➢ As of 2015, members of the “baby boomer generation” comprise 75 million people in the growing United States population. Many of these individuals will be facing the need for total hip or knee replacement. Currently, the age of onset of osteoarthritis continues to decrease and the need for total joint replacements continues to increase.
➢ In current practice, nearly all patients undergoing joint replacement receive similar preoperative, intraoperative, and postoperative management strategies. However, wide variability in outcomes and satisfaction with total joint replacement still remain. The key to understanding the cause for such varied outcomes may lie in our understanding of the genetic basis of degenerative joint disease.
➢ The future of “orthogenomic” research should be centered on clinical application focusing on early preoperative identification of at-risk patients. The goal is to establish twenty-first-century patient-specific strategies for optimizing results and expectations after adult reconstructive surgery.
Genomics, the scientific study of genes and their interrelationships with each other and the environment to determine their combined influence on disease1, has gained increasing attention over the last decade. In 2003, the completion of the Human Genome Project marked a new era in modern medicine. Under the direction of Francis Collins at the National Institutes of Health, the project set out to identify the DNA sequences that give rise to the complex human genome. The ultimate goal was to make these data widely available to clinicians and researchers with the hope that a better understanding of the genetic basis of disease would lead to more tailored therapies and, ultimately, better clinical outcomes2. Genomic research surged following the completion of the project, ushering in new genetic technologies and opportunities in health care3. The impact on clinical medicine has been widespread and profound. Genetic tests have been developed to identify mutations for complex diseases such as breast, colon, and ovarian cancer. Recently, genetic testing was used to rapidly sequence the virus responsible for a severe acute respiratory syndrome (SARS) outbreak, with the genome sequence being quickly publicized to aid in patient diagnosis4. These examples are a few of the many impactful ways in which genomics is being used to more effectively study human disease and its prevention.
Clinicians and researchers have since coined the term “personalized medicine”—the concept that a patient’s genetic profile will determine the appropriate therapy5. Across all medical specialties, there has been a realization that many diseases have a degree of genetic predisposition. By understanding the importance of genetics and the environment in shaping clinical outcomes, the future of medicine has the potential to provide more individualized care. Furthermore, the identification of mutations and genes has paved the way for gene-based pharmacotherapies6.
Genomics in Orthopaedics
The application of genomics in orthopaedics remains limited, with the publication of only a few studies centered on osteoarthritis, osteoporosis, rheumatoid arthritis, and oncology7-10. The focus of such studies has mainly been on identifying specific tumor cell markers and chemotherapeutic agents9. However, there has been limited research on how genomics can be implemented in surgical management within the field of orthopaedics. While animal models have successfully identified molecular mechanisms and biomarkers for common orthopaedic concerns such as fractures and bone-healing11, translating these discoveries to humans has proved increasingly challenging.
Researchers believe that genomics could have a profound effect in several orthopaedic specialties. In the pediatric population, the use of genomics opens new possibilities for the treatment of musculoskeletal disorders through the early identification of germ-line mutations. In adult patients undergoing surgery, the use of biomarkers and genetic testing may aid in preventing postoperative complications. As the rising cost of health care becomes a pressing issue and certain orthopaedic procedures such as adult reconstructive surgery come under close scrutiny in the United States, discoveries resulting from genomic research may provide some insight on cost-cutting measures. Such measures may include identifying the appropriate timing for surgery and the prevention of costly postoperative complications.
Genomics in Adult Reconstructive Surgery
As of 2015, the “baby boomer generation” consists of nearly 75 million persons in the growing population of the United States12. Many of these individuals will be facing the need for total hip or knee arthroplasty. It has been predicted that by 2030, “60% of this [baby boomer] generation will have more than one chronic condition, 50% (twenty-six million) will be affected by arthritis, and >33% will be obese.”13 Currently, the age of onset for osteoarthritis, also known as degenerative joint disease, continues to decrease, thereby causing the need for total joint arthroplasty to increase14. There is variability in outcomes (including complications and overall satisfaction) when patients undergoing total joint arthroplasty receive similar perioperative management. There is also a high degree of variability in the management of these patients. In these patients, the variability in both management and outcomes could in large part be due to the lack of integrating genomics into their clinical care. The key to understanding the cause for such varied outcomes may very well lie in our understanding of the genetic basis of degenerative joint disease and the genetic response to treatment15. A recent study demonstrated a promising independent biomarker for osteoarthritis progression15. An analysis of >100 synovial fluid samples from patients with osteoarthritis demonstrated that the tumor necrosis factor-stimulated gene 6 protein (TSG-6), a hyaluronan-binding protein associated with inflammation, had a significant relationship with osteoarthritis progression over a three-year period (p = 0.004)15. These biomarkers may be useful in helping surgeons to decide on the timing of total joint arthroplasty.
