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author:("Shi, dongguan")
1.  Update on basic and clinical aspects of osteoarthritis 
PMCID: PMC4486925  PMID: 26207235
2.  Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand 
Arthritis and rheumatism  2009;60(6):1710-1721.
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.
Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.
A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) (P = 9.4 × 10−7), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).
Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
PMCID: PMC4412885  PMID: 19479880
3.  A Common Variant Of Ubiquinol-Cytochrome c Reductase Complex Is Associated with DDH 
PLoS ONE  2015;10(4):e0120212.
Genetic basis of Developmental dysplasia of the hip (DDH) remains largely unknown. To find new susceptibility genes for DDH, we carried out a genome-wide association study (GWAS) for DDH.
We enrolled 386 radiology confirmed DDH patients and 558 healthy controls (Set A) to conduct a genome-wide association study (GWAS). Quality-control was conducted at both the sample and single nucleotide polymorphism (SNP) levels. We then conducted a subsequent case-control study to replicate the association between a promising loci, rs6060373 in UQCC gene and DDH in an independent set of 755 cases and 944 controls (set B).
In the DDH GWAS discovering stage, 51 SNPs showed significance of less than 10-4, and another 577 SNPs showed significance of less than 10-3. In UQCC, all the 12 genotyped SNPs showed as promising risk loci. Genotyping of rs6060373 in set A showed the minor allele A as a promising risk allele (p = 4.82*10-7). In set A, the odds ratio of allele A was 1.77. Genotyping of rs6060373 in Set B produced another significant result (p = 0.0338) with an odds ratio of 1.18 for risk allele A. Combining set A and set B, we identified a total p value of 3.63*10-6 with the odds ratio of 1.35 (1.19–1.53) for allele A.
Our study demonstrates common variants of UQCC, specifically rs6060373, are associated with DDH in Han Chinese population.
PMCID: PMC4388640  PMID: 25848760
4.  Full-thickness cartilage defects are repaired via a microfracture technique and intraarticular injection of the small-molecule compound kartogenin 
Microfracture does not properly repair full-thickness cartilage defects. The purpose of this study was to evaluate the effect of intraarticular injection of the small-molecule compound kartogenin (KGN) on the restoration of a full-thickness cartilage defect treated with microfracture in a rabbit model.
Full-thickness cartilage defects (3.5 mm in diameter and 3 mm in depth) were created in the patellar groove of the right femurs of 24 female New Zealand White rabbits. The rabbits were divided into two groups (12 in each group) based on postsurgery treatment differences, as follows: microfracture plus weekly intraarticular injection of KGN (group 1) and microfracture plus dimethyl sulfoxide (group 2). Six rabbits from each group were illed at 4 and 12 weeks after surgery, and their knees were harvested. The outcome was assessed both macroscopically, by using the International Cartilage Repair Society (ICRS) macroscopic evaluation system, and histologically, by using the modified O’Driscoll histologic scoring system. Immunohistochemistry for type II and I collagen was also conducted.
At 4 weeks, group 1 showed better defect filling and a greater number of chondrocyte-like cells compared with group 2. At 12 weeks, group 1 showed statistically significantly higher ICRS scores and modified O’Driscoll scores compared with group 2. More hyaline cartilage-like tissue was found in the defects of group 1 at 12 weeks.
Intraarticular injection of KGN enhances the quality of full-thickness cartilage defects repair after microfracture, with better defect filling and increased hyaline-like cartilage formation.
PMCID: PMC4376363  PMID: 25641548
5.  Bone Cement Solidifiliation Influence the Limb Alignment and Gap Balance during TKA 
BioMed Research International  2015;2015:109402.
