The Injury Bug: The genetic factors involved in ACL and Achilles injuries.

I’ve got a confession to make. 

As a long suffering (still!) New York Knicks fan, I cringe everytime Derrick Rose drives to the basket, gets banged around, and emerges from the scrum limping for a few steps. If he goes to ground — for whatever reason — and gets back up with a grimace, I hold my breath for a few seconds.

The same goes for Kevin Durant — though to a lesser degree since he plays for the wrong New York team. I can recognize a singular talent when I see it and selfishly want to witness it for as long as possible. But watching those long lanky legs accelerate then stop and pop makes me more than a little uneasy.

I really hate seeing injuries happen real time. The whole Jamal Murray thing traumatized me for days. And it’s not just basketball. The sight of Ronald Acuna Jr. running top speed trying to make a spectacular catch only to hobble for a couple of steps before crumbling to the ground hurt me through the screen. Same goes for footballers like Virgil Van Dijk after being taken down by a reckless challenge.

It’s nerve-racking. Never-been-injured athletes all seem to be playing the same wait-and-see crapshoot. And the thing is, I know I have good reason to be a bit apprehensive when formerly injured players plant their feet for a cut in order to move in some unexpected direction. Once players get injured, chances are it’ll be back, sometimes in the form of those non-descript “nagging” injuries. Other times, it’s a whole unpleasant redux of the original trauma. No matter how you twist and turn it, it hurts.

There’s a term for it. The injury bug. Only problem is that it’s not a bug at all. It may come down to genetics.

Injuries are not all or nothing events. Tendon and ligament tears occur across a spectrum of severity and are categorized as Grade 1, Grade 2, and Grade 3 injuries. Using Achilles tendons as an example, the following list shows how injuries are broken down according to the extent of the damage:

  • Grade 1 – Mild, with few torn tendon fibers. It produces some tenderness and sometimes minor swelling.
  • Grade 2 – Less than half of tendon fibers torn, causing pain, tenderness and some swelling. Most activities (walking, running or jumping) are accompanied by pain.
  • Grade 3 – A full rupture, often with a “pop” or other sensation in the calf area. You no longer have the power to walk, much less run or jump.

Any discussion about ACL or Achilles injuries should begin with collagen and any discussion about collagen should begin with what’s called Type I Collagen since it’s the most prevalent form in the human body. It tends to be considered the prototype for the entire collagen family which consists of 28 distinct versions. It normally comprises a chain of amino acids with a glycine making an appearance every third spot (e.g. Gly-X-Y-Gly-A-B-Gly…) It’s the presence of glycine that allows collagen to assume its signature, triple-helical formation. Another amino acid that shows up regularly — hydroxyproline — stabilizes the molecule.

The twisting nature of collagen fibers provide additional tensile strength and the finished product is relatively rigid and asymmetrical. If you’ve ever seen a rope, you have a decent idea of the general structure collagen’s triple helix takes. Its structure provides much more stregth than if it were merely a collection of fibers all running parallel. It’s a strategy that is commonly used in industrial steel rope where the helical formation of metal fibers around the core provides strength, flexibility, and the ability to handle bending stresses.

Tendons and ligaments consist mostly of Type I collagen (60-85%). The remainder consists of a mixture of glycoproteins and other collagens. The two also share a general hierarchical structure. Together, they form a long fiber that, on tendons, is spotted with cells called tenocytes along its length. These cells play a key role in maintaining a tendon’s health. Ligaments have slightly less collagen and have a higher percentage of proteoglycan in its extracellular matrix.

Treatments for severe ACL and Achilles injuries involve surgery followed by a lengthy rehab designed to allow the tears to heal and then gradually acclimate them to bearing weight again. While specific exercises have remained consistent over the last decade, new technologies have aided in the rehabilitation process. 

“Some of the newer options include BFR (Blood Flow Restriction) that allows us to strengthen muscles with lower resistance load,” says Dr. Aimee Diaz, Assistant Professor of Clinical Physical Therapy at the University of Southern California and USC Director of Physical Therapy Associates. “Collegiate and professional athletes likely have access to an AlterG which is an anti-gravity treadmill that takes weight off to allow patients to start walking or jogging while limiting their weight bearing and impact.”  

