021-9290(03)00135-0","article-title":"Collagen self-assembly and the development of tendon mechanical properties","volume":"36","author":"Silver","year":"2003","journal-title":"J. Biomech."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S0968-4328(00)00036-6","article-title":"The fibril structure of type V collagen triple-helical domain","volume":"32","author":"Mizuno","year":"2001","journal-title":"Micron"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1111\/j.1432-1033.1994.00943.x","article-title":"Structural characteristics of cross-linking sites in type V collagen of bone Chain specificities and heterotypic links to type I collagen","volume":"224","author":"Niyibizi","year":"1994","journal-title":"Eur. J. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/j.1600-0838.2005.00439.x","article-title":"The COL5A1 gene and Achilles tendon pathology","volume":"16","author":"Mokone","year":"2006","journal-title":"Scand. J. Med. Sci. Sports"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1136\/bjsm.2008.048793","article-title":"Variants within the COL5A1 gene are associated with Achilles tendinopathy in two populations","volume":"43","author":"September","year":"2009","journal-title":"Br. J. Sports Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.1177\/0363546509338266","article-title":"The COL5A1 gene is associated with increased risk of anterior cruciate ligament ruptures in female participants","volume":"37","author":"Posthumus","year":"2009","journal-title":"Am. J. Sports Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1136\/bjsm.2008.056184","article-title":"The COL1A1 gene and acute soft tissue ruptures","volume":"44","author":"Collins","year":"2010","journal-title":"Br. J. Sports Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/j.1600-0838.2010.01271.x","article-title":"Range of motion measurements diverge with increasing age for COL5A1 genotypes","volume":"21","author":"Brown","year":"2011","journal-title":"Scand. J. Med. Sci. Sports"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/(SICI)1097-0177(200006)218:2<235::AID-DVDY2>3.0.CO;2-G","article-title":"The tenascin family of ECM glycoproteins: Structure, function, and regulation during embryonic development and tissue remodeling","volume":"218","author":"Jones","year":"2000","journal-title":"Dev. Dyn."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/S0945-053X(00)00106-2","article-title":"Tenascin-C in development and disease: Gene regulation and cell function","volume":"19","author":"Jones","year":"2000","journal-title":"Matrix Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1242\/jcs.00303","article-title":"Mechanical loading regulates the expression of tenascin-C in the myotendinous junction and tendon but does not induce de novo synthesis in the skeletal muscle","volume":"116","author":"Kannus","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1177\/0363546504271986","article-title":"The Guanine-Thymine Dinucleotide Repeat Polymorphism Within the Tenascin-C Gene is Associated with Achilles Tendon Injuries","volume":"33","author":"Mokone","year":"2005","journal-title":"Am. J. Sports Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1002\/jor.22820","article-title":"Extracellular matrix proteins interact with cell-signaling pathways in modifying risk of Achilles tendinopathy","volume":"33","author":"Saunders","year":"2015","journal-title":"J. Orthop. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1093\/hmg\/ddn058","article-title":"Biological and genetic interaction between Tenascin C and Neuropeptide S receptor 1 in allergic diseases","volume":"17","author":"Vendelin","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.1093\/hmg\/ddi311","article-title":"Coding SNP in tenascin-C Fn-III-D domain associates with adult asthma","volume":"14","author":"Matsuda","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0945-053X(03)00007-6","article-title":"Identification, characterization and expression analysis of a new fibrillar collagen gene, COL27A1","volume":"22","author":"Pace","year":"2003","journal-title":"Matrix Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"31067","DOI":"10.1074\/jbc.M212889200","article-title":"A novel and highly conserved collagen (pro\u03b11(XXVII)) with a unique expression pattern and unusual molecular characteristics establishes a new clade within the vertebrate fibrillar collagen family","volume":"278","author":"Tuckwell","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1002\/jor.22278","article-title":"Investigation of variants within the COL27A1 and TNC genes and Achilles tendinopathy in two populations","volume":"31","author":"Saunders","year":"2013","journal-title":"J. Orthop. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gibbon, A., Saunders, C.J., Collins, M., Gamieldien, J., and September, A.V. (2018). Defining the molecular signatures of Achilles tendinopathy and anterior cruciate ligament ruptures: A whole-exome sequencing approach. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0205860"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1086\/383251","article-title":"A Simple Correction for Multiple Testing for Single-Nucleotide Polymorphisms in Linkage Disequilibrium with Each Other","volume":"74","author":"Nyholt","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/j.1600-0838.1997.tb00126.x","article-title":"Etiology and pathophysiology of tendon ruptures in sports","volume":"7","author":"Kannus","year":"1997","journal-title":"Scand. J. Med. Sci. Sports"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/ajmg.c.30070","article-title":"Molecular genetics in classic Ehlers-Danlos syndrome","volume":"139C","author":"Malfait","year":"2005","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1097\/GIM.0b013e3181eed412","article-title":"Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type","volume":"12","author":"Malfait","year":"2010","journal-title":"Genet. