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Novel genes identified with a possible connection to stress fracture
DOI:10.1038/bonekey.2015.7
The genetic basis of stress fractures was investigated using exome sequence capture and massive parallel sequencing using DNA samples obtained from Israeli soldiers; those with a high grade stress fracture (SF) (n=34) were compared with matched controls without fracture (n=60).
After validation in an independent population of SF cases and controls, the authors report 1,174 relevant genetic variants; 146 variants within 127 genes occurred at rates that were significantly different between soldiers with an SF and those without (P<0.05).
On further analysis of the 146 sequence variants, 20 retained significance in at least one of the models used. After FDR correction, six variants, each within a different gene, maintained significance. The outcome was the identification of six possible novel candidate genes that could underpin SF.
These genes encode: GRK1, a guanine nucleotide binding protein; nebulin, a cytoskeletal protein; RRC55, a potassium ion channel regulator in smooth muscle; ELFN2, an inhibitor of protein phosphatase I, a complex known to be involved in accumulation of bone; SIGLEC12, a potential adhesion molecule involved in osteoclast differentiation; SLC6A18, a neurotransmitter transporter.
Editor’s comment: The authors correctly state that their pooled exome sequencing seemingly unraveled novel candidate genes: unless validation by molecular and cellular experiments can be achieved, any statistically-identified genetic variation should be only considered putative for pathogenesis and SF predisposition.
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