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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., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: Published studies have tested over 90 genes for association with osteoarthritis (OA), but few positives reported have been independently replicated. Using a new case-control study, our aim was to attempt the replication of findings from 12 genes reported to have significant genetic association with OA and to further examine the role of genetic variation in six of these genes., Methods: A case-control study was undertaken in Nottingham, UK. Hospital-referred index cases with symptomatic, radiographic OA (ROA) of the knee (n=1040) or hip (n=1004) were recruited. Asymptomatic controls (n=1123) were recruited from intravenous urography waiting lists and screened for radiographic hip and knee OA. Sixty-eight polymorphisms were genotyped in IL1A, IL1B, IL1RN, IL4R, IL6, COL2A1, ADAM12, ASPN, IGF1, TGFB1, ESR1 and VDR. Statistical analysis compared allele or genotype frequencies of these polymorphisms in all asymptomatic controls and the subset of controls without ROA vs all OA, knee OA and hip OA. The analyses were adjusted for age, gender and body mass index., Results: We were unable to replicate any of the published genetic associations investigated. Our extended exploratory analyses identified some associations between polymorphisms in TGFB1, IGF1 and IL1RN and OA; but the strength of evidence varied with the control group used., Conclusion: Lack of replication is common and could be due to differences in study design, phenotype, populations examined or the occurrence of false positives in the initial study. Variants within TGFB1, IGF1 and IL1RN could have a role in OA susceptibility; however, replication of these findings is required in an independent study.

Background: Mapping has been used to convert scores from condition-specific measures into utility scores, and to produce estimates of cost-effectiveness. We sought to compare the QALY gains, and incremental cost per QALY estimates, predicted on the basis of mapping to those based on actual EQ-5D scores., Methods: In order to compare 4 different interventions 389 individuals were asked to complete both the EQ-5D and the Western Ontartio and McMaster Universities Osteoarthritis Index (WOMAC) at baseline, 6, 12, and 24 months post-intervention. Using baseline data various mapping models were developed, where WOMAC scores were used to predict the EQ-5D scores. The performance of these models was tested by predicting the EQ-5D post-intervention scores. The preferred model (that with the lowest mean absolute error (MAE)) was used to predict the EQ-5D scores, at all time points, for individuals who had complete WOMAC and EQ-5D data. The mean QALY gain associated with each intervention was calculated, using both actual and predicted EQ-5D scores. These QALY gains, along with previously estimated changes in cost, were also used to estimate the actual and predicted incremental cost per QALY associated with each of the four interventions., Results: The EQ-5D and the WOMAC were completed at baseline by 348 individuals, and at all time points by 259 individuals. The MAE in the preferred model was 0.129, and the mean QALY gains for each of the four interventions was predicted to be 0.006, 0.058, 0.058, and 0.136 respectively, compared to the actual mean QALY gains of 0.087, 0.081, 0.120, and 0.149. The most effective intervention was estimated to be associated with an incremental cost per QALY of pound6,068, according to our preferred model, compared to pound13,154 when actual data was used., Conclusion: We found that actual QALY gains, and incremental cost per QALY estimates, differed from those predicted on the basis of mapping. This suggests that though mapping may be of value in predicting the cost-effectiveness of interventions which have not been evaluated using a utility measure, future studies should be encouraged to include a method of actual utility measurement., Trial Registration: Current Controlled Trials ISRCTN93206785.

Background: Fractures of the shaft of the tibia often heal with some angulation. Although there is biomechanical evidence that such angulation alters load transmission through the joints of the lower limb, it is not clear whether it can eventually lead to osteoarthritis., Methods: One hundred and sixty-four individuals who had sustained a tibial shaft fracture were assessed in a research clinic thirty to forty-three years after the injury. The subjects were evaluated with regard to self-reported lower limb joint pain, stiffness, and disability (assessed with the Western Ontario and McMaster Universities [WOMAC] osteoarthritis questionnaire); clinical signs of osteoarthritis; and radiographic evidence of osteophytes and joint-space narrowing in the knees, ankles, and subtalar joints., Results: Twenty-two (15%) of the 151 subjects who reported no other knee injury reported at least moderate knee pain, and eight (6%) of the 145 subjects who reported no other ankle injury reported at least moderate ankle pain. Seventeen (13%) of the 135 subjects who reported no other knee or ankle injury reported at least moderate disability. The ipsilateral side demonstrated a higher prevalence than the contralateral side in terms of pain with passive ankle movement (nineteen versus nine subjects, p = 0.02), pain with passive subtalar movement (fifteen versus four subjects, p = 0.01), and radiographic signs of ankle joint space narrowing (twelve subjects versus one subject, p = 0.0055). Knee osteoarthritis was frequently bilateral. Forty-seven fractures (29%) healed with coronal angulation of > or = 5 degrees. Apart from an association between shortening of > or = 10 mm and self-reported knee pain (p = 0.016), there were no significant univariate associations between these malunions and the development of osteoarthritis. Seventeen (15%) of 114 eligible subjects had overall malalignment of the lower limb, defined as a hip-knee-ankle angle outside the normal range of 6.25 degrees of varus to 4.75 degrees of valgus. This malalignment was due to the fracture malunion in nine subjects and predated the fracture in eight. In limbs with varus or valgus malalignment, there was an excess of subtalar stiffness (p = 0.04) and a nonsignificant trend toward more frequent knee pain. In limbs with varus malalignment, there was a nonsignificant trend toward more frequent radiographic evidence of osteoarthritis in the medial compartment of the knee joint. Most of the subjects in whom osteoarthritis was observed had normal overall alignment of the lower limb., Conclusions: The thirty-year outcome after a tibial shaft fracture is usually good, although mild osteoarthritis is common. Fracture malunion is not the cause of the higher prevalence of symptomatic ankle and subtalar osteoarthritis on the side of the fracture. Although varus malalignment of the lower limb occurs occasionally and may cause osteoarthritis in the medial compartment of the knee, other factors are more important in causing osteoarthritis after a tibial shaft fracture.

