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Objective: Variation in the fat mass and obesity-associated (FTO) gene influences susceptibility to obesity. A variant in the FTO gene has been implicated in genetic risk to osteoarthritis (OA). We examined the role of the FTO polymorphism rs8044769 in risk of knee and hip OA in cases and controls incorporating body mass index (BMI) information., Methods: 5409 knee OA patients, 4355 hip OA patients and up to 5362 healthy controls from 7 independent cohorts from the UK and Australia were genotyped for rs8044769. The association of the FTO variant with OA was investigated in case/control analyses with and without BMI adjustment and in analyses matched for BMI category. A mendelian randomisation approach was employed using the FTO variant as the instrumental variable to evaluate the role of overweight on OA., Results: In the meta-analysis of all overweight (BMI≥25) samples versus normal-weight controls irrespective of OA status the association of rs8044769 with overweight is highly significant (OR[CIs] for allele G=1.14 [01.08 to 1.19], p=7.5×10(-7)). A significant association with knee OA is present in the analysis without BMI adjustment (OR[CIs]=1.08[1.02 to 1.14], p=0.009) but the signal fully attenuates after BMI adjustment (OR[CIs]=0.99[0.93 to 1.05], p=0.666). We observe no evidence for association in the BMI-matched meta-analyses. Using mendelian randomisation approaches we confirm the causal role of overweight on OA., Conclusions: Our data highlight the contribution of genetic risk to overweight in defining risk to OA but the association is exclusively mediated by the effect on BMI. This is consistent with what is known of the biology of the FTO gene and supports the causative role of high BMI in OA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: to compare the combined role of genetic variants loci associated with risk of knee or hip osteoarthritis (OA) in post-traumatic (PT) and non-traumatic (NT) cases of clinically severe OA leading to total joint replacement., Methods: A total of 1590 controls, 2168 total knee replacement (TKR) cases (33.2% PT) and 1567 total hip replacement (THR) cases (8.7% PT) from 2 UK cohorts were genotyped for 12 variants previously reported to be reproducibly associated with risk of knee or hip OA. A genetic risk score was generated and the association with PT and NT TKR and THR was assessed adjusting for covariates., Results: For THR, each additional genetic risk variant conferred lower risk among PT cases (OR=1.07, 95% CI 0.96 to 1.19; p=0.24) than NT cases (OR 1.11, 95% CI 1.06 to 1.17; p=1.55×10⁻⁵). In contrast, for TKR, each risk variant conferred slightly higher risk among PT cases (OR 1.12, 95% CI 1.07 to 1.19; p=1.82×10⁻⁵) than among NT cases (OR 1.08, 95% CI 1.03 to 1.1; p=0.00063)., Conclusions: Based on the variants reported to date PT TKR cases have at least as high a genetic contribution as NT cases.

Objective: Knee osteoarthritis (OA) has a significant genetic component. The authors have assessed the role of three variants reported to influence risk of knee OA with p<5×10-8 in determining patellofemoral and tibiofemoral Kellgren Lawrence (K/L) grade in knee OA cases., Methods: 3474 knee OA cases with sky-line and weight-bearing antero-posterior x-rays of the knee were selected based on the presentation of K/L grade ≥2 at either the tibiofemoral or patellofemoral compartments for one or both knees. Patients belonging to three UK cohorts, were genotyped for rs143383, rs4730250 and rs11842874 mapping to the GDF5, COG5 and MCF2L genes, respectively. The association between tibiofemoral K/L grade and patellofemoral K/L grade was assessed after adjusting for age, gender and body mass index., Results: No significant association was found between the rs4730250 and radiographic severity. The rs11842874 mapping to MCF2L was found to be nominally significantly associated with patellofemoral K/L grade as a quantitative trait (p=0.027) but not as a binary trait. The GDF5 single nucleotide polymorphism rs143383 was associated with tibiofemoral K/L grade (β=0.05 (95% CI 0.02 to 0.08) p=0.0011)., Conclusions: Our data indicate that within individuals affected by radiographic knee OA, OAGDF5 has a modest but significant effect on radiographic severity after adjustment for the major risk factors.