Introduction. Mechanical alignment deviation after total knee arthroplasty is a major reason for early loosening of the prosthesis. Achieving optimum cement penetration during fixation of the femoral and tibial component is an essential step in performing a successful total knee arthroplasty. Bone cement is used to solidify the bone and prosthesis. Thickness imbalance of bone cement leads to the deviation of mechanical alignment. To estimate the influence of bone cement, a retrospective study was conducted. Materials and Methods. A total of 36 subjects were studied. All the TKA were performed following the standard surgical protocol for navigated surgery by medial approach with general anaesthesia. Prostheses were fixed by bone cement. Results. We compared the mechanical axis, flexion/extension, and gap balance before and after cementation. All the factors were different compared with those before and after cementation. Internal rotation was reached with statistical significance (P = 0.03). Conclusion. Bone cement can influence the mechanical axis, flexion/extension, and gap balance. It also can prompt us to make a change when poor knee kinematics were detected before cementation.
PMCID: PMC4320926  PMID: 25688349
6.  P-Selectin: An Unpredicted Factor for Deep Vein Thrombosis after Total Hip Arthroplasty 
BioMed Research International  2014;2014:783967.
Introduction. Deep vein thrombosis (DVT) is a severe complication after total hip arthroplasty (THA). It leads to acute pulmonary embolism, a life-threatening disease. P-selectin is a 140-kDa transmembrane glycoprotein. Elevated P-selectin was associated with 1.7-fold increase in the risk of venous thrombosis. Materials and Methods. To confirm the association, a total of 91 subjects who received primary total hip arthroplasty using lateral approach performed by one skilled orthopedic surgeon were studied. All the patients were consecutively enrolled at the Center of Diagnosis and Treatment for Joint Diseases, Drum Tower Hospital affiliated to the Medical School of Nanjing University from 2010 to 2012. All the subjects received venography 3–5 days after operation. We measured P-selectin by means of a highly sensitive sandwich ELISA technique and a commercially available test reagent set. Results. No significant association was detected between P-selectin and DVT (all P  values > 0.05). ΔsP-selectin was correlated with weight, APTT after operation, history of DVT, and diagnosis of primary disease ( P values were 0.03, 0.03, 0.04, and 0.02, resp.). Conclusion. P-selectin may not be a predicted factor for deep vein thrombosis after total hip arthroplasty.
PMCID: PMC4095655  PMID: 25057500
7.  Comparison of Venous Thromboembolism after Total Hip Arthroplasty between Ankylosing Spondylitis and Osteoarthritis 
BioMed Research International  2014;2014:712895.
Objective. Ankylosing spondylitis (AS), an inflammatory rheumatic disease, will gradually lead to severe hip joint dysfunction. Total hip arthroplasty is a useful method to improve patients' quality of life. The aim of this study was to compare the incidence and risk factors of deep vein thrombosis (DVT) between AS and hip osteoarthritis. Methods. In a retrospective study, a total of 149 subjects who underwent cementless THA were studied. Clinical data, biochemical data, and surgery-related data were measured between AS and OA groups. Results. The incidence of DVT in AS group was lower than that of OA group, although no significant difference was detected (P = 0.89). The patients of AS group were much younger (P < 0.0001) and thinner (P = 0.018) compared with those of OA group. AS patients had higher ejection fraction (EF) (P = 0.016), higher platelet counts (P < 0.0001), and lower hypertension rate (P = 0.0004). The values of APTT, PT, and INR in AS patients were higher than those in OA patients (all P < 0.0001). The values of D-dimer and APTT were both significantly higher in DVT subjects than those in non-DVT subjects. Conclusion. AS patients potentially had a lower incidence of DVT compared with OA patients.
PMCID: PMC4065686  PMID: 24995324
8.  Association of Single Nucleotide Polymorphisms in Estrogen Receptor Alpha Gene with Susceptibility to Knee Osteoarthritis: A Case-Control Study in a Chinese Han Population 
BioMed Research International  2014;2014:151457.
Osteoarthritis (OA) is the most prevalent form of arthritis and its multifactorial nature has been increasingly recognized. Genetic factors play an important role in OA etiology and estrogen receptor alpha (ESR1) gene polymorphisms may be involved. This study tried to explore whether the ESR1 gene single nucleotide polymorphisms (SNPs) were associated with primary knee OA in the Chinese Han population. Two SNPs, rs2234693 and rs9340799, were genotyped in 469 cases and 522 controls. Rs2234693 was associated with knee OA in the dominant genetic model (TT + TC versus CC) (P = 0.025) and a higher T allele frequency existed (P = 0.047) among females. The combined genotype (TT + TC) (P = 0.025) and T allele (P = 0.016) were related with mild knee OA only. For rs9340799, A allele was associated with knee OA in all subjects (P = 0.031) and females (P = 0.046). Statistical differences were detected in the dominant genetic model (AA + AG versus GG) among females (P = 0.030). The combined genotype (AA + AG) (P = 0.036) and A allele (P = 0.039) were merely correlated with mild knee OA. ESR1 gene is considerably associated with knee OA etiology in the Chinese Han population.