Objective: To assess the prevalence of knee pain, disability and health status in the community, and to examine the association of pain with psychological distress., Methods: A postal survey was sent to 4057 men and women aged 40-79 yr in Nottingham. Health status was assessed using the SF-36 instrument, with the specific dimensions of physical function and mental health used to measure disability and psychological distress., Results: The overall response rate was 81.9%. The prevalence of knee pain was 28.7%, rising with age. Disability was more common in those with knee pain compared to those without pain (P < 0.001). Subjects with knee pain had lower scores for all dimensions of health. When adjusted for potential confounders, low mental health scores associated with increased odds for pain and disability (2.1, 95% CI 1.7-2.6; and 4.7, 95% CI 3.7-6.1)., Conclusions: Knee pain is common in this population and is associated with poor perceived health and significant disability. Psychological distress strongly associates with both pain and disability.

Objectives: To investigate longterm pain and disability subsequent to a tibial shaft fracture treated conservatively., Design and Setting: Subjects who had sustained a tibial shaft fracture more than 27 years ago were compared with those who had not., Subjects: 572 fracture patients (identified from the records of the plaster room) aged over 16 at the time of injury were contracted and were compared with 2285 randomly selected subjects matched for age, sex, and general practice., Main Outcome Measures: Self reported knee pain; self reported GP's diagnosis of osteoarthritis; ability to climb stairs, walk 100 yards, to bend, kneel, or stoop; and SF-36 physical functioning score., Results: Subjects were reviewed between 27 and 41 years after tibial shaft fracture (mean 35 years). Fracture patients were more likely to suffer chronic knee pain (odds ratio 1.23; 95% confidence interval (CI) 1.00, 1.51) and report being given a diagnosis of osteoarthritis by their GP (odds ratio 1.46; 95% CI 1.08, 1.97). The ability to climb stairs, walk 100 yards, and bend, kneel, or stoop was less in the fracture group than the other subjects. The SF-36 physical function score was significantly lower in the fracture group., Conclusions: More than 27 years after a tibial shaft fracture, subjects have more knee pain than the rest of the population. They also have greater difficulty performing everyday physical activities. The excess morbidity may be due to injury factors or treatment factors, and further research is needed to investigate this important association further.

Objective: To compare three questions on knee pain with respect to determined prevalence and associations with disability and structural change., Methods: Postal survey to 4057 men and women aged 40-79 years. Knee pain was defined by three questions: (A) "Have you ever had pain in or around the knee on most days for at least a month? If so, have you experienced any pain during the last year?" (B) "Have you had pain within the last year in or around the knee that occurred on most days for at least a month?" (C) "Have you had knee pain on most days of the last month?" [American College of Rheumatology (ACR) criteria for knee osteoarthritis]. Disability was assessed with the SF-36 health status questionnaire. Radiographs (AP weight bearing and skyline) were obtained on a proportion (n = 459) and graded for maximum osteophyte in any compartment., Results: Prevalence of knee pain for questions A, B, and C were 28.3%, 25.3%, and 19.3% respectively. Highest rates of disability were observed for question C (71.3% compared with 60.9% for question A). There was no major difference between questions in terms of percentage with > or = grade 1 osteophyte or > or = grade 2 osteophyte. Sensitivity and specificity of each question for > or = grade 1 osteophyte did vary, with question A being most sensitive but least specific (58.7% and 59.1%) and question C most specific (72.7%) but least sensitive (45.4%)., Conclusions: Estimates of knee pain and disability are influenced by even minor changes in question content. The ACR criteria question may be a better predictor of disability but is relatively insensitive for use in the community.