Xiaodong Qin

Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls

Adolescent idiopathic scoliosis (AIS) is a structural deformity of the spine affecting millions of children. As a complex disease, the genetic aetiology of AIS remains obscure. Here we report the results of a four-stage genome-wide association study (GWAS) conducted in a sample of 4,317 AIS patients and 6,016 controls. Overall, we identify three new susceptibility loci at 1p36.32 near AJAP1 (rs241215, Pcombined=2.95 × 10−9), 2q36.1 between PAX3 and EPHA4 (rs13398147, Pcombined=7.59 × 10−13) and 18q21.33 near BCL-2 (rs4940576, Pcombined=2.22 × 10−12). In addition, we refine a previously reported region associated with AIS at 10q24.32 (rs678741, Pcombined=9.68 × 10−37), which suggests LBX1AS1, encoding an antisense transcript of LBX1, might be a functional variant of AIS. This is the first GWAS investigating genetic variants associated with AIS in Chinese population, and the findings provide new insight into the multiple aetiological mechanisms of AIS.

Estimation of the Ideal Lumbar Lordosis to Be Restored From Spinal Fusion Surgery: A Predictive Formula for Chinese Population.

Study Design. A prospective, cross-sectional study. Objective. To determine the independent variables associated with lumbar lordosis (LL) and to establish the predictive formula of ideal LL in Chinese population. Summary of Background Data. Several formulas have been established in Caucasians to estimate the ideal LL to be restored for lumbar fusion surgery. However, there is still a lack of knowledge concerning the establishment of such predictive formula in Chinese population. Methods. A total of 296 asymptomatic Chinese adults were prospectively recruited. The relationships between LL and variables including pelvic incidence (PI), age, sex, and body mass index were investigated to determine the independent factors that could be used to establish the predictive formula. For the validation of the current formula, other 4 reported predictive formulas were included. The absolute value of the gap between the actual LL and the ideal LL yielded by these formulas was calculated and then compared between the 4 reported formulas and the current one to determine its reliability in predicting the ideal LL. Results. The logistic regression analysis showed that there were significant associations of LL with PI and age (R = 0.508, P < 0.001 for PI; R = 0.088, P = 0.03 for age). The formula was, therefore, established as follows: LL = 0.508 × PI − 0.088 × Age + 28.6. When applying our formula to these subjects, the gap between the predicted ideal LL and the actual LL was averaged 3.9 ± 2.1°, which was significantly lower than that of the other 4 formulas. Conclusion. The calculation formula derived in this study can provide a more accurate prediction of the LL for the Chinese population, which could be used as a tool for decision making to restore the LL in lumbar corrective surgery. Level of Evidence: 3

Investigation of the 53 Markers in a DNA-Based Prognostic Test Revealing New Predisposition Genes for Adolescent Idiopathic Scoliosis.

Study Design. A genetic association study of 53 single nucleotide polymorphisms (SNPs) with adolescent idiopathic scoliosis (AIS). Objective. To explore new predisposition genes of AIS in Chinese Han population Summary of Background Data. A panel of 53 SNPs were reported to be associated with curve severity of AIS. However, there is still a lack of knowledge concerning the association of these SNPs with the susceptibility of AIS in the Chinese Han population. Methods. A gene-based association study was conducted by genotyping the 53 SNPs of a prognostic test. DNA samples of 990 female patients with AIS and 1188 age-matched healthy controls were analyzed using the polymerase chain reaction-based Invader assay. The &khgr;2 test was carried out to compare the differences of genotype and allele distributions between patients with AIS and healthy controls. Results. A total of 4 SNPs were found to present significant differences in allele or genotype frequencies between the 2 groups. Compared with normal controls, patients were found to have significantly higher allele G of rs12618119 and allele A of rs9945359. Besides, patients were found to have significantly lower allele T of rs4661748 and allele C of rs4782809 than the normal controls. BIN1, CDH13, SETBP1, and SPATA21 genes could be associated with the susceptibility of AIS. Conclusion. Four new predisposition genes of AIS were identified on the basis of a large-scale case-control study. Putting all these findings together, it suggests that AIS is a multifactorial disease possibly involving different pathways such as development of central neural system and bone formation. Further studies exploring more predisposition gene are essential to illustrate the etiology of AIS and to guide the prevention or prognosis of the disease. Level of Evidence: 3

Genome-wide association study identifies novel susceptible loci and highlights Wnt/beta-catenin pathway in the development of adolescent idiopathic scoliosis

The genetic architecture of adolescent idiopathic scoliosis (AIS) remains poorly understood. Here we present the result of a 4-stage genome-wide association study composed of 5,953 AIS patients and 8,137 controls. Overall, we identified three novel susceptible loci including rs7593846 at 2p14 near MEIS1 (Pcombined = 1.19 × 10-13, OR = 1.21, 95% CI = 1.10-1.32), rs7633294 at 3p14.1 near MAGI1 (Pcombined = 1.85 × 10-12, OR = 1.20, 95% CI = 1.09-1.32), and rs9810566 at 3q26.2 near TNIK (Pcombined = 1.14 × 10-11, OR = 1.19, 95% CI = 1.08-1.32). We also confirmed a recently reported region associated with AIS at 20p11.22 (Pcombined = 1.61 × 10-15, OR = 1.22, 95% CI = 1.12-1.34). Furthermore, we observed significantly asymmetric expression of Wnt/beta-catenin pathway in the bilateral paraspinal muscle of AIS patients, including beta-catenin, TNIK, and LBX1. This is the first study that unveils the potential role of Wnt/beta-catenin pathway in the development of AIS, and our findings may shed new light on the etiopathogenesis of AIS.

