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1.  Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22 
Evangelou, Evangelos | Valdes, Ana M. | Kerkhof, Hanneke J.M | Styrkarsdottir, Unnur | Zhu, YanYan | Meulenbelt, Ingrid | Lories, Rik J. | Karassa, Fotini B. | Tylzanowski, Przemko | Bos, Steffan D. | Akune, Toru | Arden, Nigel K. | Carr, Andrew | Chapman, Kay | Cupples, L. Adrienne | Dai, Jin | Deloukas, Panos | Doherty, Michael | Doherty, Sally | Engstrom, Gunnar | Gonzalez, Antonio | Halldorsson, Bjarni V. | Hammond, Christina L. | Hart, Deborah J. | Helgadottir, Hafdis | Hofman, Albert | Ikegawa, Shiro | Ingvarsson, Thorvaldur | Jiang, Qing | Jonsson, Helgi | Kaprio, Jaakko | Kawaguchi, Hiroshi | Kisand, Kalle | Kloppenburg, Margreet | Kujala, Urho M. | Lohmander, L. Stefan | Loughlin, John | Luyten, Frank P. | Mabuchi, Akihiko | McCaskie, Andrew | Nakajima, Masahiro | Nilsson, Peter M. | Nishida, Nao | Ollier, William E.R. | Panoutsopoulou, Kalliope | van de Putte, Tom | Ralston, Stuart H. | Rivadeneira, Fernado | Saarela, Janna | Schulte-Merker, Stefan | Slagboom, P. Eline | Sudo, Akihiro | Tamm, Agu | Tamm, Ann | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Tsezou, Aspasia | Wallis, Gillian A. | Wilkinson, J. Mark | Yoshimura, Noriko | Zeggini, Eleftheria | Zhai, Guangju | Zhang, Feng | Jonsdottir, Ingileif | Uitterlinden, Andre G. | Felson, David T | van Meurs, Joyce B. | Stefansson, Kari | Ioannidis, John P.A. | Spector, Timothy D.
Annals of the rheumatic diseases  2010;70(2):349-355.
Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in the elderly. It is characterized by changes in joint structure including degeneration of the articular cartilage and its etiology is multifactorial with a strong postulated genetic component. We performed a meta-analysis of four genome-wide association (GWA) studies of 2,371 knee OA cases and 35,909 controls in Caucasian populations. Replication of the top hits was attempted with data from additional ten replication datasets. With a cumulative sample size of 6,709 cases and 44,439 controls, we identified one genome-wide significant locus on chromosome 7q22 for knee OA (rs4730250, p-value=9.2×10−9), thereby confirming its role as a susceptibility locus for OA. The associated signal is located within a large (500kb) linkage disequilibrium (LD) block that contains six genes; PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, beta), 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 (the 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.
doi:10.1136/ard.2010.132787
PMCID: PMC3615180  PMID: 21068099
2.  The effect of genome-wide association scan quality control on imputation outcome for common variants 
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 610k (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.
doi:10.1038/ejhg.2010.242
PMCID: PMC3083623  PMID: 21267008
genome-wide association study; imputation; quality control; single nucleotide polymorphism
3.  Barriers to weight loss in obese patients with knee osteoarthritis 
INTRODUCTION
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.
PATIENTS AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1308/003588410X12628812458653
PMCID: PMC3025198  PMID: 20385042
Weight loss; Obesity; Knee osteoarthritis
4.  Referral recommendations for osteoarthritis of the knee incorporating patients' preferences 
Family Practice  2010;28(1):68-74.
Background. 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.
Methods. 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’).
Results. 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.
Conclusions. 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.
doi:10.1093/fampra/cmq066
PMCID: PMC3023074  PMID: 20817791
Clinical practice guideline; gatekeeping; knee; osteoarthrits; patient preference; referral and consultation
5.  Controlled spatial and conformational display of immobilised bone morphogenetic protein-2 and osteopontin signalling motifs regulates osteoblast adhesion and differentiation in vitro 
BMC Biology  2010;8:57.
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.
Results
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.
Conclusion
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.
doi:10.1186/1741-7007-8-57
PMCID: PMC2880964  PMID: 20459712
6.  Bone density of the femoral neck following Birmingham hip resurfacing 
Acta Orthopaedica  2009;80(6):660-665.
Background Resurfacing is a popular alternative to a standard hip replacement in young arthritic patients. Despite bone preservation around the femoral component, there is little information regarding the bone quality.
Patients and methods 32 patients underwent consecutive Birmingham hip resurfacing. The bone density of the femoral neck was measured preoperatively and then at 6 weeks, 3 months, 1 year, and 2 years. The femoral neck was divided into regions of interest. Results were available for 27 hips in 26 patients.
Results The overall femoral neck bone density showed a trend towards a decrease at 6 weeks and 3 months but returned to the preoperative level at 1 year, and was maintained at 2 years. The combined superior regions of the neck showed a statistically significant decrease in bone density at 6 weeks and 3 months. This returned to preoperative levels at 1 year and was maintained at 2 years.
Interpretation Bone density appears to decrease at 6 weeks and 3 months, suggesting that care is necessary until bone density begins to recover.
doi:10.3109/17453670903486992
PMCID: PMC2823310  PMID: 19995316
7.  Injury to the Lateral Femoral Cutaneous Nerve During Minimally Invasive Hip Surgery: A Cadaver Study 
INTRODUCTION
A smaller skin incision as part of minimally invasive surgery (MIS) for total hip arthroplasty (THA) is thought to reduce local tissue trauma. Preservation of cutaneous nerves may reduce postoperative pain and improve rehabilitation. The standard lateral approach (SLA) and two MIS approaches (anterolateral [ALA] and posterior [PA]) were compared to determine which incision preserved cutaneous nerves.
PATIENTS AND METHODS
Fifteen cadaveric hip specimens were dissected to establish the course of branches of the lateral femoral cutaneous nerve. The number of branches divided by each of the three incisions was recorded.
RESULTS
The MIS incisions resulted in significantly less nerve division compared with the SLA. The mean difference between the SLA and the ALA was 4.4 (P < 0.0001), and between the SLA and the PA was 1.4 (P = 0.0005). The ALA divided significantly fewer nerves compared with the PA (mean difference = 3; P = 0.0001).
DISCUSSION
There is little evidence of the benefit of one MIS approach over another in the literature. The ALA preserved significantly more cutaneous nerves in this study. These results need corroboration with clinical outcomes to determine their significance.
doi:10.1308/003588408X261618
PMCID: PMC2430431  PMID: 18430336
Hip replacement arthroplasty
8.  No evidence of an association between mitochondrial DNA variants and osteoarthritis in 7393 cases and 5122 controls 
Annals of the Rheumatic Diseases  2012;72(1):136-139.
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1136/annrheumdis-2012-201932
PMCID: PMC3551219  PMID: 22984172
Gene Polymorphism; Osteoarthritis; Pharmacogenetics
9.  Evaluation of the genetic overlap between osteoarthritis with body mass index and height using genome-wide association scan data 
Annals of the Rheumatic Diseases  2012;72(6):935-941.
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1136/annrheumdis-2012-202081
PMCID: PMC3664369  PMID: 22956599
Osteoarthritis; Gene Polymorphism; Epidemiology

Results 1-9 (9)