Some medical and surgical disciplines have effectively implemented the use of specific genes and biomarkers to better individualize treatment. In orthopaedics, however, there remains a great void with regard to the utilization of genetic information to guide management. The purpose of the present report is to present a review of the existing body of research in “orthogenomics,” specifically, gene-based interactions and emerging work as it pertains to commonly observed postoperative complications (i.e., infection, thromboembolism, heterotopic ossification, arthrofibrosis, hyperalgesia, osteolysis, and osteonecrosis) in adult reconstructive surgery16.
Despite an increasing trend toward institutional bactericidal-specific prophylactic regimens prior to arthroplasty, infection rates have remained near 1% over the years17. Early identification remains critical in the treatment of periprosthetic joint infections. There has been an increasing trend in trying to identify genetic susceptibility or biomarkers for periprosthetic joint infection in patients undergoing total joint arthroplasty. Zhou et al. identified nearly thirty-five single-nucleotide polymorphisms (SNPs) contributing to increased susceptibility to periprosthetic joint infection following total joint arthroplasty18. SNPs are single-nucleotide substitutions of one base in the DNA structure that occur in about 1% of the general population. The data from that study suggest that the C allele and genotype C/C for the mannose-binding lectin-550 (MBL-550) SNP, genotype A/A for the MBL-54 SNP, and the G allele for the MBL-221 SNP increase the risk of periprosthetic joint infection, whereas the G allele and genotype G/G for the MBL-550 SNP decrease the risk of periprosthetic joint infection in Caucasian populations18. Deirmengian et al. studied biomarkers in the synovial fluid for periprosthetic joint infection (as classified by the Musculoskeletal Infection Society) by comparing α-defensin with leukocyte esterase reagent (LER) test strips to assess optimal diagnostic characteristics19. α-defensin, an antimicrobial peptide that is secreted into the synovial fluid by human cells in response to pathogenic presence19,20, accurately predicted periprosthetic joint infection in patients with 100% sensitivity and specificity, whereas LER, which estimates the leukocyte count in urine, only predicted periprosthetic joint infection with 78% sensitivity and specificity (p < 0.001). However, samples were collected only from the knee joint, thereby limiting the confident transfer of the authors’ conclusions to the hip joint.
Gollwitzer et al. assessed intra-articular and systemic levels of antimicrobial peptides and proinflammatory cytokines as diagnostic markers for periprosthetic joint infection21. Patients with Staphylococcus aureus infection were found to have significantly elevated levels of human beta defensin-3 (HBD-3) and human cathelicidin (LL-37) in joint aspirates as compared with patients with aseptic loosening (AUC [area under the curve] = 0.972). HBD-3 is a member of the defensin family of proteins, which impact the innate immune system, and LL-37 is an antimicrobial and immunostimulating/immunomodulating peptide. Furthermore, significant local and systemic increases in proinflammatory cytokines (interleukin-4 [IL-4], IL-6, interferon-γ [IFN-γ], and tumor necrosis factor-α [TNF-α]) were noted (AUC > 0.95)21. It also has been shown that toll-like receptor (TLR) expression in periprosthetic tissues could also be used as a biomarker for deep joint infection22. In patients undergoing total joint arthroplasty, results showed that the mean TLR-1 and TLR-6 messenger RNA (mRNA) expression were significantly elevated in infected as compared with noninfected samples (p = 0.0003)22.
The use of DNA molecular markers also has been increasingly used to classify specific bacterial microorganisms. For example, researchers have shown that the ica gene, which has a large influence on the formation of biofilm, encodes the polysaccharide intracellular adhesion (PIA) protein23. The ica gene helps to differentiate between invasive and commensal strains of S. epidermidis, which is an important cause of nosocomial infections23. These studies highlight the importance of using genetic biomarkers to accurately identify individuals who may be genetically susceptible to periprosthetic joint infection.
Perhaps the most life-threatening complication following total joint arthroplasty remains the development of venous thromboembolic events, specifically, deep-vein thrombosis resulting in the formation of a clot that could potentially result in a pulmonary embolism. Some patients still experience thrombotic events despite similar prophylactic regimens, which supports the possibility of a genetic predisposition. Bezemer et al. discussed how common genetic variants such as Factor V Leiden and prothrombin G20210A tend to only explain a fraction of venous thromboembolic events24. They found that genes involved in the complement and coagulation pathway such as glycoprotein-6 (GP6) and serpinc1 as well as genes encoding a cytochrome p450 enzyme (CYP4V2) were all significantly associated with deep-vein thrombosis (p < 0.05; false discovery rate, ≤0.10). Another meta-analysis by Gohil et al. examined 126,525 cases and 184,068 controls—across twenty-one genes and twenty-eight polymorphisms—and showed ten polymorphisms in eight genes that were significantly associated with a risk of venous thromboembolic events (p < 0.05)25. Both studies highlighted the need for extensive studies on SNPs in patients undergoing total joint arthroplasty to help elucidate which high-risk patients are actually in need of aggressive anticoagulation. Understanding genetic predisposition could potentially prevent inherent complications associated with aggressive anticoagulation in patients who are not necessarily at high risk for venous thromboembolic events.
