Environmental risk factors associated with ACL injury are generally well known and understood, whereas the genetic basis is still largely debated. A recent study, published in the British Journal of Sports Medicine, aimed to determine the lifetime genetic risk for ACL rupture.
Rupture of the anterior cruciate ligament (ACL) is a common injury resulting from contact sports and in military personnel. Such injuries can vastly reduce health-related quality of life and can causes a 10-fold increase in the risk of osteoarthritis of the knee. Beyond environmental risk factors, there is also a strong genetic basis linked to ACL rupture. Factors such as bone geometry, joint laxity and hypermobility all play a significant role.
Twin studies are well suited to uncover the genetic basis of different traits. Identical and fraternal twins share 100% and 50% of their genes, respectively. Thus, a trait which is shared more frequently between identical twins than between fraternal twins is likely to have a genetic basis. Well validated twin models have been produced to evaluate these factors.
This longitudinal study followed twin pairs from the Swedish Twin Register across 30 years. 88,414 identical and fraternal twin pairs were included to determine familial risk scores and the heritability of ACL rupture. Clinical information from Swedish hospitals was also included.
Heritability of ACL Injury
In total, 1395 participants were diagnosed with ACL rupture. The overall heritability of ACL rupture was 69%, a remarkably high genetic contribution. For comparison, the overall heritability for cancer is ~33% and for eye colour is ~98%.
Familial risk was defined as the excess risk ratio (RR) of the second twin experiencing an ACL rupture, given than the first twin had experienced such a rupture. This was higher in identical twin pairs (RR of 8.6) compared to fraternal twins (RR of 1.9). This implies a strong genetic contribution for both groups, suggesting family clustering. Understanding this genetic basis may improve counselling of athletes whose close relatives have experienced ACL rupture.
These findings have several important implications. Firstly, familial risk is currently neglected in studies of injury prevention and treatment programmes. As fraternal twins share ~50% of their genes, these results imply that preventative strategies may be particularly important for those whose close relatives have already experienced a cruciate ligament rupture. Specifically, these results suggest that an individual’s risk could increased by ~20-140% if a sibling has an ACL rupture.
The study also found that heritability scores increased from the age of 35 and onwards in both identical and fraternal twins. This could imply a genetically determined early degeneration of joint tissues. Such degenerative processes would also increase the risk of osteoarthritis and should be explored further.
Specific anatomical variations in knee bone shapes have previously been reported to increase the risk of ACL injury. As these variations are largely genetically determined, they may serve as as proxy for the overall genetic contribution.
Strengths of the Study
The study was based on the largest twin register in the world, and had limited selection bias. This allows a unique 30-year twin study, measuring the genetic basis of ACL rupture. Being based in Sweden, the findings are likely representative of industrialised countries with healthcare systems bearing equal access to all inhabitants.
Weaknesses of the Study
The injury codes used in the study did not differentiate between ACL and posterior cruciate ligament ruptures. While ACL rupture is the most common knee injury, this misclassification is still a limitation. Unfortunately, the study also could not determine which mechanisms contributed to the high genetic risk observed. For example, the patient data did not differentiate between contact and non-contact injuries, or partial versus complex tears. This limits the therapeutic implications of the findings.
Furthermore, the twin models used in the study rest on the assumption that environmental factors are relatively similar across identical and fraternal twins. However, for example, environmental factors such as shared sports participation may be more common among identical twins than in fraternal twins. Unfortunately the patient data lacked information on these environmental risk factors, so the models used could not be adjusted.
This study provides important implications for individualised injury prevention programmes in the near future. This data suggests information regarding ligament injury of near relatives must be considered when developing and validating risk prediction models from now on.