Collagen Type V alpha 1 chain and alpha-actinin-3 variants predict knee ligament injury risk in professional football players.

To investigate whether polymorphisms in collagen Type V alpha 1 chain (COL5A1), actinin alpha 3 (ACTN3) and angiotensin-converting enzyme (ACE) are associated with susceptibility to anterior cruciate ligament (ACL) and medial collateral ligament (MCL) injuries in professional football players. Between 2017 and 2025, 122 male professional football players were enroled. Genotyping was performed for COL5A1 rs12722, COL5A1 rs10628678 (formerly rs71746744), ACTN3 rs1815739 and ACE rs4341. Players were classified based on the history of ACL/MCL injuries and prospectively monitored injuries. Logistic regression was used to calculate odds ratios and 95% confidence intervals. Forty-three players sustained ACL or MCL injuries (15 before and 28 after team enrolment), including 17 ACL injuries. The COL5A1 rs10628678 dominant model (-/-+AGGG/- vs. AGGG/AGGG) was associated with an increased risk of overall knee ligament injury. The ACTN3 rs1815739 recessive model (XX vs. RR + RX) was associated with overall ligament and ACL injuries. Combined genotype analysis revealed that players with COL5A1 rs10628678 -/- and ACTN3 rs1815739 XX had the highest risk. When a simplified combined risk variable was defined (COL5A1 rs10628678 AGGG/- or -/- plus ACTN3 rs1815739 XX), this group accounted for 18.9% of the cohort and showed a significantly higher prevalence of ligament (70.7% vs. 29.3%) and ACL (30.4% vs. 10.1%) injuries. Logistic regression confirmed an independent threefold increase in risk. COL5A1 and ACTN3 variants may be associated with susceptibility to knee ligament injuries. Notably, this study suggests that both ligament-related (COL5A1) and muscle function-related genetic characteristics (ACTN3) may jointly influence injury risk. A simplified combined risk model identified nearly one-fifth of players as genetically high-risk, with an approximately threefold higher likelihood of ligament injury. These findings suggest that a single genetic test may help identify athletes at elevated risk who could potentially benefit from targeted preventive neuromuscular training strategies. Level IV.