Abstract
A non-union, especially atrophic non-unions, is a permanent failure of healing following a fracture and can be difficult to treat. Approximately 5–10% of fractures will result in a non-union during the healing process. non-unions can be classified into two types: atrophic non-union which is often due to impaired bone healing with a potential biological mechanism, and hypertrophic non-union which is due to inadequate fixation after fracture. Genetic variations also play an important role in the fracture healing response. Previous studies based on animal models have indicated that NOS2 might be greatly involved in the bone fracture healing process. In this case-control study, 346 nonunion patients were compared to 883 patients with normal fracture healing to investigate the potential genetic association between NOS2 and the fracture healing process using study subjects of Chinese Han ancestry. Twenty-seven single nucleotide polymorphisms (SNPs) covering NOS2 were genotyped in our study subjects and analyzed. In addition to the single marker-based analysis, we performed a gene-by-environment analysis to examine the potential interactions between genetic polymorphisms and some environmental factors. SNP rs2297514 showed significant association with the fracture healing process after adjusting for age and gender (OR = 1.38, P = 0.0005). Our results indicated that the T allele of rs2297514 significantly increased the risk of a non-union during the fracture healing process by 38% compared to the C allele. Further stratification analyses conducted for this SNP using data from subgroups classified by different sites of fracture indicated that significance could only be observed in the tibial diaphysis subgroup (N = 428, OR = 1.77, P = 0.0007) but not other groups including femur diaphysis, humeral shaft, ulnar shaft, and femur neck. Gene-by-environment interaction analyses of the three environmental factors showed no significant results. In this study, rs2297514 was significantly associated with the non-union status of fracture healing using a large Chinese population-based study sample. Our findings replicated those of a previous preliminary study and offered strong evidence linking NOS2 and fracture healing.
Highlights
A non-union is a permanent failure of healing following a fracture
Our results indicated that the T allele of rs2297514 significantly increased the risk of non-union during the fracture healing process by 38% compared to the C allele (Table 2)
Further stratification analyses conducted for this single nucleotide polymorphisms (SNPs) using data from different sites of fracture subgroups indicated that significance was only observed in the Tibial Diaphysis (TD) subgroup (N = 428, OR = 1.77, P = 0.0007), and no significant results were observed from the other four subgroups (Table 3)
Summary
5–10% of fractures will result in a non-union during the healing process [1]. Several factors have been associated with the development of non-unions, such as smoking, the type of fracture (open or closed), and poor mechanical stability [7]. With the widespread application of sequencing and genetic association analyses for studying the genetics of complex diseases, such as schizophrenia [9,10,11,12], several bone formation and growth-related genes and molecules were investigated for their potential contribution to the risk of developing a non-union during the fracture healing process, including pro-inflammatory cytokines (IL1 and IL6), bone morphogenetic proteins (BMPs), and tumor necrosis factor-alpha (TNF-α) [13,14,15]
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