Heterotopic ossification represents a common and sometimes clinically symptomatic complication following total joint arthroplasty. An individual’s propensity to develop heterotopic ossification following total joint arthroplasty is unpredictable; however, studies have shown an increased risk of heterotopic ossification following head trauma26. A recent study identified the initial inflammatory response and generation of a permissive tissue microenvironment as being critical for the induction of heterotopic ossification27. In the pathway of heterotopic ossification formation, bone morphogenetic protein-2 (BMP-2) initiates inflammation through the release of neuroinflammatory factors, substance P, and calcitonin gene-related peptide (CGRP) from sensory nerves. Each of these components represents a possibility for genetic predisposition. Mitchell et al. examined the frequency of sixty-one SNPs in trauma patients with fractures28 and showed that the beta-2 adrenergic receptor was associated with increased frequency of heterotopic ossification. TLR-4 and complement factor H were associated with decreased frequency of heterotopic ossification. Lin et al. used an implant osseointegration animal model to determine the gene expression dynamics during bone repair29. Genes that were increased during the healing process were identified as BMP-4, runt-related transcription factor 2, and osteocalcin.
These findings highlight the interplay among the adrenergic, immune, and alternative complement systems and their effect on the bone-remodeling pathway. Further genetic and molecular analysis can be used to identify patients at high risk of developing heterotopic ossification following total joint arthroplasty.
Increased scarring in the knee joint following arthroplasty continues to leave some patients with excessive stiffness, ultimately limiting their range of motion. Watson et al. used an adenovirus to deliver and overexpress transforming growth factor-β1 (TGF-β1) complementary DNA (cDNA) in the knee joints of immunocompromised rats30. Within five to ten days, TGF-β1 induced an increase in knee diameter and complete encasement of joints in dense scar-like tissue, locking joints at 90° of flexion. Their study showed TGF-β1 to be a potent inducer of arthrofibrosis and illustrated the proliferative potential and plasticity of articular fibroblasts. Abdel et al. described the influence of intra-articular decorin on the fibrosis genetic expression profile in a rabbit model of joint contracture31. Genetic analysis revealed a significant (p < 0.01) alteration in several fibrotic genes following intra-articular administration of decorin; however, no significant effect was shown on joint contractures. Last, Skutek et al. screened patients for arthrofibrosis after anterior cruciate ligament (ACL) reconstruction32. They highlighted how trauma such as surgery around joints does not always lead to fibrosis, which further corroborates the suggestion of a genetic predisposition. They found that a possible link may exist between arthrofibrosis and genes of the major histocompatibility complex (MHC), particularly human leukocyte antigen (HLA) genes. Patients whose DNA tested positive for HLA-Cw*07 (p = 0.022) and negative for the HLA-DQB1*06 (p = 0.045) gene were significantly shown to be associated with primary arthrofibrosis after ACL reconstruction. These HLA genes play a critical role in the human immune system and must be studied extensively to understand their genetic influence on arthrofibrosis.
The varying degree of pain experienced by patients undergoing total joint arthroplasty remains a challenging problem for many surgeons. Despite nearly replicable procedures and perioperative anesthetic-analgesic protocols, some individuals continue to show major differences in terms of the level of pain following total joint arthroplasty. Young et al. suggested that pain sensitivity and chronic pain are complex heritable traits of polygenic origin33. Of note, certain polymorphisms act to facilitate or increase pain. Those in the KCNS1 gene (encoding the potassium voltage-gated channel subfamily S member 1 protein), SCN9A gene (encoding the major sodium channel in smooth muscle cells), and IL-16 were all associated with increased sensitivity to pain. However, those in other genes such as the catechol-O-methyltransferase gene (COMT), opioid receptor gene (OPRM1), and melanocortin-1 receptor gene (MC1R) were shown to confer pain protection33.
Several alleles have been shown to modulate the efficacy of analgesic agents. Young et al.33 stressed the need for genetic testing as part of risk assessment and the diagnosis of pain in typical health-care settings. Liang et al. performed a genetic analysis of opioid-induced hyperalgesia (OIH), which is a syndrome of increased sensitivity to noxious stimuli seen after both acute and chronic administration of opioids, in mice34. β2-adrenergic receptor was most strongly associated with OIH; when a selective β2-adrenergic antagonist was used, a dose-dependent reversal of OIH was seen. These studies demonstrate the need to further categorize patients on the basis of their genetic profile in order to adequately manage pain following total joint arthroplasty.
