Genetic predisposition to fracture non-union: a case control study of a preliminary single nucleotide polymorphisms analysis of the BMP pathway

• Published in: BMC musculoskeletal disorders Vol. 12; no. 1; p. 44
• Main Authors: Dimitriou, Rozalia, Carr, Ian M, West, Robert M, Markham, Alexander F, Giannoudis, Peter V
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 10.02.2011; BioMed Central; BMC
• Subjects: Adult; Aged; Analysis; Bone Morphogenetic Protein 2 - genetics; Bone Morphogenetic Protein 7 - genetics; Bone Morphogenetic Proteins - genetics; Carrier Proteins - genetics; Case-Control Studies; Cellular signal transduction; Disease; Disease susceptibility; Female; Fracture fixation; Fractures, Ununited; Fractures, Ununited - epidemiology; Fractures, Ununited - genetics; Gene therapy; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic testing; Genetics; Genotype; Humans; Male; Middle Aged; Physiological aspects; Pilot Projects; Polymorphism, Single Nucleotide - genetics; Risk Factors; Signal transduction; Signal Transduction - genetics; Single nucleotide polymorphisms; Smad6 Protein - genetics; Studies; Teaching hospitals; Tissue engineering
• DOI: 10.1186/1471-2474-12-44
• ISSN: 1471-2474

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. 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). 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). 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.