The role of SP1 (rs1800012) in anterior cruciate ligament injuries: updated meta-analysis

The Anterior Cruciate Ligament (ACL) is vital for knee stability, and its rupture is a major orthopedic concern with significant health and economic impacts. Evidence suggests a substantial hereditary component in ACL injury susceptibility, with the COL1A1 rs1800012 (SP1) polymorphism frequently studied but with inconsistent results. To clarify the association between the rs1800012 in COL1A1 and ACL injury risk, this meta-analysis synthesized data from case-control and cohort studies focusing exclusively on ACL injuries. Systematic searches of PubMed, Embase, Web of Science, and Scopus identified studies up to June 2025. Eligible studies included individuals diagnosed with ACL injuries and healthy controls, reporting genotype frequencies for rs1800012. Pooled Odds Ratios (OR) and 95% Confidence Intervals (CI) were calculated for various genetic models using random-effects meta-analysis. Study quality was assessed via the Newcastle–Ottawa Scale, and publication bias and heterogeneity were evaluated. Nine studies (1,171 cases, 2,005 controls) were included. The TT genotype was significantly protective under the recessive model (TT vs. TG+GG: OR = 0.49, 95% CI: 0.25–0.97, p = 0.041), and also in direct genotype comparisons (TT vs. TG: OR = 0.41, 95% CI: 0.21–0.80, p = 0.009). Conversely, the TG genotype increased ACL injuries risk under the overdominant model (TG vs. TT+GG: OR = 1.28, 95% CI: 1.07–1.52, p = 0.006) and when compared to GG (TG vs. GG: OR = 1.24, 95% CI: 1.05–1.48, p = 0.014). No significant associations were observed under the allele contrast (T vs. G: OR = 1.04, 95% CI: 0.90–1.21, p = 0.61) or dominant models (TT+TG vs. GG: OR = 1.15, 95% CI: 0.97–1.37, p = 0.10). Heterogeneity was consistently low, and sensitivity analyses confirmed the robustness of these findings. No evidence of publication bias was detected. This meta-analysis demonstrates genotype-specific effects of rs1800012 on ACL injuries risk: the TT genotype is protective, while the TG genotype confers increased risk.

 

1. Szumiło P. A review of studies about the genes encoding the collagen proteins in the context of the anterior cruciate ligament rupture. Central Eur J Sport Sci Med 2014;5:91–7.

2. Perini JA, Lopes LR, Guimarães JAM, et al. Influence of type I collagen polymorphisms and risk of anterior cruciate ligament rupture in athletes: a case-control study. BMC Musculoskelet Disord 2022;23:154. DOI: https://doi.org/10.1186/s12891-022-05105-2

3. Yao S, Yung PSH, Lui PPY. Tackling the challenges of graft healing after anterior cruciate ligament reconstruction—thinking from the endpoint. Front Bioengin Biotechnol 2021;9:756930. DOI: https://doi.org/10.3389/fbioe.2021.756930

4. Martinez-Calderon J, Infante-Cano M, Matias-Soto J, et al. The incidence of sport-related anterior cruciate ligament injuries: an overview of systematic reviews including 51 meta-analyses. J Funct Morphol Kinesiol 2025;10:174. DOI: https://doi.org/10.3390/jfmk10020174

5. Shukla M, Gupta R, Pandey V, et al. COLIA1 + 1245 G > T Sp1 Binding Site Polymorphism is Not Associated with ACL Injury Risks Among Indian Athletes. Indian J Orthop 2020;54:647–54. DOI: https://doi.org/10.1007/s43465-020-00119-1

6. Kaynak M, Nijman F, van Meurs J, et al. Genetic Variants and anterior cruciate ligament rupture: a systematic review. Sports Med 2017;47:1637–50. DOI: https://doi.org/10.1007/s40279-017-0678-2

7. Flynn RK, Pedersen CL, Birmingham TB, et al. The familial predisposition toward tearing the anterior cruciate ligament: a case control study. Am J Sports Med 2005;33:23–8. DOI: https://doi.org/10.1177/0363546504265678

8. Magnusson K, Turkiewicz A, Hughes V, et al. High genetic contribution to anterior cruciate ligament rupture: Heritability ~69%. Br J Sports Med 2021;55:385. DOI: https://doi.org/10.1136/bjsports-2020-102392

9. Baker LA, Rosa GJM, Hao Z, et al. Multivariate genome-wide association analysis identifies novel and relevant variants associated with anterior cruciate ligament rupture risk in the dog model. BMC Genetics 2018;19:39. DOI: https://doi.org/10.1186/s12863-018-0626-7

10. Massidda M, Flore L, Scorcu M, et al. Collagen gene variants and anterior cruciate ligament rupture in italian athletes: a preliminary report. Genes (Basel) 2023;14:1418. DOI: https://doi.org/10.3390/genes14071418

