A. W. McCaskie

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

Summary 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.

Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22

Objectives Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component. Methods A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets. Results With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p=9.2×10−9), thereby confirming its role as a susceptibility locus for OA. Conclusion The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, β), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.

Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study

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.

Comparison of offset in Birmingham hip resurfacing and hybrid total hip arthroplasty

Hip resurfacing is being performed more frequently in the United Kingdom. The possible benefits include more accurate restoration of leg length, femoral offset and femoral anteversion than occurs after total hip arthroplasty (THA). We compared anteroposterior radiographs from 26 patients who had undergone hybrid THA (uncemented cup/cemented stem), with 28 who had undergone Birmingham Hip Resurfacing arthroplasty (BHR). We measured the femoral offset, femoral length, acetabular offset and acetabular height with reference to the normal contralateral hip. The data were analysed by paired t-tests. There was a significant reduction in femoral offset (p = 0.0004) and increase in length (p = 0.001) in the BHR group. In the THA group, there was a significant reduction in acetabular offset (p = 0.0003), but femoral offset and overall hip length were restored accurately. We conclude that hip resurfacing does not restore hip mechanics as accurately as THA.

CEMENT PRESSURISATION DURING HIP REPLACEMENT

The newer techniques of cementing aim to improve interlock between cement and bone around a femoral stem by combining high pressure and reduced viscosity. This may produce increased embolisation of fat and marrow leading to hypotension, impaired pulmonary gas exchange and death. For this reason the use of high pressures has been questioned. We compared finger-packing with the use of a cement gun by measuring intramedullary pressures during the cementing of 31 total hip replacements and measuring physiological changes in 19 patients. We also measured pressure in more detail in a laboratory model. In the clinical series the higher pressures were produced by using a gun, but this caused less physiological disturbance than finger-packing. The laboratory studies showed more consistent results with the gun technique, but for both methods of cementing the highest pressures were generated during the insertion of the stem of the prosthesis.

Assessment of Osteoarthritis Candidate Genes in a Meta-Analysis of Nine Genome-Wide Association Studies

To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.

A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for ‘in silico’ or ‘de novo’ replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. Results We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10−9 and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10−8) and follow-up studies (p=7.3×10−4). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10−7, OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10−6, OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

Randomised, prospective study comparing cemented and cementless total knee replacement - Results of press-fit condylar total knee replacement at five years

Early implants for total knee replacement were fixed to bone with cement. No firm scientific reason has been given for the introduction of cementless knee replacement and the long-term survivorship of such implants has not shown any advantage over cemented forms. In a randomised, prospective study we have compared cemented and uncemented total knee replacement and report the results of 139 prostheses at five years. Outcome was assessed both clinically by independent examination using the Nottingham knee score and radiologically using the Knee Society scoring system. Independent statistical analysis of the data showed no significant difference between cemented and cementless fixation for pain, mobility or movement. There was no difference in the radiological alignment at five years, but there was a notable disparity in the radiolucent line score. With cemented fixation there was a significantly greater number of radiolucent lines on anteroposterior radiographs of the tibia and lateral radiographs of the femur. At five years, our clinical results would not support the use of the more expensive cementless fixation whereas the radiological results are of unknown significance. Longer follow-up will determine any changes in the results and conclusions.

Radiological features predictive of aseptic loosening in cemented Charnley femoral stems

The radiological features of the cement mantle around total hip replacements (THRs) have been used to assess aseptic loosening. In this case-control study we investigated the risk of failure of THR as predictable by a range of such features using data from patients recruited to the Trent Regional Arthroplasty Study (TRAS). An independent radiological assessment was undertaken on Charnley THRs with aseptic loosening within five years of surgery and on a control group from the TRAS database. Chi-squared tests were used to test the probability of obtaining the observed data by chance, and odds ratios were calculated to estimate the strength of association for different features. Several features were associated with a clinically important increase (>twofold) in the risk of loosening, which was statistically significant for four features (p < 0.01). Inadequate cementation (Barrack C and D grades) was the most significant feature, with an estimated odds ratio of 9.5 (95% confidence interval 3.2 to 28.4, p < 0.0001) for failure.

Randomised, prospective study comparing cemented and cementless total knee replacement: RESULTS OF PRESS-FIT CONDYLAR TOTAL KNEE REPLACEMENT AT FIVE YEARS

Early implants for total knee replacement were fixed to bone with cement. No firm scientific reason has been given for the introduction of cementless knee replacement and the long-term survivorship of such implants has not shown any advantage over cemented forms. In a randomised, prospective study we have compared cemented and uncemented total knee replacement and report the results of 139 prostheses at five years. Outcome was assessed both clinically by independent examination using the Nottingham knee score and radiologically using the Knee Society scoring system. Independent statistical analysis of the data showed no significant difference between cemented and cementless fixation for pain, mobility or movement. There was no difference in the radiological alignment at five years, but there was a notable disparity in the radiolucent line score. With cemented fixation there was a significantly greater number of radiolucent lines on anteroposterior radiographs of the tibia and lateral radiographs of the femur. At five years, our clinical results would not support the use of the more expensive cementless fixation whereas the radiological results are of unknown significance. Longer follow-up will determine any changes in the results and conclusions.