[Show abstract][Hide abstract] ABSTRACT: 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 total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant.
SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.
Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.
Arthritis and Rheumatology 04/2014; 66(4):940-9. DOI:10.1002/art.38300
[Show abstract][Hide abstract] ABSTRACT: The assessment of surgical skills is an essential part of medical training. The prevalent manual evaluations by expert surgeons are time consuming and often their outcomes vary substantially from one observer to another. We present a video-based framework for automated evaluation of surgical skills based on the Objective Structured Assessment of Technical Skills (OSATS) criteria. We encode the motion dynamics via frame kernel matrices, and represent the motion granularity by texture features. Linear discriminant analysis is used to derive a reduced dimensionality feature space followed by linear regression to predict OSATS skill scores. We achieve statistically significant correlation (p-value <0.01) between the ground-truth (given by domain experts) and the OSATS scores predicted by our framework.
2014 IEEE 11th International Symposium on Biomedical Imaging (ISBI 2014); 04/2014
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
Annals of the rheumatic diseases 08/2013; 73(12). DOI:10.1136/annrheumdis-2012-203114 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Poor knee extension function after total knee arthroplasty (TKA) is associated with factors including articular geometry and alignment. Femoral trochlear geometry has evolved from symmetrical to become more prominent proximal-laterally, with the groove aligned proximal-lateral to distal-medial. This study in vitro tested the hypothesis that a modern asymmetrical prosthesis would restore patellar tracking and stability to more natural behaviour than an older symmetrical prosthesis.
Six knees had their patellar tracking measured optically during active knee extension. Medial-lateral force versus displacement stability was measured at fixed angles of knee flexion. The measurements were repeated after inserting each of the symmetrical and asymmetrical TKAs.
Significant differences of patellar lateral displacement stability, compared to normal, were not found at any angle of knee flexion. The patella tracked medial-laterally within 2.5 mm of the natural path with both TKAs. However, for both TKAs near knee extension, the patella was tilted laterally by approximately 6° and was also flexed approximately 8° more than in the natural knee.
The hypothesis was not supported: The more anatomical component design did not provide more anatomical patellar kinematics and stability.
[Show abstract][Hide abstract] ABSTRACT: Objectives
Osteoarthritis (OA) has a complex aetiology with a strong genetic component. Genome-wide association studies implicate several nuclear genes in the aetiology, but a major component of the heritability has yet to be defined at the molecular level. Initial studies implicate maternally inherited variants of mitochondrial DNA (mtDNA) in subgroups of patients with OA based on gender and specific joint involvement, but these findings have not been replicated.
The authors studied 138 maternally inherited mtDNA variants genotyped in a two cohort genetic association study across a total of 7393 OA cases from the arcOGEN consortium and 5122 controls genotyped in the Wellcome Trust Case Control consortium 2 study.
Following data quality control we examined 48 mtDNA variants that were common in cohort 1 and cohort 2, and found no association with OA. None of the phenotypic subgroups previously associated with mtDNA haplogroups were associated in this study.
We were not able to replicate previously published findings in the largest mtDNA association study to date. The evidence linking OA to mtDNA is not compelling at present.
Annals of the rheumatic diseases 09/2012; 72(1). DOI:10.1136/annrheumdis-2012-201932 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
Obesity as measured by body mass index (BMI) is one of the major risk factors for osteoarthritis. In addition, genetic overlap has been reported between osteoarthritis and normal adult height variation. We investigated whether this relationship is due to a shared genetic aetiology on a genome-wide scale.
We compared genetic association summary statistics (effect size, p value) for BMI and height from the GIANT consortium genome-wide association study (GWAS) with genetic association summary statistics from the arcOGEN consortium osteoarthritis GWAS. Significance was evaluated by permutation. Replication of osteoarthritis association of the highlighted signals was investigated in an independent dataset. Phenotypic information of height and BMI was accounted for in a separate analysis using osteoarthritis-free controls.
We found significant overlap between osteoarthritis and height (p=3.3×10−5 for signals with p≤0.05) when the GIANT and arcOGEN GWAS were compared. For signals with p≤0.001 we found 17 shared signals between osteoarthritis and height and four between osteoarthritis and BMI. However, only one of the height or BMI signals that had shown evidence of association with osteoarthritis in the arcOGEN GWAS was also associated with osteoarthritis in the independent dataset: rs12149832, within the FTO gene (combined p=2.3×10−5). As expected, this signal was attenuated when we adjusted for BMI.
We found a significant excess of shared signals between both osteoarthritis and height and osteoarthritis and BMI, suggestive of a common genetic aetiology. However, only one signal showed association with osteoarthritis when followed up in a new dataset.
