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1.
Ann Rheum Dis ; 74(10): 1861-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24928840

RESUMO

OBJECTIVES: To identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA. METHODS: The GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (p ≤5×10(-8)) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis. RESULTS: The A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR 0.71, p=2×10(-8)). The association replicated in five studies (OR 0.92, p=0.020), but the joint analysis of discovery and replication results was not genome-wide significant (p=1×10(-6)). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (p=4×10(-13)), suggesting that this SNP or a variant in linkage disequilibrium could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation. CONCLUSIONS: Results from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.


Assuntos
Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Osteoartrite do Quadril/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Condrogênese/genética , Condrogênese/fisiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/fisiopatologia , Osteogênese/genética , Osteogênese/fisiologia , Polimorfismo de Nucleotídeo Único
2.
Proc Natl Acad Sci U S A ; 109(21): 8218-23, 2012 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-22566624

RESUMO

Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in osteoarthritis (OA) and specifically in HOA have yielded only few loci, which is partly explained by heterogeneity in the OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), a proxy for cartilage thickness and an important underlying intermediate trait for HOA. In a GWAS of 6,523 individuals on hip-JSW, we identified the G allele of rs12982744 on chromosome 19p13.3 to be associated with a 5% larger JSW (P = 4.8 × 10(-10)). The association was replicated in 4,442 individuals from three United Kingdom cohorts with an overall meta-analysis P value of 1.1 × 10(-11). The SNP was also strongly associated with a 12% reduced risk for HOA (P = 1 × 10(-4)). The SNP is located in the DOT1L gene, which is an evolutionarily conserved histone methyltransferase, recently identified as a potentially dedicated enzyme for Wnt target-gene activation in leukemia. Immunohistochemical staining of the DOT1L protein in mouse limbs supports a role for DOT1L in chondrogenic differentiation and adult articular cartilage. DOT1L is also expressed in OA articular chondrocytes. Silencing of Dot1l inhibited chondrogenesis in vitro. Dot1l knockdown reduces proteoglycan and collagen content, and mineralization during chondrogenesis. In the ATDC5 chondrogenesis model system, DOT1L interacts with TCF and Wnt signaling. These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage homeostasis. DOT1L may represent a therapeutic target for OA.


Assuntos
Condrócitos/fisiologia , Condrogênese/genética , Estudo de Associação Genômica Ampla , Metiltransferases/genética , Osteoartrite do Quadril/genética , Fatores Etários , Animais , Cartilagem Articular/patologia , Cartilagem Articular/fisiologia , Linhagem Celular , Condrócitos/citologia , Variação Genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Histona-Lisina N-Metiltransferase , Humanos , Metiltransferases/metabolismo , Camundongos , Osteoartrite do Quadril/epidemiologia , Osteoartrite do Quadril/patologia , Fatores de Risco , Via de Sinalização Wnt/fisiologia
3.
Am J Hum Genet ; 89(3): 446-50, 2011 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-21871595

RESUMO

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.


Assuntos
Cromossomos Humanos Par 13/genética , Predisposição Genética para Doença/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Osteoartrite/genética , Anticorpos Monoclonais/uso terapêutico , Estudo de Associação Genômica Ampla , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Fator de Crescimento Neural/imunologia , Fator de Crescimento Neural/metabolismo , Razão de Chances , Osteoartrite/imunologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Troca de Nucleotídeo Guanina Rho , População Branca/genética
4.
Ann Rheum Dis ; 73(12): 2082-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23921993

RESUMO

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.


Assuntos
Interação Gene-Ambiente , Análise da Randomização Mendeliana , Osteoartrite do Quadril/genética , Osteoartrite do Joelho/genética , Sobrepeso/genética , Proteínas/genética , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Polimorfismo de Nucleotídeo Único
5.
Ann Rheum Dis ; 72(10): 1687-90, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23355107

RESUMO

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.


Assuntos
Lesões do Quadril/complicações , Traumatismos do Joelho/complicações , Osteoartrite do Quadril/genética , Osteoartrite do Joelho/genética , Idoso , Artroplastia de Quadril , Artroplastia do Joelho , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/etiologia , Osteoartrite do Quadril/cirurgia , Osteoartrite do Joelho/etiologia , Osteoartrite do Joelho/cirurgia , Fatores de Risco
6.
Ann Rheum Dis ; 70(9): 1599-604, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21613308

RESUMO

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.


Assuntos
Modelos Logísticos , Osteoartrite do Joelho/etiologia , Idoso , Índice de Massa Corporal , Progressão da Doença , Métodos Epidemiológicos , Feminino , Humanos , Traumatismos do Joelho/complicações , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Doenças Profissionais/diagnóstico por imagem , Doenças Profissionais/etiologia , Doenças Profissionais/prevenção & controle , Osteoartrite/genética , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/prevenção & controle , Radiografia , Fatores de Risco
7.
Ann Rheum Dis ; 70(9): 1556-61, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21616913

RESUMO

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.


