Anterior Cruciate Ligament Ruptures gene explained

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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. Injuries to the anterior cruciate ligament (ACL) of the knee commonly occur during pivoting and cutting sports. 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 signalling pathway plays an important role in the healing process of an ACL. Thus, dysregulation of this process may potentially have negative consequences on tissue capacity. The angiogenesis pathway is regulated by several growth factors and cytokines; principally the vascular endothelial growth factor (VEGF). In particular, the A isoform of this protein, encoded by the VEGFA gene, is considered to be the most potent. 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.

Polymorphisms within VEGFA and KDR were recently implicated with risk of ACL ruptures or Achilles tendinopathy (TEN) in a South African (SA) and Caucasian population. Unfortunately, there is currently no data available for the incidence rate of ACL ruptures or TEN in the South African population. Thus, the aim of this study was to identify if the previously associated functional VEGFA and KDR polymorphisms 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.

It has been reported that females tend to have an increased risk of ACL ruptures, however, the sample size of female participants (n=17) was not sufficient to show the sex-specific genetic association clearly due to the method of recruitment. Although some other limitations also need to be considered, this is the first study implicating polymorphisms 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:

It’s every athlete’s nightmare:  the dreaded Anterior Cruciate Ligament Rupture, commonly known as an ACL tear. Participants of field and court sports (which typically involve quick pivots and lateral movements) are most likely to suffer an ACL injury, though they can happen to anyone. A recent study has identified specific genes that may predispose a person to an ACL tear.  This will prove invaluable knowledge to athletes who may – among other options -- choose to wear a lateral knee brace if they know they are thus predisposed. This is yet another example of how genetic science is helping us understand our genetic traits so that we can take practical steps to protect our health.


What is the Gene Associated with ACL Tears?


Not one, but two genes have been identified with ACL tears:

1.       The Vascular Endothelial Growth Factor – A isoform (VEGFA) gene

2.       The Kinase Insert-Domain Receptor (KDR) gene 

If you recognize these terms or otherwise speak the language of Science, you can read the study that discovered this relationship here.

Can ACL Tears Be Caused by My Genetics?

Your genes can create a predisposition to an ACL tear.  There must also be an event --  some kind of awkward movement or an accident -- that places more strain on the ligament than it can endure.  Your genes play a role in maintaining the homeostatic health of your ACL.  Homeostasis refers to the body’s ability to keep parts of the body within healthy limits given changes in environment/circumstances. Any bodybuilder will tell you that when load is placed on the body, it compensates by increasing muscle fibers, bone density, vascularity (arteries and veins), and other structures. This is also true for the parts of the knee, including the ACL.  Increased demand on the ACL (short of actual tearing) will cause the body to set a higher homestatic baseline for your ACL and increase its resilience.

A study discovered a connection between your genes and the body’s natural processes for maintaining the resilience of your ACL.  Out of a study population of 98 patients, the genes in question were linked to:

·       3.3X more ACL injuries from non-contact trauma

·       2.8X increase in all ACL injuries

These results provide solid support for the theory that there is a relationship between your genes and ACL injuries.


Are ACL Tears Serious?           

Only some ACT Tears are serious – it depends on how extensive the tear is. The ACL is a ligament that looks like an “X” and connects the thigh to the shin. Because the ACL is a ligament, it cannot repair itself.   And healthy knees are fundamental to even a normal walking gait.  So, it’s not the kind of injury that you can ignore.  ACL tears over time can also lead to related conditions, like osteoarthritis. For mild ACL tears, physical therapy can sometimes limit its impact.  With more serious ACL tears, the only way to restore movement is surgery – which is never guaranteed to solve the problem.  (This is why ACL injuries often end the careers of professional athletes.)


Why Are Females More Likely to Suffer an ACL Tear?

 Statistically, females are more likely to suffer ACL tears than males.  This is a mix of physiology, as well as environment (including sports and activities females pursue at a higher rate than males.) The aforementioned study did not include a large enough study population to make findings related to sex.  Thus, we cannot say what role genetics plays in the higher rate of ACL injuries among females. However, at the incredible rate at which genomic science is moving, more findings are sure to come. Genomelink can provide you with specific information about whether you have the “ACL Tear Gene”, as well as dozens of other fascinating traits.   All you have to do is take your DNA data from providers like Ancestry and 23andme, and upload them to Genomelink for a complete analysis.

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.

Photo by chuttersnap on Unsplash

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