Video technology and wearables can be used to get data regarding movement analysis, activity, and sleep. Diaz points out that it has become increasingly common to assess an athlete’s confidence before returning to a sport. ACL research data suggests that decreased confidence can contribute to increased risk of injury upon return to sport.


Even though ACL and Achilles injuries seem to have become more common, when compared to the numbers of people engaged in sports — professional or amateur — actual injuries make up a small portion of the population. The majority of athletes can play their entire careers without suffering traumatic tendon or ligament injuries. So the million dollar question that arises is why do some players get injured while others do not? And if you want to add a follow up: Why do players who’ve suffered injuries seem more prone to them.

There are a few theories that explain why tendon/ligament injuries occur. They have evolved over time, in keeping with advances in understanding in fields as diverse as neuroscience and immunology. In the process, the understanding of injury shifted from a localized physical trauma one that involves multiple factors working in concert. 

The first theory to gain significant traction was proposed in 1978 and is familiar to just about every sports fan, though without the technical jargon. Referred to as the Mechanical Theory, it entails repeated and excessive strain on the tendon/ligament which leads to microinjuries and after time, culminates in an observable injury. In other words, it’s a question of good ol’ wear and tear. It intuitively makes sense, though that may be because it’s the explanation heard the most. 

Sometimes, wear and tear isn’t enough to explain a tendon or ligament injury. In the case of Kevin Durant’s ruptured Achilles, there was an additional factor that probably played a role.

“The highest risk factor for an injury is a prior injury to that body part,” says Diaz. “We also may see increased risk of injury to another body part when coming back.”

According to Heather Moore, a physical therapist writing in the Philadelphia Inquirer at the time of Durant’s injury, “Did Durant’s calf strain cause his Achilles rupture? The answer is yes. The reason that I can say this is because of compensation. This is something that I treat all the time because compensation is a common cause of injuries — not always a traumatic rupture like Durant’s, but it is one of the main causes of knee pain and low back pain.”

For Durant, the initial calf strain injury that he suffered in the playoffs kept him out of action for nearly a month. Things took a negative turn while making his return, though nobody knew it. While rushing his rehab for that injury, Durant may have made minor subconscious adjustments in the way his body moved as a way of compensating for his calf.

Tendons have the ability to withstand strain of up to 10x an individual’s body weight. That said, they are far from indestructible. On a basic level, they are not very different from other elastic materials used to join two objects. Exert enough strain, either all at once or over time, and it will eventually snap. However, there is a major way the human body’s connective tissues differ from industrial materials. Tendons and ligaments have the ability to regenerate and repair damage. It’s when this process falters that injuries occur.

According to the mechanical theory, tendinopathies feature a form of failed healing responses and contain a haphazard proliferation of tenocytes. A closer look would reveal a broad degeneration of tendon cells and an increase in non-collagenous matrix in damaged tissue. Where there was once order in the intracellular matrix, disorder becomes more prominent. 

Visually, the collagen fibers appear shiny, white and firm. Under normal circumstances, collagen fibers run parallel to each other. During tendinopathy, that pattern is lost. In its place, collagen appears irregular and crimped. Moreover, it suffers decreases in diameter and density. Even the composition of the injured tendon or ligament shows alterations as levels of collagen III and V, which are temporarily elevated during the healing process but dissipate later, become permanently high. The changes result in a less durable product.

Some recent studies have suggested a longer time frame for the injury. Prior to showing symptoms, researchers believe that tendons begin degrading in the early phases of loading. The strain isn’t enough to do immediate damage so people are basically asymptomatic but under the hood, what you’d see is collagen degradation exceeding synthesis. Reaching a tipping point is essentially just a question of simple mathematics.

“This finding implies that the symptoms of tendinopathy corresspond to a late phase or a prolonged disease or that abnormally high collagen turnover might be a potential risk factor for tendinopathy rather than a direct consequence of the disease.”

One of the things working in the mechanical theory’s favor is its intuitiveness. It makes perfect sense and jibes with what our eyes have told us all our lives – if you put enough strain on something, it will break. But if you peek beneath the hood of the theory’s shiny exterior, there are some glaring short-comings. The most telling is also, perhaps, the most basic. 

Using ACL injuries as an example, a study compared reporting from the International Olympic Committee (IOC), the National Collegiate Athletics Association (NCAA), data from Europe and New Zealand. They concluded that the overall rates that athletes were suffering from ACL injuries had remained constant over time. 

This relatively innocuous data point indicates that for all of the research and mitigation strategies that have grown from the mechanical theory, very little has changed. This seems to indicate that there are other factors at play not addressed by biomechanics alone. 

Over the years, a number of theories have been explored in attempts to better understand how and why ligament and tendon injuries occur. Explanations range from out of control inflammatory responses driven by cytokines to cells hitting the self-destruct button due to repetitive strain. One of the more promising possibilities is genetics. 

Going back to the very beginnings of modern genetics in the 20th century, the promise of understanding and manipulating our inherited traits has existed. From the misguided eugenics movement to the nascent attempts at gene therapy, science has always looked towards genetics as the vanguard of the new frontier. In order to understand today’s approach to genetics and its limits, it’s worth rewinding the videotape (remember those?) to 1990. 

Back then, the first installment of the Bush White House Dynasty was halfway through his one and only term as U.S. President, Home Alone was scoring big in the box office, and the Nintendo Game Boy was the only handheld game console on the market. At that time, a geneticist by the name of Francis Collins (the same man who during the COVID-19 pandemic) was serving as the director of the National Human Genome Research Institute (NHGRI), one of the 27 institutes and centers at NIH.He spearheaded a project that would take advantage of the rapidly evolving genetic technology that would allow them to sequence the entire human genome. They called it the Human Genome Project. It was wildly ambitious, especially since nobody really knew how massive our exceptional genome was. (Turned out that our genome was neither exceptional nor massive.) There was some skepticism. The whole human genome? C’mon.

At the same time, the promise of the HGP wasn’t lost on anyone if they could pull it off. If the entirety of a person’s DNA could be mapped out then people’s traits could be as well. In terms of diseases, that meant it was theoretically possible to pinpoint exact genes reponsible for non-infectious diseases and potentially correct them. On paper it seemed straightforward enough. Unfortunately, real life plays by different rules.

When the announcment that the Human Genome Project was drawing to a close was made, it was clear that decoding our DNA hadn’t gone completely as planned. For starters, significant patches of genomic real estate remained in darkness. Not only that, even with the vast tracts that were decoded, the combination A-C-G-T triplets that comprised genes (sometimes referred to as cassettes) did not all line up according to a one-gene-one-enzyme relation. While the hypothesis had been questionable for a long time, it seemed all the more unlikely with so much of the human genome spelled out. There were so many variables. 

For example, entire swaths of DNA could be influenced by distant strips of genetic code just as effectively as adjacent ones. Much later, researchers learned that the methylation of DNA (caused by environmental factors) could significantly influence what genes were expressed and that the temporary changes could be passed onto offspring. In other words, figuring out which part of the genome determines which disease develops is messier than a literal reading of our genetic code.

Still, the HGP managed to decode enough to provide scientists with tantalizing clues and a trove of data that just needed interpreting. If nothing else, it was a very good start.

Growing interest in the role of genetics in tendon and ligament injuries took two separate paths. In terms of tendinopathies, early studies linked individuals with blood group type O among Hungarian and Finnish populations. The fact that the location of the gene for blood type and a gene thought to play a role in determining the structure in the extracellular matrix of tendons. While subsequent studies reported contradictory evidence linking blood group with tendinopathies, the proverbial cat was already out of the bag and researchers would continue searching for genes responsible for injuries.