Assuntos
Osteoartrite do Joelho/genética , Canais de Cátion TRPV/genética , Idoso , Cartilagem Articular/metabolismo , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/metabolismo , Dor/etiologia , Dor/genética , Dor/metabolismo , Canais de Cátion TRPV/metabolismo , Técnicas de Cultura de Tecidos
8.
Arthritis Rheum ; 62(9): 2688-95, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20499385

RESUMO

OBJECTIVE: 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 or more rays of the fingers of each hand in patients with large joint osteoarthritis (OA). METHODS: 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. RESULTS: 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). CONCLUSION: 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.


Assuntos
Articulações dos Dedos/patologia , Ossificação Heterotópica/patologia , Osteoartrite do Quadril/patologia , Osteoartrite do Joelho/patologia , Idoso , Artroplastia de Quadril , Artroplastia do Joelho , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Fator 5 de Diferenciação de Crescimento/genética , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/patologia , Razão de Chances , Ossificação Heterotópica/complicações , Ossificação Heterotópica/genética , Osteoartrite do Quadril/etiologia , Osteoartrite do Quadril/genética , Osteoartrite do Joelho/etiologia , Osteoartrite do Joelho/genética , Polimorfismo Genético , Fatores de Risco , Fatores Sexuais
9.
Arthritis Rheum ; 62(8): 2347-52, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20506137

RESUMO

OBJECTIVE: Smad3 (or, MADH3) is a key intracellular messenger in the transforming growth factor beta signaling pathway. In mice, Smad3 deficiency accelerates growth plate chondrocyte maturation and leads to an osteoarthritis (OA)-like disease. We undertook this study to investigate the role of genetic variation in SMAD3 in the risk of large-joint OA in humans. METHODS: Ten tag single-nucleotide polymorphisms (SNPs) in the SMAD3 gene region were tested in a discovery set: 313 patients who had undergone total knee replacement, 214 patients who had undergone total hip replacement, and 520 controls from the UK. The SNP associated with both hip and knee OA was subsequently genotyped in 1,221 controls and 1,074 cases from 2 cohorts of patients with hip OA and 2,537 controls and 1,575 cases from 4 cohorts of patients with knee OA. RESULTS: A SNP (rs12901499) mapping to intron 1 of SMAD3 was associated with both knee and hip OA (P < 0.0022 and P < 0.021, respectively) in the discovery set. In all study cohorts, the major allele (G) was increased among OA patients relative to controls. A meta-analysis for knee OA yielded an odds ratio (OR) of 1.22 (95% confidence interval [95% CI] 1.12-1.34), P < 7.5 x 10(-6). For hip OA, the OR was 1.22 (95% CI 1.09-1.36), P < 4.0 x 10(-4). No evidence for heterogeneity was found (I(2) = 0%). CONCLUSION: Our data indicate that genetic variation in the SMAD3 gene is involved in the risk of both hip OA and knee OA in European populations, confirming the results from animal models on the potential importance of this molecule in the pathogenesis of OA.


Assuntos
Variação Genética , Osteoartrite do Quadril/genética , Osteoartrite do Joelho/genética , Proteína Smad3/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Íntrons , Razão de Chances , Polimorfismo de Nucleotídeo Único , População Branca/genética
10.
Ann Rheum Dis ; 69(10): 1774-8, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20472600

RESUMO

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.


Assuntos
Luxação Congênita de Quadril/complicações , Osteoartrite do Quadril/etiologia , Idoso , Estudos de Casos e Controles , Feminino , Luxação Congênita de Quadril/diagnóstico por imagem , Luxação Congênita de Quadril/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/patologia , Radiografia , Medição de Risco/métodos
11.
BMC Med Res Methodol ; 10: 57, 2010 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-20565825

RESUMO

BACKGROUND: For large scale epidemiological studies clinical assessments and radiographs can be impractical and expensive to apply to more than just a sample of the population examined. The study objectives were to develop and validate two novel instruments for self-reported knee malalignment and foot rotation suitable for use in questionnaire studies of knee pain and osteoarthritis. METHODS: Two sets of line drawings were developed using similar methodology. Each instrument consisted of an explanatory question followed by a set of drawings showing straight alignment, then two each at 7.5 degrees angulation and 15 degrees angulation in the varus/valgus (knee) and inward/outward (foot) directions. Forty one participants undertaking a community study completed the instruments on two occasions. Participants were assessed once by a blinded expert clinical observer with demonstrated excellent reproducibility. Validity was assessed by sensitivity, specificity and likelihood ratio (LR) using the observer as the reference standard. Reliability was assessed using weighted kappa (kappa). Knee malalignment was measured on 400 knee radiographs. General linear model was used to assess for the presence of a linear increase in knee alignment angle (measured medially) from self-reported severe varus to mild varus, straight, mild valgus and severe valgus deformity. RESULTS: Observer reproducibility (kappa) was 0.89 and 0.81 for the knee malalignment and foot rotation instruments respectively. Self-reported participant reproducibility was also good for the knee (kappa 0.73) and foot (kappa 0.87) instruments. Validity was excellent for the knee malalignment instrument, with a sensitivity of 0.74 (95%CI 0.54, 0.93) and specificity of 0.97 (95%CI 0.94, 1.00). Similarly the foot rotation instrument was also found to have high sensitivity (0.92, 95%CI 0.83, 1.01) and specificity (0.96, 95%CI 0.93, 1.00). The knee alignment angle increased progressively from self reported severe varus to mild varus, straight, mild valgus and severe valgus knee malalignment (ptrend <0.001). CONCLUSIONS: The two novel instruments appear to provide a valid and reliable assessment of self-reported knee malalignment and foot rotation, and may have a practical use in epidemiological studies.


