Genomic Risk Score for Advanced Osteoarthritis in Older Adults

Abstract

Objective. Prevention of osteoarthritis (OA) remains important, as there are no disease-modifying treatments. A personalized approach has the potential to better target prevention strategies. In the present study, we used recently identified genetic risk variants from genome-wide association analysis for advanced OA to calculate polygenic risk scores (PRS) for knee and hip OA and assessed PRS performance in an independent population of older communitydwelling adults.Methods. PRS were calculated in 12,093 individuals of European genetic descent ages ≥70 years who were enrolled in the Aspirin in Reducing Events in the Elderly trial. The outcome measure was knee and hip replacement (hospitalizations during the trial and self-reported joint replacements before enrollment). PRS were considered as continuous (per SD) and categorical (low risk [0-20%], medium risk [21-80%], high risk [81-100%]) variables. Logistic regression was used to examine associations between PRS and risk of joint replacement, adjusted for age, sex, body mass index, and socioeconomic status.Results. Among the participants, 1,422 (11.8%) had knee replacements and 1,297 (10.7%) had hip replacements. PRS (per SD) were associated with a risk of knee replacement (odds ratio [OR] 1.13 [95% confidence interval (95% CI) 1.07-1.20]) and hip replacement (OR 1.23 [95% CI 1.16-1.30]). Participants with high PRS had an increased risk of knee replacement ) and hip replacement ), compared to those with low PRS. Associations were stronger for PRS and hip replacement risk in women than in men. Associations were similar in sensitivity analyses that examined joint replacements before and during the trial separately.Conclusion. PRS have the potential to improve prevention of severe knee and hip OA by providing a personalized approach and identifying individuals who may benefit from early intervention.

Genetic risk of osteoarthritis operates during human skeletogenesis

“…This is the first study to identify the presence of mQTLs in human fetal cartilage and limb tissues, and our report demonstrates that the functional genetic risk of OA can be laid down during human skeletogenesis. Strides are being made within the field, with the first recent reports of polygenic risk scores (PRS) for the disease ( 52 , 53 ), yet the clinical utility of such systems is still lacking ( 54 ). We would encourage the integration of epigenetic data at the loci, along with clinical and biochemical parameters to further advance these tools for the patient benefit.…”

Genomic heterozygosity is associated with a lower risk of osteoarthritis

“…Not a novel idea since Lacaze et al . and other groups have demonstrated that genomic risk scores, calculated using known genetic risk variants, can predict an individual’s risk of developing advanced hip and knee OA [ 13 , 14 ]. A recent large meta-analysis in Cell also demonstrated that polygenic risk scores have predictive power for the odds of developing OA [ 4 ].…”

The impact of omics research on our understanding of osteoarthritis and future treatments

“…However, some of these data sets might be used much earlier as prognostic tools, to determine patient risk and to direct prevention. For example, two recent studies used the loci identified in GWAS studies to determine the 'Polygenic Risk Score' (PRS) for OA patients, with encouraging results ( [30,31], discussed in [32]). Steinbeck et al [33] provide another example of using multiomics approaches to stratify patients and potentially direct more personalized treatments in the future.…”