Zhihong Wu

Association study of tryptophan hydroxylase 1 and arylalkylamine N-acetyltransferase polymorphisms with adolescent idiopathic scoliosis in Han Chinese.

Study Design. A genetic association study of tryptophan hydroxylase 1 gene (TPH1) and arylalkylamine N-acetyltransferase gene(AANAT) with adolescent idiopathic scoliosis (AIS) in Han Chinese. Objective. To access whether TPH1 and AANAT polymorphisms are associated with the predisposition, gender, and/or severity of AIS. Summary of Background Data. Studies have shown that AIS is a multifactorial inheritance disease, but the etiology is still unknown. In addition, several lines of evidence show that melatonin deficiency is closely associated with AIS, although there are still doubts and debates. Some polymorphisms in TPH1 and AANAT, the genes of 2 critical enzymes involved in melatonin biosynthesis, may contribute to variability of melatonin production in pineal glands. Methods. We genotyped 16 reported single nuclear polymorphisms (SNPs) present in TPH1 and AANAT in 103 AIS patients and 108 controls with matched sex and age. The data of 6 SNPs with minor allele frequence (MAF) above 5% were analyzed by the allelic and genotypic association analysis, the genotype-phenotype (gender and Cobb angle) association analysis, and the haplotype analysis. Results. The single SNP analysis showed that rs10488682, located in the promoter region of TPH1, was related with the occurrence of AIS (P < 0.05). No SNP was found to be correlated with gender or Cobb angle. Two makers (rs8176799 and rs2108977) in TPH1 were found to be in strong LD [ D′ = 1.0 (95% CI, 0.9–1.0), γ2 = 0.501, LOD = 18.93] in the controls. Both global haplotype analysis and individual haplotype analysis showed that there was no haplotype significantly associated with AIS in this LD block. Conclusion. TPH1 polymorphisms were associated with AIS but not with gender and Cobb angle in AIS patients. AANAT polymorphisms were not associated with AIS. These results suggested that TPH1 was an AIS predisposition gene, and there was a close relationship between the dyssynthesis of melatonin and AIS.

Association between adolescent idiopathic scoliosis with double curve and polymorphisms of calmodulin1 gene/estrogen receptor-α gene.

Objective:  To investigate whether single nucleotide polymorphisms (SNP) of the calmodulin1 (CALM1) and estrogen receptor‐α genes correlate with double curve in adolescent idiopathic scoliosis (AIS).

Adolescent Idiopathic Scoliosis and the Single-nucleotide Polymorphism of the Growth Hormone Receptor and IGF-1 Genes

The etiology of adolescent idiopathic scoliosis is undetermined despite years of research. A number of hypotheses have been postulated to explain its development, including growth abnormalities. The irregular expression of growth hormone and insulin-like growth factor-1 (IGF-1) may disturb hormone metabolism, result in a gross asymmetry, and promote the progress of adolescent idiopathic scoliosis. Initial association studies in complex diseases have demonstrated the power of candidate gene association. Prior to our study, 1 study in this field had a negative result. A replicable study is vital for reliability. To determine the relationship of growth hormone receptor and IGF-1 genes with adolescent idiopathic scoliosis, a population-based association study was performed. Single nucleotide polymorphisms with potential function were selected from candidate genes and a distribution analysis was performed. A conclusion was made confirming the insufficiency of an association between adolescent idiopathic scoliosis and the single-nucleotide polymorphism of the growth hormone receptor and IGF-1 genes in Han Chinese.

Calcitonin enhanced lumbar spinal fusion in a New Zealand rabbit model: a study with morphologic and molecular analysis.

