A promoter polymorphism of neurotrophin 3 gene is associated with curve severity and bracing effectiveness in adolescent idiopathic scoliosis

Abstract

Study design: A genetic association study to comprehensively investigate variations of neurotrophin 3 (NTF3) gene polymorphisms in a Chinese Han population.

Objective: To explore whether the NTF3 gene polymorphisms are associated with the susceptibility, curve severity, or bracing effectiveness of adolescent idiopathic scoliosis (AIS).

Summary of background data: Scoliosis has developed in mice with NTF3 deficiency in previous studies. Increased expression of NTF3 mRNA was detected in the paravertebral muscle in AIS. Moreover, linkage study has defined a novel AIS locus on chromosome 12p while NTF3 gene is located exactly in this interval. All evidence indicates a potential role of NTF3 in the pathogenesis of AIS. As for brace treatment of AIS, continuous sensory stimulation caused by an orthosis could help awareness of body misalignment and trigger curve correction through postural reflex. While NTF3 gene is tightly associated with proprioceptive feedback mechanism to adjust postural control, we hypothesized NTF3 as a potential candidate gene associated with the bracing effectiveness.

Methods: A total of 362 AIS patients and 377 age-matched healthy controls were recruited. Two single-nucleotide polymorphisms (SNPs) were selected on the basis of the Chinese data from the HapMap project, and genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism for each SNP, respectively. Case-control study and case-only study were performed to define the contribution of NTF3 gene polymorphisms to predisposition and disease severity of AIS. Another subgroup of 120 skeletally immature AIS patients who received continuous brace treatment for minimal 2 years was genotyped, and bracing effectiveness was assessed to determine its association with NTF3 gene polymorphisms.

Results: The genotype and allele frequency distribution were similar between AIS and normal control for these 2 SNPs (χ² test: P > 0.05). For SNP rs11063714 in the promoter region of NTF3 gene, AIS patients with AA genotype showed significantly lower mean maximum Cobb angle than the patients with AG or GG genotypes (analysis of variance: P = 0.008). In addition, skeletally immature bracing AIS patients with AA genotype possessed significantly higher successful ratio of brace treatment compared with GG genotype (χ² test: P = 0.043). For SNP rs1805149, no significant association with predisposition or curve severity was detected.

Conclusion: The NTF3 gene polymorphisms are not associated with the occurrence of AIS, but the promoter polymorphism (rs11063714) is associated with the curve severity, implicating an alleviating role of NTF3 in the curve progression of AIS. In addition, the promoter polymorphism is also associated with brace responsiveness. These findings indicated that NTF3 gene might be a disease-modifying gene of AIS.