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Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11-1.23], p = 2.1 × 10(-8)) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

ObjectivesTo identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA.MethodsThe 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.ResultsThe 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.ConclusionsResults from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.

Objectives. To investigate factors associated with joint damage in early RA, and how comorbid OA might influence patient assessment and outcomes. Methods. Baseline radiographs of hands and feet from 512 participants in the Early RA Network cohort, and after 3 (±1) years, 166 of those participants yielded complete scores for RA [erosions, joint space narrowing (JSN)] and OA [JSN, osteophytes (OST)] using validated atlases. DAS28-P is the proportion of DAS28 attributed to patient-reported factors. Adjusted odds ratios were calculated using logistic regression. Results. OA was common at baseline in early RA (40% hand and 48% foot) and associated with RA radiographic score. Higher baseline RA scores were associated with increasing age and ESR, and lower DAS28-P. OST scores were associated with higher age. DAS28 and patient-reported outcomes improved, whereas RA and OA radiographic scores deteriorated by follow-up. Erosive progression was predicted by higher baseline erosions, female gender, better mental health and lower DAS28-P. Hand OST progression was predicted by baseline OST scores. Inflammatory disease activity was associated with erosive, but not with OA progression. Baseline hand OA predicted worse physical function at follow-up, but radiographic progression did not explain changes in patient-reported outcomes. Conclusion. OA is a common comorbidity that might confound radiographic and clinical assessment, but does not fully explain erosive progression or patient-reported outcomes in early RA. Early RA management should address psychosocial factors and comorbidities, as well as joint inflammation. [ABSTRACT FROM AUTHOR]

Objective To survey the use of analgesic medication 4.8 years after total joint replacement (TJR) surgery and assess the determinants of medication usage. Patients and methods Of 852 patients who had undergone TJR for osteoarthritis were recruited from secondary care. Participants (mean age, 73.7 years) responded to a questionnaire on medication use, physical function and pain (WOMAC, VAS and body pain), pain catastrophizing and illness behaviour (somatization). Results Only 37% of study participants were not on any pain relief medication, 25.1% were taking opioids, 6.9% were taking prescription NSAIDs and 25.9% were taking only non-prescription analgesics. Use of NSAIDs correlated with presence of back pain, body pain and high illness behaviour. The strongest associations with use of opioids were severe joint pain, high pain catastrophizing, body and back pain. After adjustment for covariates plus presence of pain, catastrophizing remained significantly associated with higher risk of opioid use (OR = 1.66, 95% CI: 1.13–2.43, p < 0.009) and of other prescription medication that can be used to treat pain (anti-depressants, anti-epileptics and hypnotics) (OR = 2.52, 95% CI: 1.61–3.95, p < 0.0005). Conclusions Use of opioid medication 4 years post-TJR is very high in our study population. In addition to joint, back and body pain, a major contributor to opioid use is pain catastrophizing. Our data suggest that current opioid and other analgesic prescribing patterns may benefit from considering the catastrophizing characteristics of patients. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

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. [Copyright &y& Elsevier]

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 metaanalysis 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) (r2 = 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 (r2<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. [ABSTRACT FROM AUTHOR]

The article examines the differences in risk factors influencing total hip replacement (THR) and total knee replacement (TKR) according to the presence and absence of multiple interphalangeal nodes in patients with large joint osteoarthritis (OA). The results revealed that age, sex and body mass index (BMI) are highly associated with total joint replacement in nodal OA cases than non-nodal OA cases. It was also found out that GDF5 polymorphism was associated with THR in nodal OA cases and increased height was a risk factor for THR in non-nodal OA cases.

Objective. Smad3 (or, MADH3) is a key intracellular messenger in the transforming growth factor β 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 (I² = 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. [ABSTRACT FROM AUTHOR]

The article presents a study that investigates the osteoarthritis (OA) susceptibility locus on chromosome 7q22 by a genome-wide association study. It mentions that the study examined 500,510 single-nucleotide polymorphisms (SNPs) in the Dutch Caucasian controls and OA cases. The results show that the C allele of rs3815148 on chromosome 7q22 was identified as the osteoarthritis susceptibility locus and is linked with the progression and increase risk of hand and knee OA.

The article presents the study which examines the association of nonspherical femoral head shape or pistol grip deformity and neck shaft angle as risk factors of hip osteoarthritis (OA). It focuses on the findings which indicate the increased prevalence of pistol grip deformity and an abnormally low neck shaft angle in unaffected hips are risk factors for development of hip OA. However, both a nonspherical head shape and an increase in neck shaft angle may occur as a consequence of OA.

Osteoarthritis (OA), the most prevalent form of arthritis in the elderly, is characterized by the degradation of articular cartilage and has a strong genetic component. Our aim was to identify genetic variants involved in risk of knee OA in women. A pooled genome-wide association scan with the Illumina550 Duo array was performed in 255 controls and 387 cases. Twenty-eight variants with p < 1 × 10-5 were estimated to have probabilities of being false positives ≤0.5 and were genotyped individually in the original samples and in replication cohorts from the UK and the U.S. (599 and 272 cases, 1530 and 258 controls, respectively). The top seven associations were subsequently tested in samples from the Netherlands (306 cases and 584 controls). rs4140564 on chromosome 1 mapping 5′ to both the PTGS2 and PLA2G4A genes was associated with risk of knee OA in all the cohorts studied (overall odds ratio ORMH = 1.55 95% C.I. 1.30-1.85, p < 6.9 × 10-7). Differential allelic expression analysis of PTGS2 with mRNA extracted from the cartilage of joint-replacement surgery OA patients revealed a significant difference in allelic expression (p < 1.0 × 10-6). These results suggest the existence of cis-acting regulatory polymorphisms that are in, or near to, PTGS2 and in modest linkage disequilibrium with rs4140564. Our results and previous studies on the role of the cyclooxygenase 2 enzyme encoded by PTGS2 underscore the importance of this signaling pathway in the pathogenesis of knee OA. [ABSTRACT FROM AUTHOR]