Malik et al. conducted a case-control study of the matrix metalloproteinase-1 (MMP-1), IL-6, and vitamin D receptor (VDR) genes for possible association with deep infection and aseptic loosening35. The C allele and C/C genotype for the MMP-1 SNP were highly associated with aseptic failure when compared with controls. This finding suggests that SNP markers may serve as predictors of implant survival and aid in pharmacogenomic prevention of the failure of total joint arthroplasty. Another study examined SNPs for cytokines and cytokine receptor genes for association with the severity of acetabular osteolysis and the risk of failure after total joint arthroplasty36. TNF-238*A and IL6-174*G alleles were independent predictors of the development of severe acetabular osteolysis (p = 0.005). Carriage of IL2-330*G predicted a lower cumulative hazard of failure of total hip arthroplasty due to osteolysis.
Noordin and Masri summarized the genetic mechanisms underlying periprosthetic loosening and highlighted macrophage activation by polymethylmethacrylate (PMMA) and polyethylene wear debris as the principal pathophysiological mechanism in particle-induced periprosthetic osteolysis37. Cyclooxygenase-2 (COX2) was the most highly induced gene by PMMA, with a thirtyfold increase in expression. Histological analysis further revealed that IL-1 receptor antagonist gene modification decreased the total number of inflammatory cells in engrafted human tissue containing wear debris (p < 0.01)37.
Research into coagulation abnormalities has shown that gene mutations such as Factor V Leiden and prothrombin 20210A have been associated with a higher prevalence of osteonecrosis of the knee. The research by Björkman et al. supports the hypothesis that circulatory impairments of the bone secondary to thrombosis in the microcirculation may be involved in the pathogenesis of osteonecrosis of the knee38. Zalavras et al. evaluated the association of these genes with osteonecrosis of the hip joint and found similar results39. Those authors reported that the thrombophilic Factor V Leiden mutation was associated with nontraumatic osteonecrosis of the femoral head, supporting the hypothesis that intravascular coagulation is a major pathogenetic mechanism of the disease39. Petrigliano and Lieberman discussed the genetic polymorphisms that may predispose certain patient cohorts to the development of osteonecrosis40. Those authors highlighted a study by Chen et al. that identified a gene mutation mapped to chromosome 12q13 that resulted in Type-II collagen abnormalities and autosomal-dominant inheritance of osteonecrosis of the femoral head41. Patients with this genetic form of osteonecrosis of the femoral head had normal skeletal development before the onset of the disease and had not been exposed to known environmental risk factors, such as steroids, yet they presented with typical clinical and radiographic features of osteonecrosis of the femoral head. Chen et al. further discussed SNPs in BMP-6, annexin-A2, and klotho—all instrumental genes for bone formation, metabolic activity, and vascular development41.
Although the application of genomics in orthopaedic practice remains limited, the framework to identify practical interventions has begun to be constructed. Specific to adult reconstructive surgery, the literature suggests that many investigators have been primarily focused on genes and their interactions, stressing the need for more work to explore their interactions with the environment in causing diseases. Obtaining genetic information may allow total joint arthroplasty surgeons to preoperatively stratify patients according to risk on the basis of their genetic profile and may help to establish patient-specific strategies for optimizing results after total joint arthroplasty. In doing so, surgeons may better manage expectations and outcomes in patients undergoing total joint arthroplasty.
In addition, large population-based studies would allow orthopaedic researchers to build the necessary databases to identify these genes and biomarkers. However, such large, prospective cohort studies should not be strictly limited to the adult population as these studies might even be more beneficial in pediatric patients. Ideally, surgeons would use information derived from genomic research to identify which patients would be likely to have more successful results after total joint arthroplasty. We must also add that while the focus of the present article is primarily on adult reconstructive surgery, we believe that the recommendations made here, especially as they relate to tackling disease processes, could be applied in other orthopaedic subspecialties. For example, investigating osteonecrosis in young patients with generally poor outcomes will make genetic risk profiling considerably more likely to show differences.
In conclusion, the advent of twenty-first-century personalized care of adult patients undergoing total joint arthroplasty is beginning to be realized, and the future is promising for more individualized care with an orthogenomic basis of therapy.
Source of Funding: No external funds were received in support of this study.
Investigation performed at the New York University (NYU) Langone Medical Center, Hospital for Joint Diseases, New York, NY
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. None of the authors, or their institution(s), have had any financial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, no author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
- Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated