The genetics of heterotopic ossification: insight into the bone remodeling pathway.
OBJECTIVE
Heterotopic Ossification (HO) is a significant complication after trauma occurring in 12% to 25% of fractures. Although clinical predictors have been studied to determine the likelihood of developing HO, the results have been inconsistent. This study examines genetic predictors of the HO phenotype to identify the "at-risk" patient and increase the understanding of the genetic contribution to the formation of HO.


METHODS
We examined the frequency of 61 single nucleotide polymorphisms (SNPs) in 1095 consecutive trauma patients with fractures. Radiographic studies of these patients were examined for HO in follow-up. Ten percent of the patients in the study demonstrated radiographic evidence of HO. Multivariate logistic regression was used to analyze each SNP independently while adjusting for severity of injury (as measured by the Trauma and Injury Severity Score).


RESULTS
Three SNPs (beta2-adrenergic receptor, toll-like receptor 4, complement factor H) were identified that were associated with an increased or decreased frequency of HO. The less common polymorphism of the beta2-adrenergic receptor gene was associated with increased risk of HO. For toll-like receptor 4 and complement factor H, the less common polymorphism was associated with a decreased risk of HO.


CONCLUSIONS
The SNPs identified as predictors of HO formation are representative of the adrenergic system, immune system, and the alternative complement system. This represents the interplay of multiple pathways that affect bone remodeling, aberrations of which may be found in the genome.
Mitchell
Erika J
EJ
Division of Orthopaedic Trauma, Vanderbilt University Medical Center, Nashville, TN 37232, USA. erika.j.mitchell@vanderbilt.edu
Canter
Jeffrey
J
Norris
Patrick
P
Jenkins
Judith
J
Morris
John
J
D016723:Bone Remodeling / Q000235:genetics*; D015331:Cohort Studies; D017242:Complement Factor H / Q000235:genetics; D005260:Female; D017102:Fracture Healing / Q000235:genetics*; D050723:Fractures, Bone / Q000150:complications; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D009999:Ossification, Heterotopic / Q000209:etiology / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics; D015599:Trauma Severity Indices
C493495:CFH protein, human; D018343:Receptors, Adrenergic, beta-2; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D017242:Complement Factor H