PMCID: PMC3977114  PMID: 24772413
9.  A Replication Study for the Association of rs726252 in PAPPA2 with Developmental Dysplasia of the Hip in Chinese Han Population 
BioMed Research International  2014;2014:979520.
Developmental dysplasia of the hip (DDH) is a common developmental hip disorder, which ranges from mild acetabulum malformation to irreducible hip dislocation. A previous study suggested a significant association of pregnancy-associated plasma protein-A2 (PAPPA2) with DDH susceptibility in Chinese Han population. But with the consideration of the sample size, the association was still debatable. To confirm the association of the reported single nucleotide polymorphism (SNP) in PAPPA2, rs726252 with DDH, we conducted a case-control study in a larger number of subjects. We genotyped rs726252 in 697 DDH subjects and 707 control subjects by TaqMan assay. The association between this SNP and DDH was evaluated statistically. No significant difference was found in any comparison of genotype distribution nor allele frequency between cases and controls. Our replication study indicated that the association between rs726252 and DDH in Chinese Han population was debatable. The association between PAPPA2 and DDH should be evaluated by additional studies.
PMCID: PMC3930137  PMID: 24672801
10.  Case Report: Osteochondral Avulsion Fracture of the Posteromedial Bundle of the PCL in Knee Hyperflexion 
Injury of the PCL of the knee in adults usually results in rupture rather than avulsion fracture and avulsions usually occur at the tibial insertion.
Case Description
We report an avulsion of the PCL with a femoral origin in a 22-year-old man who was injured by hyperflexion of the knee and was treated with arthroscopy. There were two parts in the partial osteochondral avulsion fracture of the PCL posteromedial (PM) bundle. One part was fixed with polydioxanone suture through drill holes and the other was removed. The fracture healed after 3 months and the knee was stable. At 11 months postoperatively the patient had returned to full-time work without pain or restrictions. The Lysholm II knee score was 95 points. Physical examination showed a negative posterior drawer sign.
Literature Review
We identified four other reported cases of PCL femoral origin avulsion fractures in adults. The subjects were 20 to 25 years old in four of five reports, including our patient. Three of the five patients had involvement of only the lateral cortex of the medial femoral condyle whereas two other patients including our patient, had an osteochondral fracture. The mechanism of PCL avulsion seems to be similar to that of a PCL rupture.
Purposes and Clinical Relevance
The hyperflexion injury may result in injury of the PM bundle of the PCL. Our case and one other in the literature suggest such avulsions need not involve the entire PCL.
PMCID: PMC3492605  PMID: 23054525
11.  Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant 
The Journal of Clinical Investigation  2013;123(11):4909-4917.
Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.
PMCID: PMC3809787  PMID: 24216480
12.  Genetic Polymorphism of NOS3 with Susceptibility to Deep Vein Thrombosis after Orthopedic Surgery: A Case-Control Study in Chinese Han Population 
PLoS ONE  2013;8(7):e70033.
