title: Genetic predisposition to fracture non-union: a case control study of a preliminary single nucleotide polymorphisms analysis of the BMP pathway.
abstract: 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.
authors.affiliation: Academic Unit of Trauma and Orthopaedic Surgery, LIMM Section Musculoskeletal Disease, Clarendon Wing, Leeds Teaching Hospitals NHS Trust, Great George Street, Leeds LS1 3EX, UK.
authors.forename: Rozalia
authors.initials: R
authors.lastname: Dimitriou
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.forename: Robert M
authors.initials: RM
authors.lastname: West
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Markham
authors.forename: Peter V
authors.initials: PV
authors.lastname: Giannoudis
mesh_terms: D000328:Adult; D000368:Aged; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005599:Fractures, Ununited / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D051905:Smad6 Protein / Q000235:genetics; D000099176:Noggin Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D051905:Smad6 Protein; D000099176:Noggin Protein; C525718:BMP2 protein, human; C497802:SMAD6 protein, human