Polymorphisms in BMP4 and FGFR1 Genes are associated with facture non-union
Guimarães JM, Guimarães IC, Duarte ME, Vieira T, Vianna VF, Fernandes MB, Vieira AR, Casado PL. Journal of Orthopedic Research. 2013; ahead of print.
Take Home Message: Genetic variations within genes involved in the early stages of bone tissue healing have been associated with either protection (FGFR1, FAM5C) or increased risk (BMP4 & FGFR1) of non-union fractures.
Fracture healing is a complex process that can sometimes result in delayed healing or non-unions. Previous research has exposed several risk factors associated with non-union fractures (e.g., poor mechanical stability, infection & pharmacological agents); however, there has been minimal research examining the role of genetic variations. Polymorphisms (genetic variations) within specific genes may explain why some patients are more susceptible to non-union fractures. Therefore, the authors investigated whether genetic variants within genes that are expressed during tissue healing may be associated with impaired fracture healing. DNA was extracted (via saliva samples) from 167 patients that had sustained humeral, femoral, or tibial fractures (66 non-union & 101 union determined after evaluation). The authors evaluated 16 single nucleotide polymorphisms from 5 genes that are active in fracture healing: BMP4, FAM5C (involved with formation of new bone cells), FGF3, FGF10, and FGFR1. A non-union fracture was defined as failure of the fracture to heal within 9 months. A union fracture was defined as no tenderness at the fracture site with full weight bearing, and a mature bone bridge with a visible principle fracture line on radiographic images. More patients had an open type (displaced through the skin) fracture in the non-union group compared with the union group, but all other clinical characteristics between the groups were similar. A patient with a nonunion was less likely to have the BMP4, FAM5C, or FGFR1 polymorphism compared with a patient in the union group. In contrast, a patient with a nonunion group had a greater frequency of the FGFR1 polymorphism. Overall, the authors found that a patient with a particular genetic variation (BMP4 GTAA haplotype) had a 3.3-fold increased risk for non-union fractures. Conversely, a patient with a different variation (FAM5C GT diploid) would have a 3.0-fold increased protection against a non-union fracture. The authors also found that age, fracture type, and BMP4 (rs17563) CT genotype are potential predictors for a non-union fracture.
Several factors can expose a patient to an increased risk of a non-union fracture (e.g., age, smoking, diabetes, location), including genetic factors such as single nucleotide polymorphisms. Interestingly, the authors also point out that single nucleotide polymorphisms can have positive affects with bone healing. It is interesting to note that if a patient carries the FGFR1 (rs13317) C allele they are twice as likely to have a non-union fracture but if they carry the FGFR1 (rs13317) T allele they are protected against a non-union fracture. This suggests that some patients may be at a greater or lower risk for nonunions due to both clinical characteristics and subtle variations in genes. Greater knowledge about genetic factors related to bone tissue healing could lead to more individualized therapies and address clinically challenging situations that often compromise proper bone healing. Future research should include larger studies investigating more genes and single nucleotide polymorphisms within each of the phases of healing to better evaluate genetic association to non-union fractures. This study further highlights the role genetics may eventually play in sports medicine, but as that day approaches we cannot lose sight that open-type fractures and other clinical characteristics (e.g., age) may also increase the risk of nonunion.
Questions for Discussion: Do you think having genotype knowledge could lead to better fracture care in the future? Do you have experience with non-union fractures?
Written by: Jane McDevitt PhD, ATC, CSCS
Reviewed by: Stephen Thomas
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