title: Association of Cytotoxic T-lymphocyte Antigen-4 Polymorphisms with Malignant Bone Tumor Risk: A Meta-analysis.
abstract: BACKGROUND
  Previous studies have assessed the association between the Cytotoxic T-lymphocyte Antigen- 4(CTLA-4) polymorphism with the risk of malignant bone tumor, but the conclusions were inconsistent. We aimed to clarify association of cytotoxic T-lymphocyte antigen-4 polymorphisms with malignant bone tumors risk by performing a meta-analysis.
  
  
  METHODS
  The databases including PubMed, EMBase databases and the Cochrane Library were searched to identify the eligible studies prior to January 30 2016. Odds ratio (OR) with 95% confidence interval (95%CI) were used to estimate the strengths of the association between the CTLA-4 polymorphism and the malignant bone tumor risks. The meta-analysis was performed by STATA 12.0.
  
  
  RESULTS
  Four individual studies with a total of 1003 cases with malignant bone tumors and 1162 controls were included in our meta-analysis. The results of meta-analysis on those data demonstrated that CTLA-4 +49G>A polymorphism was associated with the risk of Ewing's sarcoma and osteosarcoma strongly (A vs. G: : OR=1.36, 95%CI:1.20-1.54, p=0.000; AA+AG vs. GG: OR=1.35, 95%CI:1.14-1.61, p=0.001; AA vs. GG: OR=2.24, 95%CI:1.67-2.99, p=0.000; AA vs. AG+GG: OR=2.00, 95%CI:1.53-2.62, p=0.000), but CTLA-4 -318C/T polymorphism was not associated with the risk of malignant bone tumor (C vs. T: OR=0.76, 95%CI:0.76-1.08, p= 0.262; CC+CT vs. TT: OR=0.70, 95%CI:0.41-1.20, p=0.198; CC vs. TT: OR=0.69, 95%CI:0.40-1.19, p= 0.183; CC vs. CT+TT: OR=0.92, 95%CI:0.75-1.13, p= 0.419). Subgroup analysis showed that there are significantly positive correlations between CTLA-4 +49G>A polymorphism and increased risks of malignant bone tumors in large size of sample (A vs. G: OR=1.347, 95%CI: 1.172,1.548, p=0.000; AA vs. GG: OR=2.228, 95%CI: 1.608,3.085, p=0.000), Ewing's Sarcoma or Osteosarcoma (A vs. G: OR=1.361, 95%CI: 1.201,1.540, p=0.000; AA vs. GG: OR=2.236, 95%CI: 1.674,2.986, p=0.000), and PCR-RFLP or Sequencing(A vs. G: OR=1.361, 95%CI: 1.201,1.540, p=0.000; AA vs. GG: OR=2.236, 95%CI: 1.674,2.986, p=0.000), but CTLA-4 -318C/T polymorphism was not associated with the risk of malignant bone tumors in diagnosis, genotype method, and sample size (all p>0.05).
  
  
  CONCLUSIONS
  CTLA-4 +49A/G variant was associated with an increased risk of developing the malignant bone tumors, such as Ewing's sarcoma and osteosarcoma. However, it failed to show any association between CTLA-4 -318C/T polymorphism and the risk of malignant bone tumors. Future large-scale studies remain to be done to confirm our conclusions.
authors.affiliation: Department of Orthopaedics, The First Hospital of Lanzhou University, Lanzhou, China E-mail : majc10@163.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Hou
authors.forename: Xuan-Xi
authors.initials: XX
authors.lastname: Ding
authors.forename: Xiong
authors.initials: X
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Xing-Wen
authors.initials: XW
authors.lastname: Han
authors.forename: Wen-Ji
authors.initials: WJ
authors.lastname: Wang
mesh_terms: D000328:Adult; D001859:Bone Neoplasms / Q000209:etiology* / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D012516:Osteosarcoma / Q000209:etiology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012512:Sarcoma, Ewing / Q000209:etiology / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D055815:Young Adult
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human