Polygenic Risk Score Predicts Radiographic Progression in Rheumatoid Arthritis

Polygenic risk scores (PRSs) were found to predict radiographic progression in rheumatoid arthritis (RA), according to study results published in Arthritis Rheumatology.

To determine the predictability of PRSs in RA progression, the researchers used data from a genome-wide association study (GWAS) of RA susceptibility. The PRS for radiographic progression was calculated as a sum of variant alleles weighted by their relative effect sizes according to GWAS data. Patient data were collected from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort, an ongoing observational cohort study of patients receiving treatment at a rheumatology institute in Tokyo, Japan.

The primary study outcome was radiographic progression at 5 years after RA diagnosis, according to the Sharp/van der Heijde score (SHS). Patients in the top quartile of SHS were considered to have severe disease progression.

The best predictive model was selected in a training set of 500 patients and validated in a testing set of 740 patients. Multivariable regression was used to evaluate the performance of PRS as a predictor of severe progression.

A PRS developed using 43,784 single-nucleotide polymorphisms (SNPs) was significantly different between severe and nonsevere progression in both the training (P =.0064) and testing (P =.017) sets.

Patients with a PRS in the top vs lowest quintile had a significantly greater risk for severe progression (odds ratio [OR], 1.90; 95% CI, 1.26-2.86; P =.0022); the association was most significant among patients who were younger at RA onset (OR, 5.06; 95% CI, 2.07-12.4; P =.00038).

In multivariable regression models, women (OR, 2.02; 95% CI, 1.26-3.23) and patients with anticitrullinated protein antibodies (ACPAs; OR, 2.60; 95% CI, 1.41-4.80; P =.0023) were more likely to have severe RA progression. In addition, each 1-point increase in normalized PRS was associated with a 1.30-fold increase in risk for severe progression (95% CI, 1.13-1.50; P =.00019).

Additional protective factors included the use of biologic disease-modifying antirheumatic drugs (bDMARDs; OR, 0.46; 95% CI, 0.27-0.82; P =.0082) and serine at position 11 in the human leucocyte antigen (HLA)-DRB1 (OR, 0.72; 95% CI, 0.53-0.96; P =.027).

According to the study results, a PRS constructed using GWAS data on RA susceptibility was an independent predictor of radiographic progression. Other risk factors for progression included younger age at RA onset, the female sex, lower body weight, and ACPA-positivity.

One of the study limitations included the fact the predictive model was not externally validated, but instead, the RA cohort was categorized into training and testing sets.

“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,” the researchers wrote.

Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures. 

Reference

Honda S, Ikari K, Yano K, et al. Polygenic risk scores are associated with radiographic progression in patients with rheumatoid arthritis. Arthritis Rheumatol. Published online January 20, 2022. doi:10.1002/art.42051