Genetic determinants of fracture non-union: A systematic review from the literature

Approximately 10-15% of fracture patients suffer impaired healing, which is either delayed or even results in non-union. We performed a Systematic Review, aiming to examine the types and frequency of specific genetic abnormalities in patients experiencing bone fracture and to ascertain whether a genetic association exists regarding the tendency for some patients to suffer fracture non-union or postoperative non-union events. GO and KEGG analyses were used to identify the likely function of the genes involved. Furthermore, we evaluated the functional significance of single nucleotide polymorphisms using RegulomeDB and GTEx. Seven eligible studies involving 29 genes and 89 SNPs were analyzed in this review. We found that the polymorphisms in gene NOS2, NOG, BMP4, CYR61, IL1β and FGFR1 apparently predisposed patients to fracture non-union, while the polymorphisms in gene MMP13, BMP6 and FAM5C appeared to provide protection from non-union. Bioinformatics analysis suggested that these genes were enriched in inflammatory pathways, suggesting that inflammation may be a potential factor involved in fracture non-union. Three SNPs (rs17563, rs3753793 and rs2853550) had smaller RegulomeDB scores, indicating significant biological function. In conclusion, we have identified a number of genes and their polymorphisms that might contribute to a genetic susceptibility to fracture non-union. Further studies with larger cohorts will enhance our understanding of fracture non-union and may inform and direct early interventions.