Dataset Information

Study of Cysteine-Rich Protein 61 Genetic Polymorphism in Predisposition to Fracture Nonunion: A Case Control.

ABSTRACT: Background. Many factors are responsible for this impaired healing, especially in long bones, but a possible genetic predisposition for the development of this complication remains unknown till now. In the present study, we aim to examine the CYR61 gene polymorphism in fracture nonunion patients and the correlation with clinical findings. Materials and Methods. We performed SNP analysis of the CYR61 gene in 250 fracture nonunion patients and 250 healthy subjects were genotyped in this hospital-based case control study, and 56 cases were further evaluated for mRNA expression of CYR61 by real-time quantitative reverse-transcription PCR. Results. CYR61 gene TT, TG, and GG genotype frequencies of total fracture nonunion cases were 41.6%, 49.2%, and 9.20% and 54.4%, 39.2%, and 6.40% in healthy controls. Heterozygous TG genotype was found statistically significant in fracture nonunion cases compared with that in controls, whereas homozygous mutant GG genotype was not found significant. Moreover, we found that TG + GG genotypes were significantly different in serum expression of CYR61 mRNA when compared with cases (TT genotypes). Conclusions. Our result signifies that genotype of CYR61 affects the mRNA expression and acts as a risk factor that could synergistically increase the susceptibility of a patient to develop fracture nonunion.

SUBMITTER: Ali S

PROVIDER: S-EPMC4689909 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Study of Cysteine-Rich Protein 61 Genetic Polymorphism in Predisposition to Fracture Nonunion: A Case Control.

Ali Sabir S Hussain Syed Rizwan SR Singh Ajai A Kumar Vineet V Walliullah Shah S Rizvi Nazia N Yadav Manish M Ahmad Mohammad Kaleem MK Mahdi Abbas Ali AA

Genetics research international 20151210

Background. Many factors are responsible for this impaired healing, especially in long bones, but a possible genetic predisposition for the development of this complication remains unknown till now. In the present study, we aim to examine the CYR61 gene polymorphism in fracture nonunion patients and the correlation with clinical findings. Materials and Methods. We performed SNP analysis of the CYR61 gene in 250 fracture nonunion patients and 250 healthy subjects were genotyped in this hospital-b ...[more]

PMID: 26783467

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Project description:BACKGROUND:Numerous preclinical studies have revealed a critical role of cysteine-rich 61 (Cyr61) in the pathogenesis of rheumatoid arthritis (RA). But there is little literature discussing the clinical value of circulation Cyr61 in RA patients. The aim of our study is to investigate the serum Cyr61 level and its association with disease activity in RA patients. METHODS:A training cohort was derived from consecutive RA patients who visited our clinic from Jun 2014 to Nov 2018. Serum samples were obtained at the enrollment time. To further confirm discovery, an independent validation cohort was set up based on a registered clinical trial. Paired serum samples of active RA patients were respectively collected at baseline and 12 weeks after uniformed treatment. Serum Cyr61 concentration was detected by enzyme-linked immunosorbent assay. The comparison of Cyr61 between RA patients and controls, the correlation between Cyr61 levels with disease activity, and the change of Cyr61 after treatment were analyzed by appropriate statistical analyses. RESULTS:A total of 177 definite RA patients and 50 age- and gender-matched healthy controls were enrolled in the training cohort. Significantly elevated serum Cyr61 concentration was found in RA patients, demonstrating excellent diagnostic ability to discriminate RA from healthy controls (area under the curve (AUC) = 0.98, P < 0.001). In addition, the Cyr61 level in active RA patients was significantly lower than that in patients in remission/low disease activity, and it was inversely correlated with composite disease activity scores and almost all of the components in statistic. Further study in the validation cohort (n = 77) showed a significant increase of the Cyr61 level at 12 weeks in ACR responders (ACR20/50/70), while no significant change of the Cyr61 level from baseline was observed in non-responders. CONCLUSIONS:Serum Cyr61 levels were remarkably increased in RA patients compared with those in healthy controls. The Cyr61 concentration was inversely correlated with RA disease activity and upregulated in those therapeutic responders. TRIAL REGISTRATION:Combination Therapy Prevents the Relapse of RA, NCT02320630 . Registered 19 December 2014.

Project description:A non-union, especially atrophic non-unions, is a permanent failure of healing following a fracture and can be difficult to treat. Approximately 5-10% of fractures will result in a non-union during the healing process. non-unions can be classified into two types: atrophic non-union which is often due to impaired bone healing with a potential biological mechanism, and hypertrophic non-union which is due to inadequate fixation after fracture. Genetic variations also play an important role in the fracture healing response. Previous studies based on animal models have indicated that NOS2 might be greatly involved in the bone fracture healing process. In this case-control study, 346 nonunion patients were compared to 883 patients with normal fracture healing to investigate the potential genetic association between NOS2 and the fracture healing process using study subjects of Chinese Han ancestry. Twenty-seven single nucleotide polymorphisms (SNPs) covering NOS2 were genotyped in our study subjects and analyzed. In addition to the single marker-based analysis, we performed a gene-by-environment analysis to examine the potential interactions between genetic polymorphisms and some environmental factors. SNP rs2297514 showed significant association with the fracture healing process after adjusting for age and gender (OR = 1.38, P = 0.0005). Our results indicated that the T allele of rs2297514 significantly increased the risk of a non-union during the fracture healing process by 38% compared to the C allele. Further stratification analyses conducted for this SNP using data from subgroups classified by different sites of fracture indicated that significance could only be observed in the tibial diaphysis subgroup (N = 428, OR = 1.77, P = 0.0007) but not other groups including femur diaphysis, humeral shaft, ulnar shaft, and femur neck. Gene-by-environment interaction analyses of the three environmental factors showed no significant results. In this study, rs2297514 was significantly associated with the non-union status of fracture healing using a large Chinese population-based study sample. Our findings replicated those of a previous preliminary study and offered strong evidence linking NOS2 and fracture healing.

