“Phenotype” Redefined in Osteoarthritis Research
This basic science tip comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
Over the decades, the meaning of the term “phenotype” has changed. In the past it was solely applied to inherited disorders and was based on physical appearance or clinical presentation. Similarly, the term “penetrance” was applied to the variations in phenotype severity relative to normal. Over time, it has been found that penetrance is usually a reflection of different mutations for the same gene at different parts of the allele, or a mutation in one of several specific genes that could contribute to a similar phenotype.
Now, both terms have been applied to a variety of genetic and environmental circumstances that may affect physical appearance and function. In osteoarthritis research, the term “phenotype” has increasingly been used to define physical, genetic, environmental, and other variables, both past and present.
The authors of a recent abstract use a modern application for the term phenotype to systematically review the literature for studies using knee characteristics relevant for phenotyping osteoarthritis (OA).1 A comprehensive search was performed limited to observational studies of individuals with symptomatic knee OA that identified phenotypes based on OA characteristics, and then the authors assessed phenotypic association with clinically important outcomes.
Based on their abstract, 34 of 2777 citations were included in a descriptive synthesis of the data. Clinical phenotypes were investigated most frequently, followed by laboratory, imaging, and etiologic phenotypes. Eight studies defined subgroups based on outcome trajectories (pain, function, and radiographic progression). Most studies used a single patient or disease characteristic to identify subgroups, while five included characteristics from multiple domains.
Evidence from multiple studies suggested that pain sensitization, psychological distress, radiographic severity, BMI, muscle strength, inflammation, and comorbidities are associated with clinically distinct phenotypes. Gender, obesity and other metabolic abnormalities, the pattern of cartilage damage, and inflammation may delineate distinct structural phenotypes. However, only a few of the 34 studies reviewed investigated the external validity of the chosen phenotypes or their prospective validity using longitudinal outcomes.
While the authors remarked on the heterogeneity of the data included in studies investigating knee OA phenotypes, they say that the phenotypic characteristics identified in their review could form a classification framework for future studies investigating OA phenotypes.
It should be noted that the FRAX score used to calculate fragility fracture risk could be considered a phenotypically based system, the validation of which is continuing.
- Deveza LA, Melo L, Yamato TP, Mills K, Ravi V, Hunter DJ. Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. Osteoarthritis 2017 Aug 25. pii: S1063-4584(17)31156-1. doi: 10.1016/j.joca.2017.08.009. [Epub ahead of print].