title: A promoter polymorphism of tissue inhibitor of metalloproteinase-2 gene is associated with severity of thoracic adolescent idiopathic scoliosis.
abstract: METHODS
  A genetic association study of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene with adolescent idiopathic scoliosis (AIS) in a Chinese population.
  
  
  OBJECTIVE
  To determine whether a promoter polymorphism of the TIMP-2 gene correlates with the occurrence and curve severity of AIS patients.
  
  
  BACKGROUND
  Previous studies have suggested that genetic factors play an important role in the etiology of AIS. The relative anterior spinal column overgrowth due to abnormal endochondral ossification has been considered to be a significant factor in the etiopathogenesis of AIS. The specific role of matrix metalloproteases (MMPs) and their activity inhibitors, TIMPs, during endochondral ossification has been documented. The TIMP-2 is the major TIMP expressed during bone development and is located in one of the chromosomal regions linked to AIS. Therefore, the TIMP-2 gene is a potential candidate gene for AIS.
  
  
  METHODS
  This study included a total of 570 female AIS patients, who were divided into 2 groups according to curve patterns. Of them, 354 patients with right thoracic curve were in group A (326 cases with Lenke 1 type and 28 cases with Lenke 2 type), whereas 216 patients with a single lumbar curve were in group B (216 cases with Lenke 5 type). A total of 210 age-matched healthy girls were recruited as normal controls. One single-nucleotide polymorphism, -418G/C (rs8179090), in the promoter region was selected for the TIMP-2 gene. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism in each group.
  
  
  RESULTS
  No significant differences of genotype and allele frequency distribution were found between AIS patients and normal controls either in group A or in group B. The frequency of C allele was significantly higher in patients with Cobb angle 40° or more than in those with Cobb angle less than 40° in group A (P < 0.05), while this difference was not noted in group B (P > 0.05). Among the patients who reached skeletal maturity without any interference of natural history, a significantly higher average maximum Cobb angle was found in patients with C allele than in those without C allele in group A (P < 0.05). However, in group B, the mean maximum Cobb angle was similar between patients with different genotypes in both cases with left-side curves and cases with right-side curves (P > 0.05). Furthermore, for the patients whose values of thoracic kyphosis were recorded, those with C allele had smaller average thoracic kyphosis than those without C allele in group A (P < 0.05). However, such significant difference was not observed in group B.
  
  
  CONCLUSIONS
  The single-nucleotide polymorphism SNP-418G/C (rs8179090) in the promoter region of the TIMP-2 gene was not associated with the occurrence of AIS. However, it may predict curve severity of thoracic AIS. Hence, the TIMP-2 gene is a disease-modifier gene of thoracic AIS.
authors.affiliation: Spine Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Jiang
authors.forename: Bangping
authors.initials: B
authors.lastname: Qian
authors.forename: Saihu
authors.initials: S
authors.lastname: Mao
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zhao
authors.forename: Xusheng
authors.initials: X
authors.lastname: Qiu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Qiu
mesh_terms: D000293:Adolescent; D044466:Asian People; D002648:Child; D002681:China; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012600:Scoliosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012720:Severity of Illness Index; D013904:Thoracic Vertebrae / Q000473:pathology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*
chemical_list: C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2