Study Design. In this study, the effect of calcitonin on lumbar spinal fusion was studied in a New Zealand rabbit model. Objective. To investigate whether calcitonin can enhance lumbar spinal fusion in a New Zealand rabbit model and whether calcitonin can enhance expression genes involved in osteogenesis and angiogenesis. Summary of Background Data. Calcitonin is used to treat osteoporosis and diseases involving accelerated bone turnover. Studies have shown that calcitonin might also promote bone cell proliferation and bone formation, suggesting its possible role in promoting spinal fusion, but few data are available. Methods. The effect of calcitonin on lumbar spinal fusion was analyzed in 32 New Zealand rabbits. Each rabbit received 2 autologous iliac bone grafts (one between L4–L5 without fixation, one between L6–L7 with fixation). Sixteen rabbits received calcitonin (calcitonin group, 1 U/kg daily from day 1 to the day of sacrifice), whereas the other 16 did not (control). At weeks 1, 2, 4, and 8, after examination for spinal fusion with radiography, 4 rabbits from each group were sacrificed. Each graft was histologically scored under light microscopy. In addition, we analyzed the messenger RNA (mRNA) levels of collagen I (Col I), bone morphometric protein 2 (BMP-2), insulinlike growth factor–1 (IGF-1), and vascular endothelial growth factor (VEGF), genes known to be involved in osteogenesis and angiogenesis, in each graft. Results. With both fixation and without fixation, the bone grafts in rabbits receiving calcitonin showed a higher spinal fusion rate and higher histologic scores from week 2 to week 8, and had higher mRNA levels of Col I, BMP-2, IGF-1, and VEGF at all time points except BMP-2 and IGF-1 at week 1, than grafts in rabbits without receiving calcitonin. Conclusion. Calcitonin can enhance lumbar spinal fusion. One mechanism might be through upregulating genes involved in osteogenesis and angiogenesis.

Association of calmodulin1 gene polymorphisms with susceptibility to adolescent idiopathic scoliosis

Objective:  To investigate whether: (i) rs12885713 (−16C > T) and rs5871 polymorphisms in the Calmodulin1 (CALM1) gene are predisposing factors for adolescent idiopathic scoliosis (AIS); and (ii) different single nucleotide polymorphisms (SNP) correlate with different subtypes of AIS.

Genetic Polymorphism of lbx1 is Associated with Adolescent Idiopathic Scoliosis in Northern Chinese Han Population

Study Design. A case-control association study was performed to investigate the relationship between ladybird homeobox (LBX1) and adolescent idiopathic scoliosis (AIS) in northern Chinese Han population. Objective. To explore the prevalence and functional importance of LBX1 polymorphisms in patients with AIS within the northern Chinese Han population. Summary of Background Data. AIS is the most common subtype of idiopathic scoliosis. Genetic factors such as LBX1 polymorphisms have been recently proved to be associated with AIS in some populations. In this study we explored the prevalence and functional importance of the polymorphisms around LBX1 in patients with AIS within the northern Chinese Han population. Methods. Five tag single nucleotide polymorphisms (SNPs) around or in LBX1 were genotyped in 180 patients with AIS and 182 controls. And the luciferase assay was performed to explore the functional importance of the most significant SNPs. Results. We replicated that rs11190870, previously reported as the most significantly associated SNP, was enriched in our AIS cohort. In addition, we found that the T allele of rs1322331 was associated with a novel risk allele (odds ratio = 3.349, 95% confidence interval 1.742–6.436). In the following luciferase assay, the TT-type promoter showed significantly reduced transcription activity in vitro. Conclusion. Two SNPs around LBX1, rs11190870 and rs1322331 are associated with AIS in northern Chinese Han population. The T allele of rs1322331 is a novel risk allele. We hypothesize that rs1322331 might increase patients’ susceptibility to AIS by reducing LBX1-AS1 transcription and thus upregulating the function of LBX1. Level of Evidence: 3

Association of LMX1A genetic polymorphisms with susceptibility to congenital scoliosis in Chinese Han population.