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/76211","article-title":"The 3\u2032 untranslated region of messenger RNA: A molecular \u2018hotspot\u2019 for pathology?","volume":"6","author":"Conne","year":"2000","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1111\/ahg.12013","article-title":"Polymorphisms within the COL5A1 3\u2032-UTR that alters mRNA structure and the MIR608 gene are associated with Achilles tendinopathy","volume":"77","author":"Abrahams","year":"2013","journal-title":"Ann. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/ejhg.2014.107","article-title":"Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population","volume":"23","author":"Gamble","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2325967117724416","DOI":"10.1177\/2325967117724416","article-title":"Genetic factors in tendon injury: A systematic review of the literature","volume":"5","author":"Vaughn","year":"2017","journal-title":"Orthop. J. Sports Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1007\/s00264-020-04684-w","article-title":"Association of the matrix metalloproteinase 3 (MMP3) single nucleotide polymorphisms with tendinopathies: Case-control study in high-level athletes","volume":"45","author":"Knjaz","year":"2021","journal-title":"Int. Orthop."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3429","DOI":"10.1074\/jbc.270.7.3429","article-title":"Human tenascin gene. Structure of the 5\u2032-region, identification, and characterization of the transcription regulatory sequences","volume":"270","author":"Gherzi","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1080\/02640414.2016.1221524","article-title":"Polymorphisms within the COL5A1 gene and regulators of the extracellular matrix modify the risk of Achilles tendon pathology in a British case-control study","volume":"35","author":"Brown","year":"2017","journal-title":"J. Sports Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1111\/sms.14077","article-title":"The genetic association with injury risk in male academy soccer players depends on maturity status","volume":"32","author":"Hall","year":"2022","journal-title":"Scand. J. Med. Sci. Sports"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1002\/jor.24455","article-title":"Rotator Cuff Tear Susceptibility Is Associated with Variants in Genes Involved in Tendon Extracellular Matrix Homeostasis","volume":"38","author":"Figueiredo","year":"2020","journal-title":"J. Orthop. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Heffernan, S.M., Kilduff, L.P., Erskine, R.M., Day, S.H., Stebbings, G.K., Cook, C.J., Raleigh, S.M., Bennett, M.A., Wang, G., and Collins, M. (2017). COL5A1 gene variants previously associated with reduced soft tissue injury risk are associated with elite athlete status in rugby. BMC Genom., 18.","DOI":"10.1186\/s12864-017-4187-3"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1177\/1941738112472165","article-title":"Achilles tendon rupture: Risk assessment for aerial and ground athletes","volume":"5","author":"Wertz","year":"2013","journal-title":"Sports Health"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1046\/j.1365-2125.1999.00016.x","article-title":"Achilles tendinitis associated with fluoroquinolones","volume":"48","author":"Nab","year":"1999","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1186\/ar2723","article-title":"Pathogenesis of tendinopathies: Inflammation or degeneration?","volume":"11","author":"Abate","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Park, K.H., Park, J.H., Yoon, Y.K., Kwon, J.B., Kim, J.H., Lee, E., Roh, Y., Han, S.H., and Lee, J.W. (2022). Association between outdoor temperature and achilles tendon repair: A 14-years nationwide population-based cohort study. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0265041"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1177\/1941738112440957","article-title":"Tendinopathy in Sport","volume":"4","author":"Ackermann","year":"2012","journal-title":"Sports Health"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2325967118808238","DOI":"10.1177\/2325967118808238","article-title":"Epidemiology of Achilles Tendon Ruptures in the United States: Athletic and Nonathletic Injuries from 2012 to 2016","volume":"6","author":"Lemme","year":"2018","journal-title":"Orthop. J. Sports Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2325967120966041","DOI":"10.1177\/2325967120966041","article-title":"Effect of Achilles Tendon Rupture on Player Performance and Longevity in National Basketball Association Players","volume":"8","author":"Khalil","year":"2020","journal-title":"Orthop. J. Sports Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"23259671211030473","DOI":"10.1177\/23259671211030473","article-title":"Performance Outcomes After Surgical Repair of Achilles Tendon Rupture in the Women\u2019s National Basketball Association","volume":"9","author":"Hodgens","year":"2021","journal-title":"Orthop. J. Sports Med."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Goodlin, G.T., Roos, A.K., Roos, T.R., Hawkins, C., Beache, S., Baur, S., and Kim, S.K. (2017). Correction: Applying Personal Genetic Data to Injury Risk Assessment in Athletes. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0171397"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/935\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:23:04Z","timestamp":1760034184000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/935"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,4]]},"references-count":51,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["genes16080935"],"URL":"https:\/\/doi.org\/10.3390\/genes16080935","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2025,8,4]]}}}