Kenneth R Muir

Publications of Kenneth R Muir

• A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype.

  Authors: Anne-Marie Malfait, Albert B Seymour, Feng Gao, Micky D Tortorella, Marie-Pierre Hellio Le Graverand-Gastineau, Linda S Wood, Michael Doherty, Sally Doherty, Weiya Zhang, Nigel K Arden [......] Tim D Spector, Deborah J Hart, Rose A Maciewicz, Kenneth R Muir, Rosalina Das, Robert E Sorge, Susanna G Sotocinal, Ara Schorscher-Petcu, Ana M Valdes, Jeffrey S Mogil

  Annals of the rheumatic diseases. 03/2012;

  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 osteoarthritisOBJECTIVES: 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.

• Self-reported knee malalignment in early adult life as an independent risk for knee chondrocalcinosis.

  Authors: Abhishek Abhishek, Sally Doherty, Rose A Maciewicz, Kenneth R Muir, Weiya Zhang, Michael Doherty

  Arthritis care & research. 11/2011; 63(11):1550-7.

  To determine if self-reported current and early adult life knee malalignment is associated with knee chondrocalcinosis (CC). A case-control study embedded in the Genetics of Osteoarthritis andTo determine if self-reported current and early adult life knee malalignment is associated with knee chondrocalcinosis (CC). A case-control study embedded in the Genetics of Osteoarthritis and Lifestyle (GOAL) study was performed. A validated self-reported line-drawing instrument was mailed to 3,022 participants of GOAL, inquiring about knee malalignment (straight, valgus, varus) in their third decade (20s) and currently. Self-reported weight in 20s and present weight and height measured at the initial visit were used to calculate body mass index (BMI) in 20s and currently. Occupational risk was present if participants self-reported mechanically demanding activities in their longest held job. Cases were participants with radiographic CC at any tibiofemoral (TF) joints. Osteoarthritis was defined as a Kellgren/Lawrence score of ≥3 at TF joints or patellofemoral joints. Odds ratio (OR), adjusted OR, and 95% confidence interval (95% CI) were calculated for associations with knee CC. A total of 2,167 participants responded to the questionnaire, of which 7.5% respondents had knee CC. Knee CC was associated with self-reported varus (adjusted OR 1.77 [95% CI 1.05, 2.98]) and any knee malalignment in 20s (adjusted OR 1.64 [95% CI 1.02, 2.64]). This association was not restricted to the mechanically loaded TF compartment. There was no association between current knee malalignment and knee CC. Age (adjusted OR 1.73 [95% CI 1.36, 2.19]) and knee OA (adjusted OR 2.88 [95% CI 1.89, 4.38]) were associated with knee CC. There was no association between BMI in 20s (adjusted OR 1.14 [95% CI 0.92, 1.42]), occupational risk (adjusted OR 1.32 [95% CI 0.94, 1.85]), and knee CC. Early life knee malalignment, predominantly varus, is an independent risk factor for knee CC. This association is not restricted to the mechanically loaded compartment, implying a generalized predisposition throughout the knee.

• A variant in MCF2L is associated with osteoarthritis.

  Authors: Aaron G Day-Williams, Lorraine Southam, Kalliope Panoutsopoulou, Nigel W Rayner, Tonu Esko, Karol Estrada, Hafdis T Helgadottir, Albert Hofman, Throvaldur Ingvarsson, Helgi Jonsson [......] Andres Metspalu, Fernando Rivadeneira, Kari Stefansson, Unnur Styrkarsdottir, Andre G Uitterlinden, Joyce B J van Meurs, Weiya Zhang, Ana M Valdes, Michael Doherty, Eleftheria Zeggini

  American journal of human genetics. 08/2011; 89(3):446-50.

  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 forOsteoarthritis (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.

• Inverse Relationship Between Preoperative Radiographic Severity and Postoperative Pain in Patients with Osteoarthritis who Have Undergone Total Joint Arthroplasty.

  Authors: Ana M Valdes, Sally A Doherty, Weiya Zhang, Kenneth R Muir, Rose A Maciewicz, Michael Doherty

  Seminars in arthritis and rheumatism. 08/2011; 41(4):568-75.

