Polymorphisms in BMP4
and FGFR1 Genes are associated with facture non-union
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.
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.
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.
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.
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?
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
by: Jane McDevitt PhD, ATC, CSCS
Reviewed
by: Stephen
Thomas
by: Stephen
Thomas
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Guimarães JM, Guimarães IC, Duarte ME, Vieira T, Vianna VF, Fernandes MB, Vieira AR, & Casado PL (2013). Polymorphisms in BMP4 and FGFR1 genes are associated with fracture non-union. Journal of Orthopaedic Research PMID: 23939983