Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.

BACKGROUND: Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. METHODS: We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. FINDINGS: We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. INTERPRETATION: Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. FUNDING: arcOGEN was funded by a special purpose grant from Arthritis Research UK.

Assessment of a three-grade classification of complications in total ankle replacement.

BACKGROUND: Prompted by the success of hip and knee arthroplasty, total ankle replacement (TAR) has become increasingly popular as a treatment for end stage arthritis of the ankle. A 3-grade classification of complications to assist in prediction of early implant failure has been proposed. We have compared the experience of a tertiary referral center in the United Kingdom to the proposed system. METHODS: A retrospective review of the Sheffield Foot and Ankle Unit TAR database was performed from 1995 to 2010. All complications were recorded and categorized using Glazebrook et al's proposed system of increasing severity. Low-grade complications including postoperative bone fracture, intraoperative bone fracture, and wound healing problems rarely lead to revision. Medium-grade complications, technical error and subsidence, lead to failure <50% of the time. High-grade complications--deep infection, aseptic loosening, and implant failure--lead to revision >50% of the time. In our center, 217 TAR were implanted in 198 patients with a minimum follow-up of 30 months. RESULTS: The complication rate was 23%, with a revision rate of 17%. All complications recorded in our study except intraoperative bone fracture and wound healing had a failure rate of at least 50%. CONCLUSION: Unfortunately most complications associated with TAR have a significant impact on the life span of a TAR. Glazebrook et al's proposed 3-tier system did not reliably reflect our experience. Hence, we would categorize complications as either high or low risk for early failure of TAR. LEVEL OF EVIDENCE: Level IV, case series.