medwireNews: A polygenic risk score (PRS) made from genes associated with rheumatoid arthritis (RA) susceptibility may be able to predict the risk for radiographic progression among people with clinical disease, particularly those with a young age at onset, researchers report.
Yuta Kochi (Tokyo Medical and Dental University, Japan) and team constructed their PRS from the summary statistics of a large genome-wide association study meta-analysis.
The authors then evaluated the score’s association with radiographic progression using clinical information from the Japanese IORRA cohort, which was divided into training (n=500) and validation (n=740) sets.
In the total study population, the average age at RA onset was 48.6 years, 50% were taking methotrexate and 9.8% biologic DMARDs, and the median Sharp/van der Heijde score (SHS) was 16 points. Patients were divided into two groups according to whether they were in the top quartile (>35 points) for SHS increase in the 5 years following diagnosis (severe progression group) or the bottom three quartiles (nonsevere progression group).
As reported in Arthritis & Rheumatology, the best PRS model associated with radiographic progression comprised 43,784 single-nucleotide polymorphisms. This PRS significantly differed among patients in the severe versus nonsevere progression groups in both the training and validation sets.
When patients from the full cohort were divided into five groups according to their PRS, those in the top quintile had a significant 1.90-fold higher risk for severe progression than those in the bottom quintile. This rose to a 5.06-fold increased risk when the analysis was restricted to patients with a young age (≤40 years) at RA diagnosis.
Kochi et al also compared the PRS with “known factors associated with radiographic progression,” finding that its discriminatory power was comparable to that of anticitrullinated protein antibodies (ACPAs) and significantly greater than that of the HLA-DRB1 Ser11 variant for patients with young-onset RA.
In a multivariable analysis, the PRS was significantly and independently associated with risk for severe radiographic progression (odds ratio [OR]=1.30), as was ACPA positivity (OR=2.60) and female sex (OR=2.02). On the other hand, BMI (OR=0.86 per 1 kg/m2 increase), HLA-DRB1 Ser11 variants (OR=0.72), and biologic DMARD use (OR=0.46) were each associated with a significantly reduced risk for severe progression.
The researchers caution that their study had a number of limitations, including lack of validation in an independent cohort and a lower proportion of patients taking methotrexate or biologic DMARDs than in contemporary practice, “which could result in overestimation of PRS predictability for radiographic progression.”
“We therefore cannot directly apply our PRS result to current clinical practice,” they add.
Nonetheless, they conclude: “Our study reveals that genetic profiling in polygenic rheumatic diseases has potential applications in precision medicine, which should be validated and improved in future studies.”
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