  To determine cross-sectionally the influence of risk factors on chronic pain following total joint replacement (TJR) of the knee (TKR) or the hip (THR). Eight hundred sixty post-TKR and 928 post-THRTo determine cross-sectionally the influence of risk factors on chronic pain following total joint replacement (TJR) of the knee (TKR) or the hip (THR). Eight hundred sixty post-TKR and 928 post-THR patients were studied. Western Ontario and McMaster Osteoarthritis Index pain scores taken on average 3.2 years postsurgery were correlated to preoperative radiographic severity measured by Kellgren-Lawrence grade (K/L) grade for the knee, Croft grade, and minimum joint space width (minJSW) for the hip and presence of comorbidities. Known risk factors were able to explain less than 20% of the variance in pain scores post-TJR. The presence of chronic widespread pain determined a higher risk of high pain in both TKR cases (odds ratio (OR) = 3.15 95%CI 1.86-5.30) and THR cases (OR = 5.02 95%CI 2.76-9.14). Other risk factors common to both TKR and THR pain postsurgery were the presence of depression, higher body mass index, younger age, and female gender. Interestingly, low radiographic grade at the index joint presurgery (defined as tibiofemoral K/L <3 for the knee and minJSW >2 mm for the hip) resulted in a significantly increased risk of high pain post-TJR (OR = 1.56; 95%CI 1.04-2.36). The risk factors contributing to chronic pain post-TJR remain mostly unknown. Individuals with lower preoperative radiographic OA severity undergoing TJR are more likely to experience high pain post-TJR.

• A novel approach to exploring potential interactions among single-nucleotide polymorphisms of inflammation genes in gliomagenesis: an exploratory case-only study.

  Authors: E Susan Amirian, Michael E Scheurer, Yanhong Liu, Anthony M D'Amelio, Richard S Houlston, Carol J Etzel, Sanjay Shete, Anthony J Swerdlow, Minouk J Schoemaker, Patricia A McKinney, Sarah J Fleming, Kenneth R Muir, Artitaya Lophatananon, Melissa L Bondy

  Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 07/2011; 20(8):1683-9.

  Despite extensive research on the topic, glioma etiology remains largely unknown. Exploration of potential interactions between single-nucleotide polymorphisms (SNP) of immune genes is a promisingDespite extensive research on the topic, glioma etiology remains largely unknown. Exploration of potential interactions between single-nucleotide polymorphisms (SNP) of immune genes is a promising new area of glioma research. The case-only study design is a powerful and efficient design for exploring possible multiplicative interactions between factors that are independent of one another. The purpose of our study was to use this exploratory design to identify potential pair wise SNP-SNP interactions from genes involved in several different immune-related pathways for investigation in future studies. The study population consisted of two case groups: 1,224 histologic confirmed, non-Hispanic white glioma cases from the United States and a validation population of 634 glioma cases from the United Kingdom. Polytomous logistic regression, in which one SNP was coded as the outcome and the other SNP was included as the exposure, was utilized to calculate the ORs of the likelihood of cases simultaneously having the variant alleles of two different SNPs. Potential interactions were examined only between SNPs located in different genes or chromosomes. Using this data mining strategy, we found 396 significant SNP-SNP interactions among polymorphisms of immune-related genes that were present in both the U.S. and U.K. study populations. This exploratory study was conducted for the purpose of hypothesis generation, and thus has provided several new hypotheses that can be tested using traditional case-control study designs to obtain estimates of risk. This is the first study, to our knowledge, to take this novel approach to identifying SNP-SNP interactions relevant to glioma etiology.

• Nottingham knee osteoarthritis risk prediction models.

  Authors: Weiya Zhang, Daniel F McWilliams, Sarah L Ingham, Sally A Doherty, Stella Muthuri, Kenneth R Muir, Michael Doherty

  Annals of the rheumatic diseases. 05/2011; 70(9):1599-604.

  (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. This was a 12-year retrospective(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. 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. 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. 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.

• The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis.

  Authors: Ana M Valdes, Gert De Wilde, Sally A Doherty, Rik J Lories, Frances L Vaughn, Laura L Laslett, Rose A Maciewicz, Anushka Soni, Deborah J Hart, Weiya Zhang [......] Elaine M Dennison, Margaret Wheeler, Paul Leaverton, Cyrus Cooper, Tim D Spector, Flavia M Cicuttini, Victoria Chapman, Graeme Jones, Nigel K Arden, Michael Doherty

  Annals of the rheumatic diseases. 05/2011; 70(9):1556-61.

