Revision Surgery After TJR: A Family Affair?

Total joint replacement (TJR) is the ultimate procedure in patients with end-stage osteoarthritis. Knee and hip arthroplasty represent reliable treatments with favorable patient outcomes. However, revision TJR (rTJR) or other surgeon interventions such as manipulation under anesthesia (MUA) are not uncommon even if periprosthetic joint infection (PJI) is avoided. For example, joint implants may loosen aseptically due to insufficient osseointegration or joints may stiffen due to excessive deposition of collagenous scar tissue1,2. Translational studies using animal models that replicate these conditions allow development of prophylactic strategies that prevent aseptic loosening or arthrofibrosis after TJR. Identification of patients who are at risk for revision surgery would permit a range of informed decisions regarding clinical care, including prophylaxis, vigilant monitoring, and/or early intervention. Revision surgery is linked to a range of comorbidities, as well as modifiable and nonmodifiable risk factors. Genetic variation drives many biological processes. Therefore, Dr. Brüggemann and colleagues examined whether rTJR has a genetic component.

Unlike in classic congenital disorders, familial analysis to determine inheritance of traits that predispose to rTJR is not realistic. Arthroplasty often occurs later in life, while surgical procedures and devices for joint replacement continue to evolve during each generation. Instead, Brüggemann and colleagues performed a genomewide association study (GWAS) using a database obtained from >60,000 DNA samples (blood or saliva) in the Swedish Twin Registry. The authors retrieved a subcohort of ∼1,100 twins who underwent TJR. A subset of these patients was subsequently recommended for revision surgery within ∼10 years for aseptic loosening or other reasons. Twin studies involving monozygotic and dizygotic twins provide duplicate measurements of genotype-phenotype correlations, permitting calculation of genetic versus environmental determinants (Falconer’s formula). However, because it is rare for both siblings in a twin pair to require rTJR (that is, twins were not concordant for this phenotype), this study was unable to leverage such twin information; instead, it leveraged the power of a well-annotated genetic database.

Brüggemann and colleagues characterized a number of single-nucleotide polymorphisms (SNPs) that exhibited significant correlations with rTJR. Fascinatingly, SNPs linked to aseptic loosening include an apoptosis and autophagy-related gene (ELAPOR2, also known as EIG121L) that is implicated in bone morphogenetic protein (BMP) signaling in frogs3, and a transmembrane protein (SLC6A6) that transports the osteocyte-derived metabolite taurine4. The risk of revision for any reason was also increased by genetic variation in the SLC6A6 gene and the gene encoding calmodulin-binding transcription activator 1 (CAMTA1), which is an ancient protein involved in intracellular calcium signaling5. Collectively, SNPs in genes involved in bone formation or calcium signaling represent specific genetic biomarkers for revision risk.

One key question is whether the identified rTJR-related nucleotide variations also mechanistically affect osseointegration of implants. The answer depends on whether the SNP can affect the function or regulation of the gene and its expression in a relevant cell type. For example, if an SNP in the SLC6A6 gene resides in an intron, an optimistic interpretation is that it could affect expression of the gene by altering mRNA splicing, but it is more likely that such a position rules out a mechanistic role. Oddly enough, 1 SNP is located in the coding region of the gene that provides the molecular genetic basis for the common blood types A, B, AB, or O in the ABO blood group system. The observed variation defines blood type B, because it alters the activity of the encoded glycosyl-transferase responsible for generating A and/or B antigens on erythrocytes. Although this specific genetic variation reflects increased revision risk, it is unlikely to be causative. Rather, the statistical association observed in this study informs surgeons that patients with blood type B have more than a threefold higher chance of revision surgery.

The study by Brüggemann et al. provides solid progress in the field because it was expertly designed and executed with a high level of statistical rigor to define novel genetic associations rather than mechanistic causality. Nevertheless, studies on genetic factors in surgical outcomes are limited by variations in the surgical procedures (e.g., device, anatomy, surgeon), patient conditions (e.g., obesity, diabetes, smoking), and database parameters (e.g., population size, medical coding). Expanding the genetic frontiers in TJR surgery will require massive data acquisition via multi-institutional international efforts that aid in the identification of not only genetic and environmental factors associated with disease conditions, but also the interactions between these factors as they alter heritability patterns. Irrespective of these limitations, this study defines novel genetic biomarkers for increased risk of rTJR, a clinically important end point, that permit informed decisions regarding patient care.