Polygenic and Multifactorial Contributions to Knee Injury Susceptibility

Abstract

Physical activity is widely recognized for its health benefits, increasingly so due to the sedentary lifestyle and high caloric intake of the global population. Regular exercise has numerous benefits for human health and well-being, including the reduction of cardiovascular disease, diabetes, various forms of cancer, and the improvement of mental health. However, sport-related injuries occur most frequently within the physically active group of people. This paper explores factors that increase risk for knee injury beyond participation in physical activities, such as genetic and heritable components, biomechanical and anatomical alignment, variation in genes, and connective tissue disorders. This paper also analyzes various potential solutions to identifying risk factors and preventing knee-associated injuries, while discussing limitations in accessibility of these solutions and treatments to the public. Finally, a personal experience is highlighted for specific insight on what it is like to live with knee-related pain and injury.

Background

From 1999 to 2008, an estimated 6,664,324 knee injuries were presented to U.S. Emergency departments, at a rate of 2.29 knee injuries per 1,000 people. When observing sport-related injuries, anterior cruciate ligament (ACL) tears are widely recognized, with an estimated 200,000 to 400,000 recorded ACL tears occurring annually in the United States, and more than 2 million worldwide. While external forces can be the primary cause of knee injuries, our understanding and advancements in science are constantly evolving, and it has become increasingly important to address how polygenic factors and a multifactorial component contribute to knee related injuries.

Research shows that up to 69% of ACL injury susceptibility is hereditary, where specific polymorphisms (notably variants in collagen genes) result in an increase in the likelihood of sports-related ligament and tendon injuries. It is through the understanding of these hereditary and multifactorial predispositions that can allow for improved injury prevention efforts. However, as of now, commercially available genetic tests remain premature, and current evidence is largely derived from candidate gene studies with limited sample sizes and genetic diversity.

The question now starts to revolve around how we can promote widespread educational information on the topic, while creating accessible and commercially available resources for the population’s awareness of possible genetic predispositions, with the objective to increase injury prevention and decrease overall knee-related injuries.

Polygenic factors

“Polygenic” refers to a single physical trait or characteristic that is controlled by multiple, independent genes rather than just one. Thus, polygenic diseases are caused by the joint contribution of a number of independently acting or interacting polymorphic genes (genes that exist in multiple alleles across a population).

Individuals who sustain ligament injuries through non-contact mechanisms have, on average, higher cumulative polygenic risk scores than those whose injuries occurred through direct contact. For instance, epidemiological evidence has consistently shown that a considerable proportion of ACL injuries occur without direct contact, most often during rapid acceleration, pivoting, or landing maneuvers. Ligaments are primarily composed of type I and type III collagen, which together maintain tensile strength, elasticity, and resistance to mechanical stress. The gene COL5A1 is a collagen type V alpha 1 chain gene, which plays an important role in regulating fiber diameter and the assembly of collagen fibers. Polymorphisms within this gene have shown to impact the classic form of Ehlers-Danlos syndrome, characterized by joining hyper mobility and other joint dysfunctions. Furthermore, polymorphisms in the COL1A1 gene can alter and consequently affect the collagen type I properties, leading to increased susceptibility to injuries. First discovered in 1996, a frequently studied genetic variation is a G to T point mutation lying within the first intron of the gene, altering shape, which affects the binding site for the transcription factor Sp1.

On the other hand, genetic polymorphisms in non-collagenous extracellular matrix (ECM) proteins and matrix remodeling enzymes significantly alter connective tissue integrity, predisposing individuals to tendon and ligament tears. These variations typically lead to altered mechanical strength, elasticity, or accelerated degradation of tissues like the ACL.

Lastly, genes that dictate the baseline inflammatory profile (e.g., cytokines) can slow healing efforts and increase vulnerability to chronic wear and tear, eventually predisposing individuals to conditions like knee osteoarthritis (OA). Knee OA is a multifactorial disorder with a polygenic genetic architecture, which can make understanding the genetic origins of knee OA challenging. Specifically, disrupted cell signaling cascades trigger knee OA by fundamentally uncoupling tissue repair from inflammation. In healthy joints, TGF-β binds to specific receptors and activated intracellular SMAD2/3 proteins to maintain cartilage and prevent hypertrophy (cellular enlargement). During OA progression, altered receptor use contributes to the disruption of this protective cascade. When protective TGF-β signals are silenced and pro-inflammatory pathways dominate, this can lead to enzyme overexpression and matrix destruction, where an influx of Matrix Metalloproteinases (MMp’s) and ADAMTS enzymes are expressed, and these enzymes break down the structural network of type II collagen and aggrecan in the knee.

Multifactorial elements

“Multifactorial” refers to a condition, trait, or outcome that is caused or influenced by a combination of different elements. In medicine and genetics, complex diseases can result from the interaction of polygenic genes with lifestyle and environmental factors.

Biomechanical alignment is the optimal positioning of the body’s bones, joints, and muscles, where physical stress can be evenly distributed to prevent injury, reduce joint wear, and improve athletic performance. Anatomical factors such as Q-angle, pelvic width, and lower-limb alignment are all involved in biomechanical alignment of the knee.

The quadriceps (Q) angle is formed by the Q line of pull from the middle of the patella to the anterior superior iliac spine. The average Q angle is 14 degrees in men and 17 degrees in women. Women typically have a wider pelvis, which affects alignment of the knee joint, and explains where there is a wider Q angle compared to men. Excessive increase and decrease in Q angle affects the knee extensor mechanism and can cause various complications over time.

In a “balanced knee,” body weight is divided evenly across both the inside (medial) and outside (lateral) knee compartments. When the leg is not perfectly straight, the weight-bearing axis of the leg is not balanced, leading to overload on one side which can be associated with ligament, cartilage, and meniscus problems. In the “bow-legged” or varus knee, the majority of bodyweight passes through the inside (medial) of the knee. These effects can be worsened by obesity, overuse, or concurrent joint problems. In a “knock-kneed” or valgus patient, the outside (lateral) of the knee can be overloaded in the same manner. This can lead to structural abnormalities that are worsened by other knee pathologies.

In order to diagnose malalignment of the lower extremity, a doctor needs to conduct a thorough examination of the knee and perform a series of tests to check overall alignment of the limb. Certain tests may also be utilized to determine the extent of the issue and the next course of action, which may include X-rays or an MRI.

Patella alta and trochlear dysplasia are key anatomical factors causing chronic patella instability and can significantly increase risks of dislocation, frequently requiring surgical intervention such as a trochleoplasty or tibial tubercle osteotomy. Trochelar dysplasia is an anatomical abnormality of the knee where the normal, deep V-shaped groove at the end of the femur is abnormally flat, shallow, or even convex. Patella alta is a knee condition where the kneecap sits abnormally high in relation to the thigh bone. Frequent dislocation events can lead to stretched ligaments, damaged cartilage, and deterioration of the bone.

Risk assessment

Recognizing and understanding risk factors is critical in diagnosing soft tissue knee injuries (STKIs). Risk factors can be categorized as either patient-related (intrinsic) or external (extrinsic), and patient factors can be further subdivided into non-modifiable and modifiable.

Non-modifiable patient factors include sex, age, previous knee injury, family history, and generalized joint hypermobility (GJH). Women have been found to exhibit a higher incidence of STKI’s, primarily due to biomechanical differences (wider pelvis) and hormonal differences (estrogen and relaxin causes increased laxity, especially in ligaments). Individuals are at higher risk when under the age of 30, because of rapid skeletal growth, insufficient neuromuscular control, and participation in high-risk sports. Previous injuries have the highest rates of recurrence, especially in younger men returning to sport at high intensity following reconstruction. Family history plays a role through inherited susceptibility because of biomechanical traits and behavioral patterns such as sports participation, as well as GJH, which is often hereditary.

Modifiable patient factors include body mass index (BMI), biomechanical function, and neuromuscular control. Increased BMA increases axial loading and dynamic valgus forces on the knee, while abnormal joint alignment or movement patterns can lead to increased stress on soft tissue structures. Similarly, when neuromuscular control is insufficient, dynamic stability is impaired as forces are redirected from the active support of muscles and tendons to the passive restraint of ligaments. Unlike intrinsic factors, these modifiable elements typically provide opportunities for intervention like targeted training, injury prevention programs, and weight management strategies.

External factors include level of participation, type of exposure, playing surface, weather conditions, and footwear. STKIs can result from both contact and non-contact mechanisms, with non-contact injuries making up the majority. This leads into how sports are classified by high and low risk levels, with high-risk sports involving high-energy maneuvers such as cutting, pivoting, landing from jumps, decelerating suddenly, and making sharp turns.

Solutions

Neuromuscular training programs (NMT) are designed to improve biomechanics, muscle strength, and proprioception (the body’s subconscious ability to sense its down position, movement, and force in space). Core components include training landing stabilization through plyometrics, improving strength and resistance, proprioceptive training through balance, and enforcing better agility and technique. This specialized type of physical therapy training is usually applied two to three times a week for thirty to sixty minutes at a time, depending on the individual. Some programs that are widely known and recognized are Prevent Injury and Enhance Performance (PEP), Good Life with osteoArthritis Denmark (NEMEX/GLA:D), and FIFA 11+.

Commercially available genetic injury tests include cellular and organ injury tests, as well as musculoskeletal and sport injury susceptibility tests. The latter is direct-to-consumer, meaning genetic panels are commercially available to identify a person’s genetic predisposition to soft-tissue or athletic injuries without the need for a physician’s referral, medical history check, or a clinic visit. However, this also means that these tests are classified as wellness or lifestyle products rather than diagnostic medical tools, and as a result are not covered by insurance. In addition to paying out of pocket, public awareness is very low. Despite being highly accessible, surveys published have revealed low adoption even among athletes, and these tests are often overshadowed due to the fact that the public often associates DNA testing almost exclusively as ancestry or major disease risk (such as cancer screening).

Not everyone has the ability to pay out of pocket for a test, and not everyone has the time or money to dedicate to NMT. As a result, the general public is often uneducated on how to most effectively prevent knee-related injuries.

Personal experience

I chose to write about this topic because of my own experiences. I have had chronic knee pain due to biomechanical and multifactorial risks since 2020. As an athletic person, my knees have sustained debilitating cartilage degeneration, leading to patellofemoral arthritis, and several kneecap dislocations. In terms of seeking medical treatment, I have had over 5 MRI’s, countless orthopedic consultations, years of physical therapy, and two surgeries: one performed in October of 2025 and one coming up in July of 2026. My risk factors include (but is not limited to): miserable misalignment syndrome, trochlear dysplasia, increased Q-angle on my left knee, knocked knees, and a family history of arthritis, ligament tears, and athletic sport participation.

Conclusion

It is a common pattern for individuals to find out about their risk factors only after getting treatment for knee-related injuries, if at all. In an ideal world, widespread public access to tools for risk factor identification, education, and treatment would be accessible to all. Furthermore, physical therapy should not only be a tool utilized post-injury, but something that could be ideally implemented for everyone, regardless of physical state.

Current evidence and data regarding risk factors for knee complications is largely derived from candidate gene studies with limited sample sizes and ethnic diversity, and results have not been consistently replicated across populations. Building a stronger data set across diverse areas, individuals, and risk factors can build a foundation towards further solutions that may be created as scientific development and technology continues to unfold.

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