  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). TheTo 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). 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. 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. 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.

• The GDF5 rs143383 polymorphism is associated with osteoarthritis of the knee with genome-wide statistical significance.

  Authors: Ana M Valdes, Evangelos Evangelou, Hanneke J M Kerkhof, Agu Tamm, Sally A Doherty, Kalle Kisand, Ann Tamm, Irina Kerna, Andre Uitterlinden, Albert Hofman [......] Elaine M Dennison, Weiya Zhang, Kenneth R Muir, John P A Ioannidis, Margaret Wheeler, Rose A Maciewicz, Joyce B van Meurs, Nigel K Arden, Tim D Spector, Michael Doherty

  Annals of the rheumatic diseases. 05/2011; 70(5):873-5.

• Large scale replication study of the association between HLA class II/BTNL2 variants and osteoarthritis of the knee in European-descent populations.

  Authors: Ana M Valdes, Unnur Styrkarsdottir, Michael Doherty, David L Morris, Massimo Mangino, Agu Tamm, Sally A Doherty, Kalle Kisand, Irina Kerna, Ann Tamm [......] Sarah Metrustry, Ingileif Jonsdottir, Gudbjorn F Jonsson, Helgi Jonsson, Thorvaldur Ingvarsson, Cyrus Cooper, Timothy J Vyse, Tim D Spector, Kari Stefansson, Nigel K Arden

  PloS one. 01/2011; 6(8):e23371.

  Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs)Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR)  = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the meta-analysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r(2) = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r(2)<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals.

• Mild acetabular dysplasia and risk of osteoarthritis of the hip: a case-control study.

  Authors: Daniel F McWilliams, Sally A Doherty, Wendy D Jenkins, Rose A Maciewicz, Kenneth R Muir, Weiya Zhang, Michael Doherty

  Annals of the rheumatic diseases. 10/2010; 69(10):1774-8.

  To determine whether mild variation in acetabular depth (AD) and shape is a risk factor for osteoarthritis (OA) of the hip. The unaffected contralateral hip of patients with unilateral hip OA wasTo determine whether mild variation in acetabular depth (AD) and shape is a risk factor for osteoarthritis (OA) of the hip. 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. 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. Constitutional mild acetabular dysplasia appears to increase the risk of hip OA.

• Role of the Nav1.7 R1150W amino acid change in susceptibility to symptomatic knee osteoarthritis and multiple regional pain.

  Authors: Ana M Valdes, Nigel K Arden, Frances L Vaughn, Sally A Doherty, Paul E Leaverton, Weiya Zhang, Kenneth R Muir, Evadnie Rampersaud, Elaine M Dennison, Mark H Edwards, Karen A Jameson, M Kassim Javaid, Tim D Spector, Cyrus Cooper, Rose A Maciewicz, Michael Doherty

  Arthritis care & research. 10/2010; 63(3):440-4.

  To assess the genetic association of pain in patients with knee osteoarthritis (OA) and those with multiple regional pain with the R1150W variant in the α-subunit of the voltage-gated sodium channelTo assess the genetic association of pain in patients with knee osteoarthritis (OA) and those with multiple regional pain with the R1150W variant in the α-subunit of the voltage-gated sodium channel Na(V)1.7. Knee OA patients from 2 UK cohorts (1,411 from the Genetics of Osteoarthritis and Lifestyle study and 267 from the Hertfordshire Cohort Study; 74% with symptomatic OA) with Western Ontario and McMaster Universities OA Index (WOMAC) pain scores were genotyped for rs6746030 (encoding the R1150W change). One hundred seventy-six knee OA patients (53% symptomatic) from the Clearwater Osteoarthritis Study were also tested. A total of 4,295 samples (both affected and unaffected OA) from all 3 studies with data on multiple regional pain were tested. Fixed-effects meta-analyses were carried out with the WOMAC, symptomatic OA (adjusting for radiographic severity), and multiple regional pain as outcomes. No association with the WOMAC was seen in the UK cohorts. Overall, the meta-analysis of WOMAC yielded a summary statistic of β = 0.47 (95% confidence interval [95% CI] 0.04, 0.89; P = 0.030) for the variant allele. The meta-analysis of symptomatic versus asymptomatic OA did not demonstrate an association with rs6746030 (odds ratio [OR] 0.90 [95% CI 0.71, 1.15], P = 0.38). The meta-analysis of multiple regional pain resulted in a significant OR of 1.40 (95% CI 1.08, 1.80; P = 0.0085). No interstudy heterogeneity was seen for any of the analyses. We find evidence that the R1150W amino acid change in the Na(V)1.7 α-chain is associated with multiple regional pain. This variant is confirmed to be involved in genetic susceptibility to pain, but it does not appear to have a major role in OA-specific pain.