11. Sivertsen EA, Haug KBF, Kristianslund EK, et al. No Association between risk of anterior cruciate ligament rupture and selected candidate collagen gene variants in female elite athletes from high-risk team sports. Am J Sports Med 2019;47:52–8. DOI: https://doi.org/10.1177/0363546518808467

12. Bell RD, Shultz SJ, Wideman L, Henrich VC. Collagen gene variants previously associated with anterior cruciate ligament injury risk are also associated with joint laxity. Sports Health 2012;4:312–8. DOI: https://doi.org/10.1177/1941738112446684

13. Georgiev GP, Telang M, Landzhov B, et al. The novel epiligament theory: differences in healing failure between the medial collateral and anterior cruciate ligaments. J Experiment Orth 2022;9:10. DOI: https://doi.org/10.1186/s40634-021-00440-0

14. Yu X, Hu J, Li Y, et al. ACL injury management: a comprehensive review of novel biotherapeutics. Front Bioeng Biotechnol 2024;12:1455225. DOI: https://doi.org/10.3389/fbioe.2024.1455225

15. Xiang G, Huang L, Zhang X, et al. Molecular characteristics and promoter analysis of porcine COL1A1. Genes 2022;13:1971. DOI: https://doi.org/10.3390/genes13111971

16. Kuznetsova NV, McBride DJ, Leikin S. Changes in thermal stability and microunfolding pattern of collagen helix resulting from the loss of alpha2(I) chain in osteogenesis imperfecta murine. J Mol Biol 2003;331:191–200. DOI: https://doi.org/10.1016/S0022-2836(03)00715-0

17. Chang SW, Shefelbine SJ, Buehler MJ. Structural and mechanical differences between collagen homo- and heterotrimers: relevance for the molecular origin of brittle bone disease. Biophys J 2012;102:640–8. DOI: https://doi.org/10.1016/j.bpj.2011.11.3999

18. Anjankar SD, Poornima S, Raju S, et al. Degenerated intervertebral disc prolapse and its association of collagen I alpha 1 Spl gene polymorphism: A preliminary case control study of Indian population. IJOO 2015;49:589–94. DOI: https://doi.org/10.4103/0019-5413.168765

19. Pluijm SMF. Collagen type I 1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women. Ann Rheumatic Dis 2004;63:71–7. DOI: https://doi.org/10.1136/ard.2002.002287

20. Rodrigues AM, Girão MJBC, da Silva IDCG, et al. COL1A1 Sp1-binding site polymorphism as a risk factor for genital prolapse. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:1471–5. DOI: https://doi.org/10.1007/s00192-008-0662-3

21. Jin H, Van’T Hof RJ, Albagha OME, Ralston SH. Promoter and intron 1 polymorphisms of COL1A1 interact to regulate transcription and susceptibility to osteoporosis. Human Mol Gen 2009;18:2729–38. DOI: https://doi.org/10.1093/hmg/ddp205

22. Jacob Y, Anderton RS, Cochrane Wilkie JL, et al. Genetic variants within NOGGIN, COL1A1, COL5A1, and IGF2 are associated with musculoskeletal injuries in elite male Australian football league players: a preliminary study. Sports Medicine-Open 2022;8:126. DOI: https://doi.org/10.1186/s40798-022-00522-y

23. Zhao D, Zhang Q, Lu Q, et al. Correlations Between the Genetic Variations in the COL1A1, COL5A1, COL12A1, and β-fibrinogen Genes and Anterior Cruciate Ligament Injury in Chinese Patients(a). J Athl Train 2020;55:515–21. DOI: https://doi.org/10.4085/1062-6050-335-18

24. Khoschnau S, Melhus H, Jacobson A, et al. Type I collagen alpha1 Sp1 polymorphism and the risk of cruciate ligament ruptures or shoulder dislocations. Am J Sports Med 2008;36:2432–6. DOI: https://doi.org/10.1177/0363546508320805

25. Stepien-Slodkowska M, Ficek K, Zietek P, et al. Is the combination of COL1A1 gene polymorphisms a marker of injury risk? J Sport Rehabil 2017;26:234–8. DOI: https://doi.org/10.1123/jsr.2015-0151

26. Pruna R, Artells R, Ribas J, et al. Single nucleotide polymorphisms associated with non-contact soft tissue injuries in elite professional soccer players: influence on degree of injury and recovery time. BMC Musculoskelet Dis 2013;14:221. DOI: https://doi.org/10.1186/1471-2474-14-221

27. Guo R, Gao S, Shaxika N, et al. Associations of collagen type 1 α1 gene polymorphisms and musculoskeletal soft tissue injuries: a meta-analysis with trial sequential analysis. Aging (Albany NY) 2024;16:8866. DOI: https://doi.org/10.18632/aging.205846