Assuntos
Artroplastia do Joelho/instrumentação , Mau Alinhamento Ósseo/diagnóstico , Pé/fisiologia , Osteoartrite do Joelho/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Análise de Falha de Equipamento , Feminino , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Padrões de Referência , Rotação , Sensibilidade e Especificidade
13.
Semin Arthritis Rheum ; 43(5): 588-92, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24188720

RESUMO

OBJECTIVE: Neuropathic pain (NP) mechanisms contribute to the pain experience in osteoarthritis (OA). We aimed to characterise the factors that contribute to NP-like symptoms in knee OA patients. PATIENTS AND METHODS: A total of 139 patients with knee OA were recruited from secondary care, and completed a nurse- administered PainDetect questionnaire (PD-Q ), a visual analogue scale (VAS) for pain intensity, and the Western Ontario MacMaster questionnaire (WOMAC). Cases with any previous history of total joint replacement were excluded. RESULTS: Almost 75% of patients had non-zero PD-Q scores, and 34% had PD-Q scores corresponding to possible NP. No association was seen between PD-Q scores and duration of symptoms, gender, and radiographic severity. Possible NP was strongly associated (p < 1 × 10(-3)) with worse quality of life scores, worse sleep scores, higher pain intensity, worse WOMAC pain, stiffness and function scores. A history of previous knee surgery (arthroscopy, ligament repair or meniscectomy) was strongly associated with possible NP (odds ratio [OR] = 6.86; 95% CI = 1.78-26.43; p < 0.005). This association remained statistically significant after adjustment for pain intensity (OR = 6.37; 95% CI = 1.55-26.11; p < 0.010) whereas an association between history of knee surgery and the other measures of pain was found to be mediated by PD-Q scores. CONCLUSIONS: NP-like symptoms are highly prevalent in patients with clinically severe painful OA and are a significant contributor to decreased quality of life and higher pain intensity. The cross-sectional association with previous history of knee surgery suggests that some of the NP-like symptoms may result from nerve damage.


Assuntos
Articulação do Joelho/cirurgia , Neuralgia/etiologia , Osteoartrite do Joelho/complicações , Idoso , Estudos Transversais , Feminino , Humanos , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neuralgia/fisiopatologia , Osteoartrite do Joelho/fisiopatologia , Osteoartrite do Joelho/cirurgia , Medição da Dor , Qualidade de Vida , Índice de Gravidade de Doença , Inquéritos e Questionários
14.
Semin Arthritis Rheum ; 41(4): 568-75, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21868060

RESUMO

OBJECTIVES: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Osteoartrite do Quadril/cirurgia , Osteoartrite do Joelho/cirurgia , Dor Pós-Operatória/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Joelho/diagnóstico por imagem , Radiografia , Fatores de Risco , Índice de Gravidade de Doença
15.
Arthritis Care Res (Hoboken) ; 63(3): 440-4, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21031562

RESUMO

OBJECTIVE: 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 channel Na(V)1.7. METHODS: 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. RESULTS: No association with the WOMAC was seen in the UK cohorts. Overall, the meta-analysis of WOMAC yielded a summary statistic of ß = 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. CONCLUSION: 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.


Assuntos
Síndromes da Dor Regional Complexa/genética , Mutação , Osteoartrite do Joelho/genética , Canais de Sódio/genética , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Síndromes da Dor Regional Complexa/diagnóstico , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.7 , Razão de Chances , Osteoartrite do Joelho/diagnóstico por imagem , Medição da Dor , Fenótipo , Radiografia , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Reino Unido , Estados Unidos
16.
PLoS One ; 6(8): e23371, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21853121

RESUMO

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.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA-D/genética , Glicoproteínas de Membrana/genética , Osteoartrite do Joelho/genética , Polimorfismo de Nucleotídeo Único/genética , População Branca/genética , Idoso , Butirofilinas , Estudos de Casos e Controles , Feminino , Loci Gênicos/genética , Marcadores Genéticos , Genética Populacional , Humanos , Desequilíbrio de Ligação/genética , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
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