title: Single Nucleotide Polymorphisms in Osteogenic Genes in Atrophic Delayed Fracture-Healing: A Preliminary Investigation.
abstract: UpdateThis article was updated on September 10, 2014, because of a previous error. On page 1242, in the byline, and on page 1247, in the author addresses, the academic degree for Henry J. Donahue had previously read "MD." The degree now reads "PhD."
  
  
  BACKGROUND
  We propose that fracture-healing potential is affected by the patient's genome. This genotype is then phenotypically expressed by the patient at the time of injury. We examined the hypothesis that patients who exhibit delayed or impaired fracture-healing may have one or more single nucleotide polymorphisms (SNPs) within a series of genes related to bone formation.
  
  
  METHODS
  We performed a population-based, case-controlled study of delayed fracture-healing. Sixty-two adults with a long-bone fracture were identified from a surgical database. Thirty-three patients had an atrophic nonunion (delayed healing), and twenty-nine displayed normal fracture-healing. These patients underwent buccal mucosal cell harvesting. SNP genotyping was performed with use of bead array technology. One hundred and forty-four SNPs (selected from HapMap) within thirty genes associated with fracture-healing were investigated. Three SNPs did not segregate in the population and were excluded from the analysis. Eight of the remaining SNPs failed the test for Hardy-Weinberg equilibrium (p value smaller than the Bonferroni-corrected level of 0.05/141 = 0.000355) and were excluded.
  
  
  RESULTS
  Five SNPs on four genes were found to have a p value of <0.05 in the additive genetic model. Of these five significant SNPs, three had an odds ratio (OR) of >1, indicating that the presence of the allele increased the risk of nonunion. The rs2853550 SNP, which had the largest effect (OR = 5.9, p = 0.034), was on the IL1B gene, which codes for interleukin 1 beta. The rs2297514 SNP (OR = 3.98, p = 0.015) and the rs2248814 SNP (OR = 2.27, p = 0.038) were on the NOS2 gene coding for nitric oxide synthase. The remaining two SNPs had an OR of <1, indicating that the presence of the allele may be protective against nonunion. The rs3819089 SNP (OR = 0.26, p = 0.026) was on the MMP13 gene for matrix metallopeptidase 13, and the rs270393 SNP (OR = 0.30, p = 0.015) was on the BMP6 gene for bone morphogenetic protein 6.
  
  
  CONCLUSIONS
  Variations in the IL1B and NOS2 genes may contribute to delayed fracture-healing and warrant further investigation.
  
  
  CONCLUSIONS
  Impaired fracture union may have genetic contributions.
authors.affiliation: Departments of Orthopaedics and Rehabilitation (V.S., H.J.D., D.F., J.G., and J.S.R.), Pharmacology (K.E.V.), and Public Health Sciences (A.B.), Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail address for J.S. Reid: jreid@hmc.psu.edu.
authors.forename: Vikram
authors.initials: V
authors.lastname: Sathyendra
authors.affiliation: Departments of Orthopaedics and Rehabilitation (V.S., H.J.D., D.F., J.G., and J.S.R.), Pharmacology (K.E.V.), and Public Health Sciences (A.B.), Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail address for J.S. Reid: jreid@hmc.psu.edu.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Donahue
authors.affiliation: Departments of Orthopaedics and Rehabilitation (V.S., H.J.D., D.F., J.G., and J.S.R.), Pharmacology (K.E.V.), and Public Health Sciences (A.B.), Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail address for J.S. Reid: jreid@hmc.psu.edu.
authors.forename: Kent E
authors.initials: KE
authors.lastname: Vrana
authors.affiliation: Departments of Orthopaedics and Rehabilitation (V.S., H.J.D., D.F., J.G., and J.S.R.), Pharmacology (K.E.V.), and Public Health Sciences (A.B.), Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail address for J.S. Reid: jreid@hmc.psu.edu.
authors.forename: Arthur
authors.initials: A
authors.lastname: Berg
authors.affiliation: Departments of Orthopaedics and Rehabilitation (V.S., H.J.D., D.F., J.G., and J.S.R.), Pharmacology (K.E.V.), and Public Health Sciences (A.B.), Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail address for J.S. Reid: jreid@hmc.psu.edu.
authors.forename: David
authors.initials: D
authors.lastname: Fryzel
authors.affiliation: Departments of Orthopaedics and Rehabilitation (V.S., H.J.D., D.F., J.G., and J.S.R.), Pharmacology (K.E.V.), and Public Health Sciences (A.B.), Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail address for J.S. Reid: jreid@hmc.psu.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gandhi
authors.affiliation: Departments of Orthopaedics and Rehabilitation (V.S., H.J.D., D.F., J.G., and J.S.R.), Pharmacology (K.E.V.), and Public Health Sciences (A.B.), Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail address for J.S. Reid: jreid@hmc.psu.edu.
authors.forename: J Spence
authors.initials: JS
authors.lastname: Reid
mesh_terms: D001284:Atrophy; D016022:Case-Control Studies; D005260:Female; D017102:Fracture Healing / Q000235:genetics*; D005599:Fractures, Ununited / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010012:Osteogenesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013997:Time Factors