28. Wang C, Li H, Chen K, et al. Association of polymorphisms rs1800012 in COL1A1 with sports-related tendon and ligament injuries: a meta-analysis. Oncotarget 2017;8:27627–34. DOI: https://doi.org/10.18632/oncotarget.15271

29. Burstein D, Hoffman G, Mathur D, et al. Detecting and adjusting for hidden biases due to phenotype misclassification in genome-wide association studies. medRxiv 2023; 2023.01.17.23284670. doi:10.1101/2023.01.17.23284670 DOI: https://doi.org/10.1101/2023.01.17.23284670

30. Borzemska B, Cięszczyk P, Żekanowski C. The genetic basis of non-contact soft tissue injuries-are there practical applications of genetic knowledge? Cells 2024;13:1828.

31. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700. DOI: https://doi.org/10.1136/bmj.b2700

.32. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603–5. DOI: https://doi.org/10.1007/s10654-010-9491-z

33. Martorell-Marugan J, Toro-Dominguez D, Alarcon-Riquelme ME, Carmona-Saez P. MetaGenyo: a web tool for meta-analysis of genetic association studies. BMC Bioinformatics 2017;18:563. DOI: https://doi.org/10.1186/s12859-017-1990-4

34. Prabhakar S, John R, Dhillon M, Anand A. Are COL1A1 gene polymorphisms associated with anterior cruciate ligament tear in the Indian population? Results of a preliminary case-control study. Muscles Ligaments Tendons J 2018;8:015. DOI: https://doi.org/10.32098/mltj.01.2018.03

35. Ficek K, Cieszczyk P, Kaczmarczyk M, et al. Gene variants within the COL1A1 gene are associated with reduced anterior cruciate ligament injury in professional soccer players. J Sci Med Sport 2013;16:396–400. DOI: https://doi.org/10.1016/j.jsams.2012.10.004

36. Posthumus M, September AV, Keegan M, et al. Genetic risk factors for anterior cruciate ligament ruptures: COL1A1 gene variant. Br J Sports Med 2009;43:352–6. DOI: https://doi.org/10.1136/bjsm.2008.056150

37. Gibbon A, Raleigh SM, Ribbans WJ, et al. Functional COL1A1 variants are associated with the risk of acute musculoskeletal soft tissue injuries. J Orthop Res 2020;38:2290–8. DOI: https://doi.org/10.1002/jor.24621

38. Bulbul A, Ari E, Apaydin N, Ipekoglu G. The impact of genetic polymorphisms on anterior cruciate ligament injuries in athletes: A meta-analytical approach. Biology 2023;12:1526. DOI: https://doi.org/10.3390/biology12121526

39. Mann V, Hobson EE, Li B, et al. A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest 2001;107:899–907. DOI: https://doi.org/10.1172/JCI10347

40. Thornton G, Shrive N, Frank C. Ligament creep recruits fibres at low stresses and can lead to modulus‐reducing fibre damage at higher creep stresses: a study in rabbit medial collateral ligament model. J Orthop Res 2002;20:967–74. DOI: https://doi.org/10.1016/S0736-0266(02)00028-1

41. Sundberg A, Högberg J, Tosarelli F, et al. Sport-specific injury mechanisms and situational patterns of ACL injuries: a comprehensive systematic review. Sports Med 2025;55:2489–527. DOI: https://doi.org/10.1007/s40279-025-02271-w

42. Udomsinprasert W, Yuktanandana P, Tanpowpong T, et al. Adiponectin gene rs1501299 polymorphism is associated with increased risk of anterior cruciate ligament rupture. Biomed Rep 2019;10:133–9. DOI: https://doi.org/10.3892/br.2018.1180

43. Candela V, Longo UG, Berton A, et al. Genome-wide association screens for anterior cruciate ligament tears. J Clin Med 2024;13:2330. DOI: https://doi.org/10.3390/jcm13082330

44. Chen B, Cole JW, Grond-Ginsbach C. Departure from hardy weinberg equilibrium and genotyping error. Front Genet 2017;8:167. DOI: https://doi.org/10.3389/fgene.2017.00167

45. Goodlin GT, Roos AK, Roos TR, et al. Applying personal genetic data to injury risk assessment in athletes. PLoS One 2015;10:e0122676. DOI: https://doi.org/10.1371/journal.pone.0122676

46. Collins M, September AV. Are commercial genetic injury tests premature? Scand J Med Sci Sports 2023;33:1584–97. DOI: https://doi.org/10.1111/sms.14406

47. Borzemska B, Cięszczyk P, Żekanowski C. The genetic basis of non-contact soft tissue injuries-are there practical applications of genetic knowledge? Cells 2024;13:1828. DOI: https://doi.org/10.3390/cells13221828