The role of <i>SP1</i> (<i>rs1800012</i>) 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.