Objective Alterations in DNA methylation patterns have been found to correlate with several diseases including osteoarthritis (OA). The aim of this study was to identify, for the first time, the genome-wide DNA methylation profiles of human articular chondrocytes from OA cartilage and healthy control cartilage samples. Methods DNA methylation profiling was performed using Illumina Infinium HumanMethylation27 in 25 patients with OA and 20 healthy controls. Subsequent validation was performed by genome-wide expression analysis using the Affymetrix Human Gene 1.1 ST array in an independent cohort of 24 patients with OA. Finally, the most consistent genes in both assays were amplified by quantitative reverse transcriptase PCR in a validation cohort of 48 patients using microfluidic real-time quantitative PCR. Appropriate bioinformatics analyses were carried out using R bioconductor software packages and qBase plus software from Biogazelle. Results We found 91 differentially methylated (DM) probes, which permitted us to separate patients with OA from healthy controls. Among the patients with OA, we detected 1357 DM probes that identified a tight cluster of seven patients who were different from the rest. This cluster was also identified by genome-wide expression in which 450 genes were differentially expressed. Further validation of the most consistent genes in an independent cohort of patients with OA permitted us to identify this cluster, which was characterised by increased inflammatory processes. Conclusions We were able to identify a tight subgroup of patients with OA, characterised by an increased inflammatory response that could be regulated by epigenetics. The identification and isolation of this subgroup may be critical for the development of effective treatment and disease prevention.

Objectives The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. Methods The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44 449 individuals), and de novo in 14 534 independent samples, all of European descent. Results None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. Conclusions Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Objective: Some studies indicate that the mitochondrion is implicated in osteoarthritis (OA). To test the hypothesis that mitochondrial DNA (mtDNA) haplogroups contribute to the prevalence and severity of knee OA, we analyzed the European mtDNA haplogroups in a Spanish population of patients with knee OA and healthy control subjects.Methods: We combined the single‐base extension assay with the polymerase chain reaction–restriction fragment length polymorphism technique to obtain the different single‐nucleotide polymorphisms that characterize the European haplogroups in 457 patients with knee OA and 262 radiologic controls. Knee OA radiographs had previously been classified as grades 1–4 according to Kellgren/Lawrence (K/L) scoring system.Results: Individuals carrying haplogroup J showed a significantly decreased risk of knee OA (odds ratio [OR] 0.460 [95% confidence interval (95% CI) 0.282–0.748], P = 0.002). In terms of K/L scores, patients carrying haplogroup J had a less severe progression of knee OA (OR 0.351 [95% CI 0.156–0.787], P = 0.012), while those carrying haplogroup U had a more severe progression (OR 1.788 [95% CI 1.094–2.922], P = 0.025).Conclusion: People carrying haplogroup J may be at a lower risk of developing knee OA, and those carrying this haplogroup in whom knee OA does not develop may have a less severe progression of the disease. Patients with knee OA carrying haplogroup U may have a more severe progression of the disease. These results indicate that mtDNA haplogroups contribute to the pathogenesis of OA.