Annals of the rheumatic diseases 09/2012; 72(6). DOI:10.1136/annrheumdis-2012-202081 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The relevance of Henry's pelvic deltoid and its contribution to hip abductor strength is often not considered in hip arthroplasty. This small cadaveric study (n = 11) aimed to quantify the relative contributions of the pelvic deltoid muscles to abductor strength and to assess how different surgical approaches(anterolateral, direct lateral and posterior) impact on each of these muscle groups. We inspected the path of each approach and measured the cross-sectional area of the hip abductors, from which the contribution of each muscle to abductor moment was derived. We concluded that the posterior approach has the least impact on the pelvic deltoid and overall abductor moment.
The Journal of arthroplasty 08/2012; 28(2). DOI:10.1016/j.arth.2012.06.018 · 2.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
The Lancet 07/2012; 2012 Jul 2. [Epub ahead of print](9844-PMID:22763110). DOI:10.1016/S0140-6736(12)60681-3 · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Topography and surface chemistry have a profound effect on the way in which cells interact with an implant, which in turn impacts on clinical use and performance. In this paper we examine an electrochemical polishing approach in H2SO4/methanol that can be applied to the widely used orthopaedic/dentistry implant material, Ti6Al4V, to produce structured surfaces. The surface roughness, as characterized by R(a), was found to be dependent on the time of electropolishing but not on the voltage parameters used here. The surface chemistry, however, was dependent on the applied electrochemical potential. It was found that the chemical composition of the surface layer was modified during the electrochemical process, and at high potentials (9.0 V) a pure TiO2 layer of at least 10 nm was created on top of the bulk alloy. Characterization of these surfaces with rat cells from the osteoblast lineage provided further evidence of contact guidance by microscale topography with morphology analysis correlating with surface roughness (R(a) 300–550 nm). Formation of a bone-like matrix after long-term culture on these surfaces was not strongly dependent upon R(a) values but followed the voltage parameter. These findings suggest that the surfaces created by treatment at higher voltages (9.0 V) produced a nanoscale layer of pure TiO2 on the Ti6Al4V surface that influenced the programme of cellular differentiation culminating in osteogenesis.
[Show abstract][Hide abstract] ABSTRACT: Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11-1.23], p = 2.1 × 10(-8)) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients.
The American Journal of Human Genetics 08/2011; 89(3):446-50. DOI:10.1016/j.ajhg.2011.08.001 · 10.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Trainee surgeons must acquire expert status in the context of reduced hours, reduced operating room time and the need to learn complex skills involving screen-mediated techniques, computers and robotics. Ever more sophisticated surgical simulation strategies have been helpful in providing surgeons with the opportunity to practise, but not all of these strategies are widely available. Similarities in the motor skills required in skilled musical performance and surgery suggest that models of music learning, and particularly skilled motor development, may be applicable in training surgeons. More attention should be paid to factors associated with optimal arousal and optimal performance in surgical training - lessons learned from helping anxious musicians optimise performance and manage anxiety may also be transferable to trainee surgeons. The ways in which the trainee surgeon moves from novice to expert need to be better understood so that this process can be expedited using current knowledge in other disciplines requiring the performance of complex fine motor tasks with high cognitive load under pressure.
The Medical journal of Australia 05/2011; 194(9):463-5. · 4.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoarthritis is a common disorder in which there is not only extensive degeneration but also an aberrant attempt at repair in joints. Stem cell therapy could provide a permanent, biological solution, with all sources of stem cells (embryonic, fetal and adult) showing some degree of potential. Mesenchymal stromal/stem cells, however, appear to be the leading candidates because of their ability to be sourced from many or all joint tissues. They may also modulate the immune response of individuals, in a manner influenced by local factors. This biological behavior of stem cells renders the application of regulatory standardizations challenging in comparison to pharmaceutical therapies. However, this would not be an issue if endogenous stem cells were activated to effect repair of an arthritic joint.
Regenerative Medicine 05/2011; 6(3):351-66. DOI:10.2217/rme.11.21 · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: GPs have to respond to conflicting policy developments. As gatekeeper they are supposed to manage the growing demand for specialist services and as patient advocate they should be responsive to patients' preferences. We used an innovative approach to develop a referral guideline for patients with chronic knee pain that explicitly incorporates patients' preferences.
A guideline development group of 12 members including patients, GPs, orthopaedic surgeons and other health care professionals used formal consensus development informed by systematic evidence reviews. They rated the appropriateness of referral for 108 case scenarios describing patients according to symptom severity, age, body mass, co-morbidity and referral preference. Appropriateness was expressed on scale from 1 ('strongly disagree') to 9 ('strongly agree').
Ratings of referral appropriateness were strongly influenced by symptom severity and patients' referral preferences. The influence of other patient characteristics was small. There was consensus that patients with severe knee symptoms who want to be referred should be referred and that patient with moderate or mild symptoms and strong preference against referral should not be referred. Referral preference had a greater impact on the ratings of referral appropriateness when symptoms were moderate or severe than when symptoms were mild.