Objectives: The aim of this study was to assess if genetic variation in the PACE4 (paired amino acid converting enzyme 4) gene Pcsk6 influences the risk for symptomatic knee osteoarthritis (OA)., Methods: Ten PCSK6 single nucleotide polymorphisms were tested for association in a discovery cohort of radiographic knee OA (n=156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout mice and wild-type C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P, pain behaviours in response to intrathecal substance P and pain behaviour in the abdominal constriction test., Results: In the discovery cohort of radiographic knee OA, an intronic single nucleotide polymorphism at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an OR=1.35 (95% CI 1.17 to 1.56; p=4.3×10(-5) and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout mice were significantly protected against pain in a battery of algesiometric assays., Conclusions: These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why, in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain.

Objective: To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA)., Methods: The Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile-Ile and risk of symptomatic and asymptomatic knee OA was assessed., Results: The TRPV1 585 Ile-Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile-Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue., Conclusions: A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.

Objectives: (1) To develop risk prediction models for knee osteoarthritis (OA) and (2) to estimate the risk reduction that results from modification of potential risk factors., Method: This was a 12-year retrospective cohort study undertaken in the general population in Nottingham, UK. Baseline risk factors were collected by questionnaire. Incident radiographic knee OA was defined by Kellgren and Lawrence (KL) score ≥2. Incident symptomatic knee OA was defined by KL ≥2 plus knee pain. Progression of knee OA was defined by KL ≥1 grade increase from baseline. A logistic regression model was used for prediction. Calibration and discrimination of the models were tested in the Osteoarthritis Initiative (OAI) population and Genetics of Osteoarthritis and Lifestyle (GOAL) population. ORs of the models were compared with those obtained from meta-analysis of existing literature., Results: From a community sample of 424 people aged over 40, 3 risk prediction models were developed. These included incidence of radiographic knee OA, incidence of symptomatic knee OA and progression of knee OA. All models had good calibration and moderate discrimination power in OAI and GOAL. The ORs lied within the 95% CIs of the published studies. The risk reduction due to modifying obesity at the individual and the population levels were demonstrated., Conclusions: Risk prediction of knee OA based on the well established, common modifiable risk factors has been established. The models may be used to predict the risk of knee OA, and risk reduction due to preventing a specific risk factor.

Objective: To determine whether mild variation in acetabular depth (AD) and shape is a risk factor for osteoarthritis (OA) of the hip., Methods: The unaffected contralateral hip of patients with unilateral hip OA was compared with hips of asymptomatic controls without hip OA, derived from the Nottingham Genetics Osteoarthritis and Lifestyle case-control study. Standardised anteroposterior x-rays of the pelvis were used to measure centre edge (CE) angle and AD. Cut-off points for narrow CE angle and shallow AD were calculated from the control group (mean -1.96 × SD). The relative risk of hip OA associated with each feature was estimated using OR and 95% CI and adjusted risks were calculated by logistic regression., Results: In controls, both the CE angle and the AD were lower in the left hip than in the right hip. The CE angle related to age in both hips, and AD of the right hip was lower in men than in women. The contralateral unaffected hip in patients with unilateral hip OA had a decreased CE angle and AD compared with controls, irrespective of side. The lowest tertile of the CE angle in contralateral hips was associated with an eightfold risk of OA (aOR 8.06, 95% CI 4.87 to 13.35) and the lowest tertile of AD was associated with a 2.5-fold risk of OA (aOR 2.53, 95% CI 1.28 to 5.00). Significant increases in the risk of OA were also found as the CE angle and AD decreased., Conclusion: Constitutional mild acetabular dysplasia appears to increase the risk of hip OA.