Deep vein thrombosis is one of the common complications of orthopedic surgery. Studies indicated that genetic factors played a considerable role in the pathogenesis of deep vein thrombosis. Endothelial nitric oxide synthase which encoded by nitric oxide synthase 3 (NOS3), can generate nitric oxide in endothelial cells. As a predominant regulator for vascular homeostasis, nitric oxide might be involved in the pathogenesis of thrombosis. It had been proved that the NOS3 polymorphism (rs1799983) was associated with the development of cardiovascular diseases. Our objective was to evaluate the association between the NOS3 polymorphism (rs1799983) and deep vein thrombosis after orthopedic surgery in Chinese Han population. The polymorphism was genotyped in 224 subjects with deep vein thrombosis after orthopedic surgery and 580 controls. Allele and genotype frequencies were compared between subjects with deep vein thrombosis and control subjects. The allele and genotype frequencies of the NOS3 polymorphism (rs1799983) were significantly different between subjects with deep vein thrombosis and control subjects. There were also significant differences when the subjects were stratified by gender, surgery type and hypertension status. These findings suggested that the NOS3 polymorphism (rs1799983) was associated with susceptibility to the deep vein thrombosis after orthopedic surgery in Chinese Han population, and NOS3 might play a role in the development of deep vein thrombosis after orthopedic surgery.
PMCID: PMC3724670  PMID: 23922896
13.  Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium 
To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes.
Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. To investigate whether different OA definitions result in different association results, we created hip OA definitions used within the consortium in the Rotterdam Study-I and tested the association of hip OA with gender, age and BMI using one-way ANOVA. For radiographic OA, we standardized the hip, knee and hand ROA definitions and calculated prevalence's of ROA before and after standardization in 9 cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment.
In this consortium, all studies with symptomatic OA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee, hip and hand radiographic OA 5, 4 and 7 different definitions were used, respectively. Different hip OA definitions do lead to different association results. For example, we showed in the Rotterdam Study-I that hip OA defined as “at least definite JSN and one definite osteophyte” was not associated with gender (p=0.22), but defined as “at least one definite osteophyte” was significantly associated with gender (p=3×10−9). Therefore, a standardization process was undertaken for radiographic OA definitions. Before standardization a wide range of ROA prevalence's was observed in the 9 cohorts studied. After standardization the range in prevalence of knee and hip ROA was small. Standardization of SOA phenotypes was not possible due to the case-control design of the studies.
Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.
PMCID: PMC3236091  PMID: 21059398
14.  Association of the D repeat polymorphism in the ASPN gene with developmental dysplasia of the hip: a case-control study in Han Chinese 
Developmental dysplasia of the hip (DDH) is a common skeletal disease, which is characterized by abnormal seating of the femoral head in the acetabulum. Genetic factors play a considerable role in the etiology of DDH. Asporin (ASPN) is an ECM protein which can bind to TGF-β1 and sequentially inhibit TGF-β/Smad signaling. A functional aspartic acid (D) repeat polymorphism of ASPN was first described as an osteoarthritis-associated polymorphism. As TGF-β is well known as an important regulator in the development of skeletal components, ASPN may also be involved in the etiology of DDH. Our objective is to evaluate whether the D repeat polymorphism of ASPN is associated with DDH in Han Chinese.
The D repeat polymorphism was genotyped in 370 DDH patients and 445 control subjects, and the allelic association of the D repeat was examined.
From D11 to D18, eight alleles were identified. D13 allele is the most common allele both in control and DDH groups, the frequencies are 67.3% and 58.1% respectively. In the DDH group, a significantly higher frequency of the D14 allele and significantly lower frequency of D13 was observed. The association of D14 and D13 was found in both females and males after stratification by gender. There was no significant difference in any other alleles we examined.
Our results show an obvious association between the D repeat polymorphism of ASPN and DDH. It indicates that ASPN is an important regulator in the etiology of DDH.
PMCID: PMC3241371  PMID: 21329514
15.  Association of a single nucleotide polymorphism in growth differentiate factor 5 with congenital dysplasia of the hip: a case-control study 
Arthritis Research & Therapy  2008;10(5):R126.
Congenital dysplasia of the hip is an abnormal seating of the femoral head in the acetabulum, mainly caused by shallow acetabulum and lax joint capsule. Genetic factors play a considerable role in the pathogenesis of congenital dysplasia of the hip. The gene growth differentiate factor 5 (GDF5) has been implicated in skeletal development and joint morphogenesis in humans and mice. A functional single nucleotide polymorphism (SNP) in the 5'-untranslated region of GDF5 (rs143383) was reported to be associated with osteoarthritis susceptibility. As a key regulator in morphogenesis of skeletal components and soft tissues in and around the joints, GDF5 may be involved in the aetiology and pathogenesis of congenital dysplasia of the hip. Our objective is to evaluate if the GDF5 SNP is associated with congenital dysplasia of the hip in people of Han Chinese origin.
