A pilot study of peripheral blood DNA methylation models as predictors of knee osteoarthritis radiographic progression: data from the Osteoarthritis Initiative (OAI)

Abstract

Knee osteoarthritis (OA) is a leading cause of chronic disability worldwide, but no diagnostic or prognostic biomarkers are available. Increasing evidence supports epigenetic dysregulation as a contributor to OA pathogenesis. In this pilot study, we investigated epigenetic patterns in peripheral blood mononuclear cells (PBMCs) as models to predict future radiographic progression in OA patients enrolled in the longitudinal Osteoarthritis Initiative (OAI) study. PBMC DNA was analyzed from baseline OAI visits in 58 future radiographic progressors (joint space narrowing at 24 months, sustained at 48 months) compared to 58 non-progressors. DNA methylation was quantified via Illumina microarrays and beta- and M-values were used to generate linear classification models. Data were randomly split into a 60% development and 40% validation subsets, models developed and tested, and cross-validated in a total of 40 cycles. M-value based models outperformed beta-value based models (ROC-AUC 0.81 ± 0.01 vs. 0.73 ± 0.02, mean ± SEM, comparison p = 0.002), with a mean classification accuracy of 73 ± 1% (mean ± SEM) for M- and 69 ± 1% for beta-based models. Adjusting for covariates did not significantly alter model performance. Our findings suggest that PBMC DNA methylation-based models may be useful as biomarkers of OA progression and warrant additional evaluation in larger patient cohorts.

The Combination of an Inflammatory Peripheral Blood Transcriptome and Imaging Biomarkers Enhance Prediction of Radiographic Progression in Knee Osteoarthritis.

“…Therefore, prognostic biomarkers have been sought by industry, frustrated by the challenges of drug development in OA. To date, no single prognostic biomarker has been sufficient, and the predictive value of those described have been modest (e.g., OR of 1.2-1.4) (49). In our studies, we show that the predictive value of an inflammatory PBL transcriptome alone is comparable to that of BML by MRI, with OR in the range of 2-4.…”

“…What is the importance of these findings? In addition to shedding light on discrete pathogenic processes, the identification of biomarkers predictive of progression is of fundamental importance for the development of new treatment targets through increased efficiencies of trials of diseasemodifying agents (49). There are many obstacles to structure modification studies in OA, including heterogeneity in etiology and the variability in the progression of the disease in clinical trial populations.…”

“…There have been other recent publications that show the predictive value of genomic or imaging biomarkers on progression. A recent FNIH (Foundation of the NIH) study as part of the OA biomarker consortium identified several promising candidates systemic biomarkers such as urine collagen (uCTXII and uCTX1a) as predictors of pain and structural worsening of OA(49). The final baseline model included uCTXII and sNTXI and had an AUC of 0.586.…”

The combination of an inflammatory peripheral blood gene expression and imaging biomarkers enhance prediction of radiographic progression in knee osteoarthritis

“…Dunn et al have studied the peripheral blood methylation status in the radiographic progressors relative to non-progressors in a small cohort of OAI subjects. The epigenetics patterns in peripheral blood mononuclear cells had an AUC of 0.81 in predicting radiographic progressors [52].…”

DNA Methylation Signatures of Bone Metabolism in Osteoporosis and Osteoarthritis Aging-Related Diseases: An Updated Review

“…However, DNA methylation patterns in blood may also have a great potential as non-invasive biomarkers by modulating the expression of genes involved in OA pathogenesis. One of the first reported pilot studies on this topic investigates the possibility of predicting future radiographic progression of knee osteoarthritis on the basis of the epigenetic signature in blood [ 40 ]. A DNA methylation study was performed by using Illumina Infinium HumanMethylation450k or 850k arrays on 58 future radiographic progressors compared (cases) to 58 non-progressors (controls).…”