• Lifetime body mass index, other anthropometric measures of obesity and risk of knee or hip osteoarthritis in the GOAL case-control study.

  Authors: K L Holliday, D F McWilliams, R A Maciewicz, K R Muir, W Zhang, M Doherty

  Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 10/2010; 19(1):37-43.

  To examine the risk of large joint osteoarthritis (OA) in those becoming overweight during early adult life, and to assess the risks associated with high body mass index (BMI) and otherTo examine the risk of large joint osteoarthritis (OA) in those becoming overweight during early adult life, and to assess the risks associated with high body mass index (BMI) and other anthropometric measures of obesity. BMI, waist and hip circumference were measured in the GOAL case-control study comprising hip OA cases (n=1007), knee OA cases (n=1042) and asymptomatic controls (n=1121). Retrospective estimates of lifetime weight, body shape and other risk factors were collected using an interview-lead questionnaire. Odds ratios (ORs), adjusted OR (aOR), 95% confidence intervals (CIs) and P values were calculated using logistic regression analysis. BMI was associated with knee OA (aOR 2.68, 95% CI 2.33-3.09, P-trend<0.001) and hip OA (aOR 1.65, 95% CI 1.46-1.87, P-trend<0.001). Those who became overweight earlier in adulthood showed higher risks of lower limb OA (P-trend<0.001 for knee OA and hip OA). Self-reported body shape was also associated with knee OA and hip OA, following a similar pattern to current and life-course BMI measures. Waist:hip ratio (WHR) at time of examination did not associate with OA independently of BMI, except in women-only analysis. Waist circumference was associated with lower limb OA risk. Becoming overweight earlier in adult life increased the risks of knee OA and hip OA. Different distribution patterns of adiposity may be related to OA risk in women.

• Interaction between 5 genetic variants and allergy in glioma risk.

  Authors: Minouk J Schoemaker, Lindsay Robertson, Annette Wigertz, Michael E Jones, Fay J Hosking, Maria Feychting, Stefan Lönn, Patricia A McKinney, Sarah J Hepworth, Kenneth R Muir, Anssi Auvinen, Tiina Salminen, Anne Kiuru, Christoffer Johansen, Richard S Houlston, Anthony J Swerdlow

  American journal of epidemiology. 06/2010; 171(11):1165-73.

  The etiology of glioma is barely known. Epidemiologic studies have provided evidence for an inverse relation between glioma risk and allergic disease. Genome-wide association data have identifiedThe etiology of glioma is barely known. Epidemiologic studies have provided evidence for an inverse relation between glioma risk and allergic disease. Genome-wide association data have identified common genetic variants at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A-CDKN2B), 11q23.3 (rs498872, PHLDB1), and 20q13.33 (rs6010620, RTEL1) as determinants of glioma risk. The authors investigated whether there is interaction between the effects of allergy and these 5 variants on glioma risk. Data from 5 case-control studies carried out in Denmark, Finland, Sweden, and the United Kingdom (2000-2004) were used, totaling 1,029 cases and 1,668 controls. Risk was inversely associated with asthma, hay fever, eczema, and "any allergy," significantly for each factor except asthma, and was significantly positively associated with number of risk alleles for each of the 5 single nucleotide polymorphisms. There was interaction between asthma and rs498872 (greater protective effect of asthma with increasing number of risk alleles; per-allele interaction odds ratio (OR) = 0.65, P = 0.041), between "any allergy" and rs4977756 (smaller protective effect; interaction OR = 1.27, P = 0.047), and between "any allergy" and rs6010620 (greater protective effect; interaction OR = 0.70, P = 0.017). Case-only analyses provided further support for atopy interactions for rs4977756 and rs498872. This study provides evidence for possible gene-environment interactions in glioma development.