The GDF5 SNP was genotyped in 338 children with congenital dysplasia of the hip and 622 control subjects.
The SNP was significantly associated with congenital dysplasia of the hip (p = 0.0037; odds ration (OR) = 1.40; 95% confidence interval (CI) = 1.11 to 1.75). A significant difference was detected in female samples when stratified by gender (p = 0.0053; OR = 1.46; 95% CI = 1.21 to 1.91), and in hip dislocation when stratified by severity (p = 0.0078; OR = 1.43; 95% CI = 1.11 to 1.85).
Our results indicate that GDF5 is important in the aetiology of congenital dysplasia of the hip. To the authors' knowledge this is the first time that a definite association with the congenital dysplasia of the hip susceptibility has been detected.
PMCID: PMC2592816  PMID: 18947434
16.  Lack of association between the CALM1 core promoter polymorphism (-16C/T) and susceptibility to knee osteoarthritis in a Chinese Han population 
BMC Medical Genetics  2008;9:91.
CALM1 gene encodes calmodulin (CaM), an important and ubiquitous eukaryotic Ca2+-binding protein. Several studies have indicated that a deficient CaM function is likely to be involved in the pathogenesis of osteoarthritis (OA). Using a convincing genome-wide association study, a Japanese group has recently demonstrated a genetic association between the CALM1 core promoter polymorphism (-16C/T transition SNP, rs12885713) and OA susceptibility. However, the subsequent association studies failed to provide consistent results in OA patients of differently selected populations. The present study is to evaluate the association of the -16C/T polymorphism with knee OA in a Chinese Han population.
A case-control association study was conducted. The polymorphism was genotyped in 183 patients who had primary symptomatic knee OA with radiographic confirmation and in 210 matched controls. Allelic and genotypic frequencies were compared between patients and control subjects.
No significant difference was detected in genotype or allele distribution between knee OA and control groups (all P > 0.05). The association was also negative even after stratification by sex. Furthermore, no association between the -16C/T SNP genotype and the clinical variables age, sex, BMI (body mass index) and K/L (Kellgren/Lawrence) score was observed in OA patients.
The present study suggests that the CALM1 core promoter polymorphism -16C/T is not a risk factor for knee OA susceptibility in the Chinese Han population. Further studies are needed to give a global view of this polymorphism in pathogenesis of OA.
PMCID: PMC2576056  PMID: 18940010
17.  Association of single-nucleotide polymorphisms in RHOB and TXNDC3 with knee osteoarthritis susceptibility: two case-control studies in East Asian populations and a meta-analysis 
Conflicting findings on the association of single nucleotide polymorphisms (SNPs) in RHOB and TXNDC3 with susceptibility to knee osteoarthritis (OA) have been reported in European Caucasians. To examine the associations of these SNPs with OA in East Asian populations and to evaluate their global significance, we conducted two case-control studies in 955 Chinese and 750 Japanese patients.
We genotyped the previously implicated SNPs rs585017 (in RHOB) and rs4720262 (in TXNDC3) in patients with primary symptomatic knee OA with radiographic confirmation and in matched control individuals, and analyzed their associations. We further conducted a meta-analysis of the study findings together with those of previously reported European studies using the DerSimonian-Laird procedure.
A significant association of RHOB with knee OA was observed in male Chinese patients (P = 0.02). No significant associations were found for RHOB in any other comparisons in the East Asian populations. The association of TXNDC3 was replicated in Chinese female (P = 0.04) and Japanese (P = 0.03) patients, although none of these associations persisted after Bonferroni correction. Significant association (P = 0.02 for the allelic frequency) with nonsignificant heterogeneity was found in the East Asian replication study. No significant association was found in any comparison in the meta-analysis for all studies.
Our study replicates the association, previously reported in European Caucasians, of TXNDC3 with knee OA susceptibility in an East Asian population.
PMCID: PMC2483443  PMID: 18471322

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