Background: Physical activity is being recommended as an intervention for seemingly almost universal improvements to health. A potential concern with this recommendation for increased exercise is that some believe increased levels of activity may lead to increased incidence of osteoarthritis of the knee (knee OA), as a result of accelerated "wear and tear" of the major joints., Objective: To investigate the hypothesis that the occurrence of knee OA may be related to the duration of participation in some forms of sport and active recreation., Methods: The relation between habitual exercise, reported by a cross section of people surveyed in England, and self reported knee OA was investigated. Data were derived from the Allied Dunbar National Fitness Survey (1990-91). A matched retrospective case-control design was used and a new exposure classification system which categorised different grades of activities for different time periods for each subject's lifetime participation in regular physical activities was developed. Additional data on knee injuries sustained and bodily composition were also included in a multivariate analysis., Results: From 4316 people originally interviewed, 216 eligible cases (66 men, 150 women) were identified (mean age 57.1). Each case was matched to four controls. When habitual sport/exercise participation were examined during a subject's life, only exposure to regular long walks and being physically active between the ages of 20 and 24 suggested any association with developing knee OA later in life. The only strong association found was a greatly increased risk of knee OA having previously sustained a knee injury (p<0.01, odds ratio 8.0 (95% confidence interval 2.0 to 32.0))., Conclusions: There was little evidence to suggest that increased levels of regular physical activity throughout life lead to an increased risk of knee OA later in life. Previous knee injury was associated with an increased risk of knee OA. Additionally, most injuries were caused through participation in physical activities. Hence, when deciding on participation in activities, it is worth taking the likelihood of joint injury into consideration, as the chance of injury is greater in some activities than others.

Objectives: Systemic lupus erythematosus (SLE) patients of Afro-Caribbean and Asian origin living in the United Kingdom have a more severe spectrum of disease compared with the white population but whether this is attributable to genetic host factors or environmental factors is unclear. This study examines time from first symptom to onset of persistent proteinuria, as a marker of renal disease, to assess which factors are important., Methods: The 189 patients studied were ascertained using multiple methods and included 161 white, 22 Afro-Caribbean and six Asian patients. Time of first observation of persistent proteinuria (>/=0.5 g/day) was taken as onset of renal SLE. Initial univariate analysis to determine which factors are associated with onset of renal disease was followed by using a Cox's proportional hazards regression model enabling analysis of several prognostic factors at the same time. Variables included three measures of socioeconomic status, ethnic group and the presence or absence of different autoantibodies., Results: There was no effect from any socioeconomic variable. Using forwards stepwise selection, the following had independent effects (p<0.05) on the development of renal SLE: Afro-Caribbean race (hazard rate ratio 4.4 (1.9-10.2), compared with white population); and the presence of IgG anti-cardiolipin antibodies (hazard rate ratio 2.6 (1.2-5.7))., Conclusion: Differing socioeconomic factors do not explain the increased frequency of lupus nephritis in Afro-Caribbean patients with SLE, but rather there are important genetic or other host differences. The independent effect of IgG anti-cardiolipin antibodies warrants further investigation.

Objective: To assess the effect of a home based exercise programme, designed to improve quadriceps strength, on knee pain and disability., Methods: 191 men and women with knee pain aged 40-80 were recruited from the community and randomised to exercise (n = 113) or no intervention (n = 78). The exercise group performed strengthening exercises daily for six months. The primary outcome measure was change in knee pain (Western Ontario McMaster Osteoarthritis index (WOMAC)). Secondary measures included visual analogue scales (VAS) for pain on stairs and walking and WOMAC physical function scores., Results: WOMAC pain score reduced by 22.5% in the exercise group and by 6.2% in the control group (between group difference p < 0.05, unpaired t test). VAS scores for pain also reduced in the exercise group compared with the control group (p < 0.05). Physical function scores reduced by 17.4% in the exercise group and were unchanged in controls (p < 0.05)., Conclusion: A simple programme of home quadriceps exercises can significantly improve self reported knee pain and function.