Study Design. A genetic association study of single nucleotide polymorphisms (SNPs) for the LMX1A gene with congenital scoliosis (CS) in the Chinese Han population. Objective. To determine whether LMX1A genetic polymorphisms are associated with susceptibility to CS. Summary of Background Data. CS is a lateral curvature of the spine due to congenital vertebral defects, whose exact genetic cause has not been well established. The LMX1A gene was suggested as a potential human candidate gene for CS. However, no genetic study of LMX1A in CS has ever been reported. Methods. We genotyped 13 SNPs of the LMX1A gene in 154 patients with CS and 144 controls with matched sex and age. After conducting the Hardy-Weinberg equilibrium test, the data of 13 SNPs were analyzed by the allelic and genotypic association with logistic regression analysis. Furthermore, the genotype-phenotype association and haplotype association analysis were also performed. Results. The 13 SNPs of the LMX1A gene met Hardy-Weinberg equilibrium in the controls, which was not in the cases. None of the allelic and genotypic frequencies of these SNPs showed significant difference between case and control groups (P > 0.05). However, the genotypic frequencies of rs1354510 and rs16841013 in the LMX1A gene were associated with CS predisposition in the unconditional logistic regression analysis (P = 0.02 and 0.018, respectively). Genotypic frequencies of 3 SNPs at rs6671290, rs1354510, and rs16841013 were found to exhibit significant differences between patients with CS with failure of formation and the healthy controls (P = 0.019, 0.007, and 0.006, respectively). Besides, in the model analysis by using unconditional logistic regression analysis, the optimized model for the 3 genotypic positive SNPs with failure of formation were rs6671290 (codominant; P = 0.025, Akaike information value = 316.6, Bayesian information criterion = 333.9), rs1354510 (overdominant; P = 0.0017, Akaike information value = 312.1, Bayesian information criterion = 325.9), and rsl6841013 (overdominant; P = 0.0016, Akaike information value = 311.1, Bayesian information criterion = 325), respectively. However, the haplotype distributions in the case group were not significantly different from those of the control group in the 3 haplotype blocks. Conclusion. To our knowledge, this is the first study to identify that the SNPs of the LMX1A gene might be associated with the susceptibility to CS and different clinical phenotypes of CS in the Chinese Han population. Level of Evidence: 4

Association Study Between the Polymorphisms of the Fat Mass- and Obesity-Associated Gene with the Risk of Intervertebral Disc Degeneration in the Han Chinese Population

OBJECTIVE Insights gained from studies suggest that genetic factors are major contributors to the onset and progression of intervertebral disc degeneration (IVDD). The aim of this study is to investigate whether fat mass- and obesity-associated (FTO) gene polymorphisms are related to the disease in Han Chinese People. METHODS 118 IVDD cases and 113 healthy subjects were enrolled in this study. Forty-four single nucleotide polymorphisms (SNP) in the FTO gene were tested and analyzed by the VeraCode GoldenGate Genotyping Assay. RESULTS A novel SNP rs11076008 was identified in the association analysis between the genotype and the phenotype. There was statistical significance in the expression of SNP rs11076008 in an allelic frequency distribution (p=0.003) and genotype (p=0.014) using the method of multi-test correction. CONCLUSION SNP rs11076008 of the FTO gene is associated with IVDD and may play an important role in developing IVDD in Han Chinese People. Our findings provide valuable information regarding the genetic etiology of IVDD in the investigated cohort.

Imaging study of wedge changes in the vertebral bodies and intervertebral discs in adolescent idiopathic scoliosis

Objective:  To observe wedge changes in the vertebral bodies and intervertebral discs in progressive adolescent idiopathic scoliosis before and after conservative treatment with braces, and to explore the correlation between wedge changes in the vertebral bodies or intervertebral discs and scoliosis curves.

Five known tagging DLL3 SNPs are not associated with congenital scoliosis: A case-control association study in a Chinese Han population.

AbstractGenetic etiology hypothesis is widely accepted in the development of congenital scoliosis (CS). The delta-like 3 (DLL3) gene, a member of the Notch signaling pathway, was implicated to contribute to human CS. In this study, a case–control association study was conducted to determine the association of single nucleotide polymorphism (SNP) in the DLL3 gene with CS in a Chinese Han Population. Five known tagging SNPs of the DLL3 gene were genotyped among 270 Chinese Han subjects (128 nonsyndromic CS patients and 142 matched controls). CS patients were divided into 3 types: type I—failure of formation (29 cases), type II—failure of segmentation (50 cases), and type III—mixed defects (49 cases). The 5 SNPs were analyzed by the allelic and genotypic association analysis, genotype–phenotype association analysis, and haplotype analysis. Allele frequencies of 5 tagging SNPs (SNP1: rs1110627, SNP2: rs3212276, SNP3: rs2304223, SNP4: rs2304222, and SNP5: rs2304214) in CS cases and controls were comparable and there were no available inheritance models. The SNPs were not associated with clinical phenotypes. Moreover, the 5 makers in the DLL3 gene were found to be in strong linkage disequilibrium (LD). Both global haplotype and individual haplotype analyses showed that the haplotypes of SNP1/SNP2/SNP3/SNP4/SNP5 did not correlate with the disease (P >0.05). Together, these data suggest that genetic variants of the DLL3 gene are not associated with CS in the Chinese Han population.