• Involvement of different risk factors in clinically severe large joint osteoarthritis according to the presence of hand interphalangeal nodes.

  Authors: Ana M Valdes, Daniel McWilliams, Nigel K Arden, Sally A Doherty, Margaret Wheeler, Kenneth R Muir, Weiya Zhang, Cyrus Cooper, Rose A Maciewicz, Michael Doherty

  Arthritis and rheumatism. 05/2010; 62(9):2688-95.

  To quantify the differences in risk factors influencing total hip replacement (THR) and total knee replacement (TKR) based on the presence versus absence of multiple interphalangeal nodes in 2 orTo quantify the differences in risk factors influencing total hip replacement (THR) and total knee replacement (TKR) based on the presence versus absence of multiple interphalangeal nodes in 2 or more rays of the fingers of each hand in patients with large joint osteoarthritis (OA). A group of 3,800 patients with large joint OA who underwent total joint replacement (1,201 of whom had the nodal phenotype) and 1,906 control subjects from 2 case-control studies and a population-based cohort in the UK were studied. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for the risk of total joint replacement in association with age, sex, body mass index (BMI), height, and prevalence of the T allele in the GDF5 rs143383 polymorphism. ORs for total joint replacement were compared between cases of nodal OA and cases of non-nodal OA and between patients who underwent TKR and those who underwent THR. Age, sex, and BMI had significantly higher ORs for an association with total joint replacement in nodal OA cases than in non-nodal OA cases. The GDF5 polymorphism was significantly associated with THR in cases of nodal OA, but not in cases of non-nodal OA, and increased height was a risk factor for THR in non-nodal OA cases only. Female sex was a protective risk factor for TKR in non-nodal OA cases (OR 0.60, 95% CI 0.52-0.70) but was predisposing for TKR in the nodal form of OA (OR 1.83, 95% CI 1.49-2.26). The nodal phenotype was associated with a significantly higher risk of undergoing both THR and TKR (OR 1.46, 95% CI 1.09-1.94) and also a significantly higher risk of bilateral TKR (OR 1.70, 95% CI 1.37-2.11), but, paradoxically, was associated with a lower risk of bilateral THR (OR 0.72, 95% CI 0.56-0.91). Nodal and non-nodal forms of large joint OA have significantly different risk factors and outcomes, indicating a different etiology for the 2 forms of OA. With regard to the likelihood of undergoing THR, this appears to be, at least in part, genetically determined.

• Self-reported knee and foot alignments in early adult life and risk of osteoarthritis.

  Authors: Daniel F McWilliams, Sally Doherty, Rose A Maciewicz, Kenneth R Muir, Weiya Zhang, Michael Doherty

  Arthritis care & research. 04/2010; 62(4):489-95.

  To determine whether self-reported early adult life malalignment of knees or feet are risk factors for knee or hip osteoarthritis (OA). Participants in the Genetics of Osteoarthritis and LifestyleTo determine whether self-reported early adult life malalignment of knees or feet are risk factors for knee or hip osteoarthritis (OA). Participants in the Genetics of Osteoarthritis and Lifestyle case-control database were sent a questionnaire (n = 3,022) containing line-drawing instruments for self-reported knee and foot alignment at ages 20-29 years. Respondents were categorized as having straight, valgus, or varus knee, and straight, toe-in, or toe-out feet. Radiographic criteria were used to define current isolated knee or hip OA, combined knee and hip OA, or non-OA controls. Odds ratios (ORs), adjusted ORs, and 95% confidence intervals (95% CIs) were calculated and logistic regression was performed. The response rate was 72%; 87.5% of responders (n = 1,901) completed the alignment questions. Increased risk of isolated knee OA occurred with early adult varus (adjusted OR 5.16, 95% CI 2.87-9.41) and valgus knees (adjusted OR 3.16, 95% CI 1.04-9.64). The positive association between knee OA and toe-in foot was explained by varus knee. There was an increased risk of combined knee/hip OA from varus (adjusted OR 4.52, 95% CI 2.39-8.53) and valgus knees (adjusted OR 3.07, 95% CI 0.99-9.54). Varus knee was associated with risk of medial tibiofemoral OA, whereas valgus knee was associated with risk of lateral tibiofemoral and lateral patellofemoral OA. Toe-out foot was associated with reduced medial patellofemoral OA. For knee OA, a multiplicative interaction analysis between occupational risks and varus/valgus yielded an OR(int) of 3.20 (95% CI 1.08-9.49). Constitutional alignment of the leg in terms of varus or valgus knee or foot rotation may be a significant factor in determining development and distribution of knee but not hip OA.