Selecting the Last "Substantially" Touching Vertebra as Lowest Instrumented Vertebra in Lenke Type 1A Curve: Radiographic Outcomes With a Minimum of 2-year Follow-Up.

Study Design. Retrospective study. Objective. To compare the long-term outcomes of correction surgery for Lenke 1A scoliosis patients among those with non-Substantially Touched Vertebra (nSTV), nSTV+1, or STV selected as lowest instrumented vertebra (LIV). Summary of Background Data. Previous studies have documented good outcomes when last touching vertebra (LTV) was selected as LIV; however, it is sometimes confusing to determine the proper LTV when central sacral vertical line (CSVL) slightly touches the vertebra. Methods. A total of 104 patients were included in the study with a minimum of 2-year follow-up after selective posterior thoracic instrumentation. STV was defined as the LTV where CSVL was between the pedicles or touching the pedicle. nSTV was defined as the LTV where CSVL was touching the corner of the vertebra lateral to the pedicle border. Patients with nSTV, nSTV+1, or STV selected as LIV were assigned to three groups with clinical outcomes compared among them. Factors associated with the incidence of adding-on were analyzed. Results. Distal adding-on was observed in 23 patients (22.1%). The incidence of distal adding-on was significantly higher in nSTV group than STV group or nSTV+1 group. Several risk factors significantly associated with adding-on were identified, including the distance between LIV and STV/nSTV+1, preoperative proximal thoracic curve and sagittal vertical axis, postoperative lumbar lordosis, apical translation, trunk shift, and radiographical shoulder height. Logistic regression analysis showed that the distance between LIV and STV/nSTV+1 (LIV−STV <0 or LIV−(nSTV+1) <0) was the only independent factor associated with the incidence of adding-on (odds ratio = 27.1, 95% confidence interval = 2.3–311.2, P = 0.002). Conclusion. Differentiating STV from nSTV properly can facilitate the determination of optimal LIV and decrease the incidence of distal adding-on. Selecting STV or nSTV+1 as LIV could yield a promising outcome for Lenke 1A scoliosis patients undergoing selective posterior thoracic fusion. Level of Evidence: 3

The TGFB1 gene is associated with curve severity but not with the development of adolescent idiopathic scoliosis: a replication study in the Chinese population

BackgroundThe transforming growth factor beta-1 (TGFB1) gene was recently reported to be a new susceptible gene of adolescent idiopathic scoliosis (AIS) in Russian population. This study aimed to replicate the relationship between the TGFB1 gene and the susceptibility of AIS in a Chinese population, and to further describe its association with the curve severity.MethodsA total of 1251 female AIS patients and 994 age-matched healthy controls were included in this study. The rs1800469 of TGFB1 gene was genotyped for all participants using the PCR-based Invader assay. The differences of genotype and allele distributions between AIS patients and healthy controls were assessed using the Chi-square test. One-way ANOVA test was used to compare the mean Cobb angles among patients with different genotypes.ResultsThere was no significant difference in terms of the genotype and the allele frequency between the patients and the controls. The mean Cobb angle was 34.7 ± 11.9° (range 25–61°). Case-only analysis showed that rs1800469 was significantly associated with the curve severity. Patients with genotype TT had remarkably higher curve magnitude (39.1 ± 12.8°) than those with genotype CT (34.8 ± 11.1°) or CC (32.1 ± 10.6°).ConclusionsThe TGFB1 gene may not be a predisposition gene of AIS in the Chinese population. However, it can play a role in the curve progression of AIS. Replication studies in other ethnic groups are warranted to understand the implication of TGFB1 gene in AIS.

Cross-cultural adaptation and validation of the Chinese version of Toronto Extremity Salvage Score for patients with extremity sarcoma

ObjectiveAs a widely used instrument for patients with extremity sarcoma, the Toronto Extremity Salvage Score (TESS) has never been cross-culturally adapted for Chinese population. The objective of our study was to investigate the comprehensibility, reliability and validity of the Chinese version of TESS for use in patients with extremity sarcoma.MethodsA consensus version of the Chinese TESS was developed under the review of a committee according to international guidelines. 64 patients were recruited to complete the Chinese TESS, the Musculoskeletal Tumor Society (MSTS) Rating Scale, and the Quality of Life Questionnaire Core 30 (QLQ-C30). Reliability was assessed using the intra-class correlation coefficient (ICC) and Cronbach’s α. Validity was assessed with Pearson’s correlation between the similar domains of the two questionnaires.ResultsThe ICCs for the test–retest reliability was 0.932 for the upper extremity questionnaire and 0.893 for lower extremity questionnaire, respectively. The Cronbach’s α was 0.953 for the lower extremity questionnaire and 0.921 for the upper extremity questionnaire, respectively. Convergent validity of the TESS based on Pearson correlation coefficients indicated significantly moderate to high correlations between the TESS and the MSTS as well as the QLQ-C30, with r ranging from 0.535 to 0.782.ConclusionsThe Chinese TESS is a comprehensible, reliable, and valid instrument that can be utilized for future cross-cultural international studies of extremity sarcoma.

