How is "Anterior Cruciate Ligament Rupture" encoded by the genome?
It is well-known that regular sports and physical activities are important to maintaining our health, but it is also true that all sports carry at least some risk of injury. For example, injuries to the anterior cruciate ligament (ACL) of the knee commonly occur in sports that require pivots. Unfortunately, this injury is not without severe consequences as the ACL never fully heals, and studies report between 10% and 90% of all patients develop premature osteoarthritis.
Studies have shown that the angiogenesis signaling pathway plays an important role in the healing process of an ACL. Thus, dysregulation of this process may have negative consequences on tissue capacity. Several growth factors and cytokines regulate the angiogenesis pathway— principally, the vascular endothelial growth factor (VEGF). Kinase insert-domain receptor (KDR), encoded by the KDR gene, is the main signalling receptor for VEGFA and mediates the mitogenic and chemotactic actions of the ligand. Genetic variations within VEGFA and KDR were recently associated with the risk of ACL ruptures or Achilles tendinopathy (TEN) in a South African (SA) and Caucasian population. However, there is currently no data for the incidence rate of ACL ruptures or TEN in the South African population. Thus, this study aimed to identify if the previously associated functional VEGFA and KDR variations are similarly associated with the risk of ACL ruptures in a South African population.
Researchers conducted a case-control genetic association study on 100 controls and 98 patients with surgically-diagnosed ACL ruptures, including with non-contact mechanisms of injury (NON). All participants were genotyped for five functional polymorphisms in the VEGFA gene and KDR gene. The results suggested that the GG genotype for rs2071559 (KDR) was associated with a 2.8-fold increased risk of ACL rupture (all mechanisms of injury) and a 3.3-fold increased risk of non-contact ACL ruptures in the male participants. Additionally, the AG genotype was associated with a 1.9-fold reduced risk of ACL rupture in male participants. The rs2071559 polymorphism (A→G) is known to reduce KDR transcription and lower the protein level of the receptor, resulting in reduced activity of VEGFA, which regulates the angiogenesis pathway. Therefore, insufficient angiogenic response following mechanical loading may potentially impair the ability of the ligament to adapt and heal, thus resulting in weakened tissue. Moreover, it has been reported that individuals with copies of both alleles (AG) may potentially be able to better regulate the biochemical response to loading without the detrimental consequences of having either too much or too little protein. While other studies have shown women to be more at risk of ACL ruptures, this study particularly didn’t have enough female participants.
This is the first study implicating variations within the KDR gene with an associated risk of ACL ruptures in a South African population and successfully identified the association between the rs2071559 polymorphism and risk of ACL ruptures in male participants. Read more about the study here: https://www.ncbi.nlm.nih.gov/pubmed/28502223
Are you interested in learning more about your genetic tendency for anterior cruciate ligament ruptures? You can login to your Genomelink dashboard to see this new genetic trait.