Objectives: (1) To determine the importance of quadriceps strength, structural change, and psychological status in terms of knee pain in the community. (2) To determine the relative importance of quadriceps function, structural change, and psychological status with respect to disability in subjects with knee pain., Methods: 300 men and women with pain and 300 controls without pain (aged 40-79) were seen. Isometric quadriceps strength (MVC) was measured and muscle activation was assessed by twitch superimposition. Disability (Western Ontario McMaster Osteoarthritis Index (WOMAC)) and anxiety and depression were assessed (Hospital Anxiety and Depression Index (HAD)). Radiographs were obtained of the tibiofemoral and patellofemoral joints and total score for osteophyte, narrowing, and sclerosis calculated for each knee., Results: Subjects with knee pain had lower voluntary quadriceps strength than those without pain (p < 0.005). Quadriceps activation was also lower (p < 0.005), but did not fully explain the reduction in strength. When analysed by multiple logistic regression: quadriceps strength (odds ratio 18.8, CI 4.8, 74.1 for MVC < or = 10 kgF); depression (odds ratio 2.4, CI 1.0, 5.5 for HAD score > or = 8); and radiographic change (odds ratio 4.1, CI 1.9, 8.6 for radiographic score > or = 4) were independently associated with pain. In those with knee pain, disability was independently associated with quadriceps strength (odds ratio 8.2, CI 1.5, 44.4 for MVC < or = 10 kgF) and depression (odds ratio 6.2, CI 2.1, 18.0 for HAD score > or = 8); but not with radiographic score., Conclusions: Quadriceps strength is strongly associated with knee pain and disability in the community, even when activation and psychological factors are taken into account. This has important therapeutic implications.

Objective: To investigate the effect of smoking on the development of systemic lupus erythematosus (SLE), and the association between alcohol consumption and the disease., Methods: 450 subjects (150 SLE patients and 300 controls) from Nottingham, UK were interviewed in a case-control study. Controls were matched to cases for age and sex. All patients met at least four of the American Rheumatology Association criteria for SLE. Controls were randomly selected from the Nottingham Family Health Services Authority register. Information was collected by interview administered questionnaire concerning demographic variables, smoking histories, and drinking habits., Results: Analysis of the data by conditional logistic regression revealed current smokers to have a significantly increased risk of development of SLE compared with never smokers (odds ratio (OR) 1.95, 95% confidence intervals (CI) 1.14, 3.31), although ex-smokers were not at increased risk. There was also suggestion of a marked, highly significant negative association between SLE and alcohol consumption, the magnitude of which increased with units consumed., Conclusions: This study suggests that current smokers are at increased risk of developing SLE compared with non-smokers and ex-smokers. In contrast, alcohol consumption seems to be negatively associated with the disease.

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.

Objectives: To determine the geographical distribution of cases of systemic lupus erythematosus (SLE) in a defined geographical area in the East Midlands, UK, and, in particular, to search for spatial variation in cases that may implicate the role of environmental factors in SLE aetiology., Methods: Six methods of case ascertainment were used. The postcode of the patient's domicile at time of first definite symptom of SLE was used for analysis which included case mapping, probability mapping by electoral ward, and variogram analysis., Results: The study area population of 613,700 contained 200 SLE patients, 188 of whom experienced their first symptom whilst residing in the area. Case mapping revealed 12 SLE patients residing within an area of one square mile, including four men and six patients with RNP antibodies. The use of probability mapping showed five wards in close proximity to each other to have a greater number of SLE cases than would be expected by chance (p < 0.1). The 'cluster' of patients seen on the case map fell into two wards which showed a significant excess of cases only when combined (p = 0.006). The variogram of the incidence rates for each ward did not confirm any structure or pattern to the distribution of cases for the whole area., Conclusions: Some areas have a greater than expected prevalence of SLE. The normal result from variogram analysis suggests that the cause(s) for these excess number of cases does not have an effect across the whole study area.