• Multiple loci on 8q24 associated with prostate cancer susceptibility.

  Authors: Ali Amin Al Olama, Zsofia Kote-Jarai, Graham G Giles, Michelle Guy, Jonathan Morrison, Gianluca Severi, Daniel A Leongamornlert, Malgorzata Tymrakiewicz, Sameer Jhavar, Ed Saunders [......] Christopher J Woodhouse, Alan Thompson, Tim Christmas, Chris Ogden, Colin Cooper, Jenny L Donovan, Freddie C Hamdy, David E Neal, Rosalind A Eeles, Douglas F Easton

  Nature genetics. 09/2009;

  Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility.

• Comparing cost-utility estimates: does the choice of EQ-5D or SF-6D matter?

  Authors: Tracey H Sach, Garry R Barton, Claire Jenkinson, Michael Doherty, Anthony J Avery, Kenneth R Muir

  Medical care. 09/2009; 47(8):889-94.

  BACKGROUND: A number of different measures can be used within cost-utility analyses, we compared results according to both the EQ-5D and SF-6D. METHODS: A randomized trial was conducted to compare 4BACKGROUND: A number of different measures can be used within cost-utility analyses, we compared results according to both the EQ-5D and SF-6D. METHODS: A randomized trial was conducted to compare 4 options for people with knee pain. Over the 2 year trial period, the change in cost to health-service was estimated, and both the EQ-5D and SF-6D were used to estimate the change in quality-adjusted life years (QALYs). Using a complete case analysis, the cost-utility (incremental cost-effectiveness ratio [ICER]) of each option, according to both the EQ-5D and SF-6D, was calculated and assessed in relation to the cost-effectiveness threshold of pound20,000 per QALY. RESULTS: Of the 389 participants, 247 had complete cost, EQ-5D and SF-6D data. According to the EQ-5D, option 1 had an estimated ICER of pound10,815 (compared with option 4), option 2 was dominated by option 1, and option 3 was subject to extended dominance. Conversely, according to the SF-6D, option 3 had an ICER of pound9999 (compared with option 4), option 2 had an ICER of pound36,883 (compared with option 3), and option 1 was subject to extended dominance. CONCLUSION: The EQ-5D and SF-6D estimated that different options (1 and 3, respectively) were cost-effective at the pound20,000 per QALY threshold, demonstrating that the choice of measure does matter.

• Comparing the performance of the EQ-5D and SF-6D when measuring the benefits of alleviating knee pain.

  Authors: Garry R Barton, Tracey H Sach, Anthony J Avery, Michael Doherty, Claire Jenkinson, Kenneth R Muir

  Cost effectiveness and resource allocation : C/E. 02/2009; 7:12.

  ABSTRACT: OBJECTIVE: To assess the practicality, validity and responsiveness of using each of two utility measures (the EQ-5D and SF-6D) to measure the benefits of alleviating knee pain. METHODS:ABSTRACT: OBJECTIVE: To assess the practicality, validity and responsiveness of using each of two utility measures (the EQ-5D and SF-6D) to measure the benefits of alleviating knee pain. METHODS: Participants in a randomised controlled trial, which was designed to compare four different interventions for people with self-reported knee pain, were asked to complete the EQ-5D, SF-6D, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at both pre- and post-intervention. For both utility measures, we assessed their practicality (completion rate), construct validity (ability to discriminate between baseline WOMAC severity levels), and responsiveness (ability to discriminate between three groups: those whose total WOMAC score, i) did not improve, ii) improved by <20%, and iii) improved by >/=20%). RESULTS: The EQ-5D was completed by 97.7% of the 389 participants, compared to 93.3% for the SF-6D. Both the EQ-5D and SF-6D were able to discriminate between participants with different levels of WOMAC severity (p < 0.001). The mean EQ-5D change was -0.036 for group i), 0.091 for group ii), and 0.127 for group iii), compared to 0.021, 0.023 and 0.053 on the SF-6D. These change scores were significantly different according to the EQ-5D (p < 0.001), but not the SF-6D. CONCLUSION: The EQ-5D and SF-6D had largely comparable practicality and construct validity. However, in contrast to the EQ-5D, the SF-6D could not discriminate between those who improved post-intervention, and those who did not. This suggests that it is more appropriate to use the EQ-5D in future cost-effectiveness analyses of interventions which are designed to alleviate knee pain. TRIAL REGISTRATION: Current Controlled Trials ISRCTN93206785.

