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Objective To evaluate whether gene expression profiles could serve as biomarkers of symptomatic knee osteoarthritis (OA) by examining gene expression profiles in peripheral blood leukocytes (PBLs) from patients with OA compared with those from non-OA controls, and to determine whether candidate genomic biomarkers (PBL expression of inflammatory genes) predict an increased risk of disease progression in patients with symptomatic radiographic knee OA. Methods Three independent cohorts of patients with knee OA and non-OA control subjects were studied. Two cohorts (a learning cohort and a validation cohort) were recruited at New York University Hospital for Joint Diseases (NYUHJD), and 1 cohort (a validation cohort) was recruited at Duke University Medical Center. PBL gene expression was assessed using Affymetrix microarray and was confirmed by quantitative polymerase chain reaction (qPCR). Radiographic progression at 2 years was assessed in 86 patients. Results We identified 173 genes that were significantly up-regulated or down-regulated (≥1.5-fold change) in OA PBLs, at a false discovery rate of 5%. Cluster analysis revealed 2 distinct subgroups among the patients with OA: those in whom the expression of interleukin-1β (IL-1β) was increased ≥2-fold compared with controls, and those in whom the expression of IL-1β was comparable with that in controls. Overexpression of IL-1β in these OA subclasses was validated using qPCR in all 3 cohorts. Patients with the inflammatory 'IL-1β signature' had higher pain scores and decreased function and were at higher risk of radiographic progression of OA. Conclusion PBLs from patients with symptomatic knee OA display a characteristic transcriptome profile. Moreover, increased expression of IL-1β identifies a subset of patients with OA who have increased pain and are at higher risk of radiographic progression of OA. [ABSTRACT FROM AUTHOR]