Referral decisions for patients with osteoarthritis of the knee should only be guided by symptom severity and patients' referral preferences. The guideline development group seemed to have given priority to avoiding inefficient resource use in patients with mild symptoms and to respecting patient autonomy in patients with severe symptoms.
Family Practice 02/2011; 28(1):68-74. DOI:10.1093/fampra/cmq066 · 1.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Imputation is an extremely valuable tool in conducting and synthesising genome-wide association studies (GWASs). Directly typed SNP quality control (QC) is thought to affect imputation quality. It is, therefore, common practise to use quality-controlled (QCed) data as an input for imputing genotypes. This study aims to determine the effect of commonly applied QC steps on imputation outcomes. We performed several iterations of imputing SNPs across chromosome 22 in a dataset consisting of 3177 samples with Illumina 610 k (Illumina, San Diego, CA, USA) GWAS data, applying different QC steps each time. The imputed genotypes were compared with the directly typed genotypes. In addition, we investigated the correlation between alternatively QCed data. We also applied a series of post-imputation QC steps balancing elimination of poorly imputed SNPs and information loss. We found that the difference between the unQCed data and the fully QCed data on imputation outcome was minimal. Our study shows that imputation of common variants is generally very accurate and robust to GWAS QC, which is not a major factor affecting imputation outcome. A minority of common-frequency SNPs with particular properties cannot be accurately imputed regardless of QC stringency. These findings may not generalise to the imputation of low frequency and rare variants.
European journal of human genetics: EJHG 01/2011; 19(5):610-4. DOI:10.1038/ejhg.2010.242 · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.
Annals of the rheumatic diseases 12/2010; 70(5):864-7. DOI:10.1136/ard.2010.141473 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Annals of the rheumatic diseases 11/2010; 70(2):349-55. DOI:10.1136/ard.2010.132787 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The interfacial molecular mechanisms that regulate mammalian cell growth and differentiation have important implications for biotechnology (production of cells and cell products) and medicine (tissue engineering, prosthetic implants, cancer and developmental biology). We demonstrate here that engineered protein motifs can be robustly displayed to mammalian cells in vitro in a highly controlled manner using a soluble protein scaffold designed to self assemble on a gold surface.
A protein was engineered to contain a C-terminal cysteine that would allow chemisorption to gold, followed by 12 amino acids that form a water soluble coil that could switch to a hydrophobic helix in the presence of alkane thiols. Bioactive motifs from either bone morphogenetic protein-2 or osteopontin were added to this scaffold protein and when assembled on a gold surface assessed for their ability to influence cell function. Data demonstrate that osteoblast adhesion and short-term responsiveness to bone morphogenetic protein-2 is dependent on the surface density of a cell adhesive motif derived from osteopontin. Furthermore an immobilised cell interaction motif from bone morphogenetic protein supported bone formation in vitro over 28 days (in the complete absence of other osteogenic supplements). In addition, two-dimensional patterning of this ligand using a soft lithography approach resulted in the spatial control of osteogenesis.
These data describe an approach that allows the influence of immobilised protein ligands on cell behaviour to be dissected at the molecular level. This approach presents a durable surface that allows both short (hours or days) and long term (weeks) effects on cell activity to be assessed. This widely applicable approach can provide mechanistic insight into the contribution of immobilised ligands in the control of cell activity.
[Show abstract][Hide abstract] ABSTRACT: Obesity contributes to the development of knee osteoarthritis and complicates its surgical treatment. The aim of this study was to explore barriers to effective weight management in obese patients with knee osteoarthritis.
A cross-sectional questionnaire study was performed in an elective out-patient setting and on an orthopaedic ward on patients with a body mass index (BMI) of 30 kg/m2 or over and knee osteoarthritis.
Of 47 patients approached, 45 agreed to participate. Forty of 45 patients (89%) had tried to lose weight at some point, 35 of 40 (87.5%) by adjusting their diet. Forty of 45 (89%) patients considered lack of motivation to be the greatest barrier to weight loss and only 13 of 45 (28%) pain in the knee. Patients with a BMI of less than 40 kg/m2 expressed a preference for dietary advice to help with weight loss, compared with those with a BMI of over 40 kg/m2 who expressed a preference for an NHS or other support group.
Obesity is a significant problem for many patients with knee osteoarthritis. Attendance at an orthopaedic clinic is an opportunity to address obesity, by providing information about diet and possibly support groups for morbidly obese patients. Patients may be motivated to lose weight to improve their symptoms.
Annals of The Royal College of Surgeons of England 04/2010; 92(4):338-40. DOI:10.1308/003588410X12628812458653 · 1.27 Impact Factor