• Identification of new genetic risk factors for prostate cancer.

  Authors: Michelle Guy, Zsofia Kote-Jarai, Graham G Giles, Ali Amin Al Olama, Sarah K Jugurnauth, Shani Mulholland, Daniel A Leongamornlert, Stephen M Edwards, Jonathan Morrison, Helen I Field [......] Tim Christmas, Chris Ogden, Cyril Fisher, Charles Jameson, Colin S Cooper, Dallas R English, John L Hopper, David E Neal, Douglas F Easton, Rosalind A Eeles

  Asian journal of andrology. 01/2009;

  There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recentlyThere is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.Asian Journal of Andrology advance online publication, 1 December 2008; doi: 10.1038/aja.2008.18.

• Effects of dietary intervention and quadriceps strengthening exercises on pain and function in overweight people with knee pain: randomised controlled trial.

  Authors: Claire M Jenkinson, Michael Doherty, Anthony J Avery, Anna Read, Moira A Taylor, Tracey H Sach, Paul Silcocks, Kenneth R Muir

  BMJ (Clinical research ed.). 01/2009; 339:b3170.

  OBJECTIVE: To determine whether dietary intervention or knee strengthening exercise, or both, can reduce knee pain and improve knee function in overweight and obese adults in the community. DESIGN:OBJECTIVE: To determine whether dietary intervention or knee strengthening exercise, or both, can reduce knee pain and improve knee function in overweight and obese adults in the community. DESIGN: Pragmatic factorial randomised controlled trial. SETTING: Five general practices in Nottingham. PARTICIPANTS: 389 men and women aged 45 and over with a body mass index (BMI) of > or = 28.0 and self reported knee pain. INTERVENTIONS: Participants were randomised to dietary intervention plus quadriceps strengthening exercises; dietary intervention alone; quadriceps strengthening exercises alone; advice leaflet only (control group). Dietary intervention consisted of individualised healthy eating advice that would reduce normal intake by 2.5 MJ (600 kcal) a day. Interventions were delivered at home visits over a two year period. MAIN OUTCOME MEASURES: The primary outcome was severity of knee pain scored with the Western Ontario McMaster (WOMAC) osteoarthritis index at 6, 12, and 24 months. Secondary outcomes (all at 24 months) included WOMAC knee physical function and stiffness scores and selected domains on the SF-36 and the hospital anxiety and depression index. RESULTS: 289 (74%) participants completed the trial. There was a significant reduction in knee pain in the knee exercise groups compared with those in the non-exercise groups at 24 months (percentage risk difference 11.61, 95% confidence interval 1.81% to 21.41%). The absolute effect size (0.25) was moderate. The number needed to treat to benefit from a > or = 30% improvement in knee pain at 24 months was 9 (5 to 55). In those randomised to knee exercise improvement in function was evident at 24 months (mean difference -3.64, -6.01 to -1.27). The mean difference in weight loss at 24 months in the dietary intervention group compared with no dietary intervention was 2.95 kg (1.44 to 4.46); for exercise versus no exercise the difference was 0.43 kg (-0.82 to 1.68). This difference in weight loss was not associated with improvement in knee pain or function but was associated with a reduction in depression (absolute effect size 0.19). CONCLUSIONS: A home based, self managed programme of simple knee strengthening exercises over a two year period can significantly reduce knee pain and improve knee function in overweight and obese people with knee pain. A moderate sustained weight loss is achievable with dietary intervention and is associated with reduced depression but is without apparent influence on pain or function. TRIAL REGISTRATION: Current Controlled Trials ISRCTN93206785.