One of the most popular strategies for exploring the links between genetics and injuries entails working backard from the injury. Since tendon and ligament damage entails collagen, the logical thing to do is to identify the genes responsible for its production and to investigate whether they play a role in injuries. There are a lot of them so the first task researchers faced was narrowing down the list of candidates. They settled on a handful: COL1A1; COL5A1; COL12A1; COL14A1; TNC; MMP3; TGFB1; GDF-5.

It didn’t take long for scientists to whittle that down further, finally choosing to focus on COL1A1, COL5A1, and TNC. With a shortlist in hand, they were able to get as granular as identifying single nucleotide polymorphisms (SNPs) — essentially a single base pair change that doesn’t end up changing the gene’s end product — that may alter the expression of the gene. For example, in the case of COL5A1, the change entails swapping a cytosine to thymine.

COL5A1 is believed to play a rolein both Achilles and ACL injuries. It codes for the alpha-chain of Type V collagen. Even though it is a minor collagen, it plays an important role in the organization and regulation of Type I collagen.

The TNC gene is another candidate risk factor for tendon or ligament damage. Unlike COL5A1, TNC doesn’t code for collagen at all. It’s involved in the production of an extra-cellular matrix protein, Tenascin-C, that binds to other proteins in the matrix and acts as a scaffold for the strands of collagen. It regulates the components that comprise the matrix.

COL1A1 research has provided contradictory data, at best. 

“The research seems to be more consistent with the COL5A1 gene,” says Dr. Calvin Hwang, sports medicine physician at Stanford Health Care. “Patients with one particular genotype, the CC variant, have been shown to have lower rates of tendon-ligament injuries, including Achilles tendon rupture, ACL tears, and tennis elbow. Again, this is only association and not causation.”

According to Hwang, there are a host of issues that need to be addressed before anything definitive can be said about the role of genes in tendon and ligament injuries. This is because there is no way to definitively prove causation with these studies at this point, only associations. Randomizing someone to a particular genotype remains a challenge.What’s more, there is the possibility of a confounder, e.g. people with a certain genotype are also more likely to have another reason to be at higher or lower risk for injury and is the actual reason for the change in risk.

Recently, the genetic theory has expanded beyond just searching for genes associated with collagen production. A number of studies have explored the role injuries play in altering gene expression at the site of trauma. An American Journal of Sports Medicine study took biopsies of torn ACLs intra-operatively and stained the torn ligament. The researchers were looking for gene expression of various ligament healing factors, including COL1A1 and COL5A1. They found increased expression of these genes in the torn ligaments of patients with acute injuries compared to intermediate and chronic injuries.

Another particular area that has shown promise involves non-coding RNA (ncRNA). Normally, RNA is responsible for converting the code carried by DNA into proteins in a multistep process. In the same way, there are significant regions of DNA that do not code for anything, not all RNAs directly contribute to protein synthesis. Labeling these strands as “junk”, as they once did with DNA, is misleading. Research has shown that these areas play important roles in the regulation of protein synthesis.

There is growing evidence that ncRNAs regulate processes in healthy and diseased tissue. According to Ilaltdinov et al., a better understanding of this may provide new targets for therapy down the line.

Indeed, genetic approaches to soft musculoskeletal injuries promise to revolutionize the mitigation, diagnosis, and treatment of injuries. The growing proactice of genetic screening may one day test for SNPs, such as teh CC variant of the COL5A1 gene associated with tendon or ligament damage. The information can then be used to design workouts that cater to their phenotype. More dramatically, the possibility of utilizing future versions of CRISPR to permanently correct harmful SNPs. The recent clinical trials of Intellia’s treatment for Transthyretin Amyloidosis proves that CRISPR can be introduced into the body and be used to correct mutations long term. Unfortunately, the sports world is long way from being able to capitalize on most genetic insights currently available. 

“At least from a sports medicine perspective, the challenge is figuring out what we would do with this information,” says Hwang. “There’s currently no effective way to manipulate or change a person’s genes to alter expression and change the risk of injury.”

WORDS: Marc Landas.

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