Project description:BACKGROUND: Despite the known multi-factorial nature of atrophic fracture non-unions, a possible genetic predisposition for the development of this complication after long bone fractures remains unknown. This pilot study aimed to address this issue by performing a preliminary SNP analysis of specific genes known to regulate fracture healing. METHODS: A total of fifteen SNPs within four genes of the Bone Morphogenetic Protein (BMP) pathway (BMP-2, BMP-7, NOGGIN and SMAD6) were examined, in 109 randomly selected patients with long bone fractures as a result of motor vehicle accident, fall or direct blow. There were sixty-two patients with atrophic non-union and forty-seven patients (54 fractures) with uneventful fracture union. Overall SNPs frequencies were computed with respect to patient's age, gender, smoking habits, fracture-associated parameters and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), and tested for their association to the impaired bone healing process, using binary logistic regression (STATA 11.1; StataCorp, Texas USA). RESULTS: Statistical analysis revealed age to be an important covariate in the development of atrophic non-union (p = 0.01, OR 1.05 [per year]), and two specific genotypes (G/G genotype of the rs1372857 SNP, located on NOGGIN and T/T genotype of the rs2053423 SNP, located on SMAD6) to be associated with a greater risk of fracture non-union (p = 0.02, OR 4.56 and p = 0.04, OR 10.27, respectively, after adjustment for age). CONCLUSIONS: This is the first clinical study to investigate the potential existence of genetic susceptibility to fracture non-union. Even though no concrete conclusions can be obtained from this pilot study, our results indicate the existence of a potential genetically predetermined impairment within the BMP signalling cascade, initiated after a fracture and when combined with other risk factors could synergistically increase the susceptibility of a patient to develop non-union. Further research is desirable in order to clarify the genetic component and its role and interaction with other risk factors in the development of atrophic long bone non-union, as simple genetic testing may contribute to the early identification of patients at risk in the future and the on-time intervention at the biologic aspects of bone healing.

Project description:ObjectiveTo explore the expression of cysteine-rich protein 61 (Cyr61) in ischemic renal fibrosis and the role of Cyr61 in mediating the activation of renal fibroblasts.Methods(1) The rat model of renal fibrosis was established after ischemia-reperfusion acute renal injury (IR-AKI). We detected the renal function by biochemical test, evaluated the fibrosis by Masson staining, and detected the expression of Cyr61 by western blotting. (2) Bioinformatics technique was adopted to analyze the expression of Cyr61 in activated renal fibroblasts. (3) Normal rat kidney fibroblast cells (NRK-49F cells) with over-expression of Cyr61 (Cyr61+) and low-expression of it (Cyr61--) were established by plasmid transfection. Then part of the cells were activated by TGF-β1 and NRK-49F cells were divided into control group, activated group, Cyr61+/Cyr61-- group and Cyr61+/Cyr61-- activated group. The expression of Cyr61 and fibrosis related factors (Col1α1, Col3α1, MMP9, and MMP13) were ascertained by PCR and western blotting. Cell proliferation was discovered by CCK8 method, cell cycle was analyzed by flow cytometry, and the transcription of cell senescence related factors (P53, P21, Rb, and P16) were ascertained by PCR method.Results(1) In the process of fibrosis after IR-AKI, the area of collagen fiber was most obviously at AKI 1W, while the Cyr61 protein was at the lowest level at AKI 1W. (2) Gene chip analysis showed that the expression of Cyr61 was decreased in renal fibroblasts after IR. (3) Compared with control group, Cyr61+ group expressed less Col1α1 or Col3α1, as well as more MMP9 and MMP13. At the same time, the proliferation of Cyr61+ group decreased and cells in G1 phases increased with more transcription of P53, P21, and Rb (all P < 0.05). Compared with activated group, the results of Cyr61+ activated group were similar to the above. The above effects of low expression group were just the opposite. In addition, there was no difference in the transcription of P16 among these groups (P > 0.05).ConclusionCyr61 may not only inhibit the fibrotic phenotype of fibroblasts, but may also inhibit proliferation by promoting fibroblasts arrest in G1 phase through the P53/P21/Rb interrelated cell senescence pathway, subsequently affecting the process of ischemic renal fibrosis.

Dataset Information

Study of Cysteine-Rich Protein 61 Genetic Polymorphism in Predisposition to Fracture Nonunion: A Case Control.

Publications

Study of Cysteine-Rich Protein 61 Genetic Polymorphism in Predisposition to Fracture Nonunion: A Case Control.

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