Replication of Association Between 53 Single-Nucleotide Polymorphisms in a DNA-Based Diagnostic Test and AIS Progression in Chinese Han Population.

Study Design. A case-only study. Objective. The aim of this study was to evaluate the association of the 53 single-nucleotide polymorphisms (SNPs) in a prognostic test with curve progression in Chinese adolescent idiopathic scoliosis (AIS) patients. Summary of Background Data. “ScoliScore” was the first diagnostic kit developed for curve progression of AIS in the white population. To date, there is still a paucity of validation of ScoliScore in Chinese Han population. Methods. A total of 670 AIS patients were included in the study, with 313 patients assigned to the nonprogression group and the other 357 patients assigned to the progression group. A panel of 53 SNPs encompassed in ScoliScore were genotyped using the PCR-based Invader assay. The allele frequencies were compared between AIS patients with progressive curve and those with nonprogressive curve. Results. SNP rs9945359 and rs17044552 are the only 2 SNPs that had significantly different allele frequencies between the 2 groups. Allele A of rs9945359 was significantly higher in the progression group than in the nonprogression group (25.7% vs 19.5%, P = 0.01), and allele A of rs17044552 was significantly lower in the progression group (11.5% vs 16.4%, P = 0.01). The odds ratio (OR) of these 2 SNPs were 1.42 [95% confidence interval (95% CI) 1.09–1.88] and 0.65 (95% CI 0.47–0.91), respectively. As for the allele frequencies of the other 51 SNPs, no significant difference was found between the 2 groups. Conclusion. ScoliScore could not be able to predict the curve progression of AIS in Chinese Han population. However, the role of this test in other populations cannot be totally excluded, and additional replication studies in other ethnic groups are warranted to evaluate the significance of these SNPs. Level of Evidence: 4

Initial Correction Rate Can be Predictive of the Outcome of Brace Treatment in Patients With Adolescent Idiopathic Scoliosis.

Study Design: A retrospective study. Objective: To determine the definite cut-off value of initial correction rate (ICR) that could be predictive of bracing outcome in patients with adolescent idiopathic scoliosis. Summary of Background Data: Earlier studies showed that braced patients with a better ICR could finally have a higher probability of successful outcome. However, it remains controversial what definitive cut-off value of ICR is required to accurately predict the outcome. Materials and Methods: A cohort of 488 adolescent idiopathic scoliosis patients who have completed the brace treatment with a minimum of 2-year follow-up were included in the current study. Curve progression of ⩽5 degrees was used to define the success of brace treatment. The success group and the failure group were compared in terms of initial Risser sign, initial age, sex, curve pattern, initial curve magnitude, and ICR. The receiver operating characteristics curve was used to define the definite cut-off point of initial curve correction rate. A logistic regression model was created to determine the independent predictors of the bracing outcome. Results: At the beginning of brace treatment, the mean age of the cohort was 13.2±1.5 years, and the mean curve magnitude was 29.5 ± 6.6 degrees. At the final follow-up, 368 patients were successfully treated by bracing. Compared with the success group, the failure group was found to have significantly younger age, lower Risser sign, and lower ICR. According to the receiver operating characteristic curve, the best cut-off value of ICR was 10%. The logistic regression model showed that ICR was significantly associated with the outcome of brace treatment with an odds ratio of 9.61. Conclusions: Patients with low ICR, low Risser sign, and young age could have a remarkably high risk of bracing failure. A rate of 10% was the optimal cut-off point for ICR, which can be used to effectively stratify braced patients.

Genetic polymorphism of Nucks1 is associated with the susceptibility of adolescent idiopathic scoliosis

Study Design. A genetic association study. Objective. The aim of this study was to investigate whether NUCKS1 is a susceptible gene of adolescent idiopathic scoliosis (AIS) in Chinese population and to further narrate its association with the clinical phenotypes. Summary of Background Data. AIS is characterized by late onset of menarche and disturbed growth rhythm. Previous studies showed that NUCKS1 is associated with age at menarche and pubertal height growth. Methods. Single-nucleotide polymorphism rs951366 of NUCKS1 was genotyped in 972 patients and 1454 healthy controls. The differences of genotype and allele distributions between AIS patients and healthy controls were evaluated using the &khgr;2 test. One-way analysis of variance test was used to compare the relationship between different genotypes and clinical features including tissue expression of NUCKS1, age at menarche, and curve magnitude. Results. Patients were found to have a significantly lower frequency of CC than the controls (5.9% vs. 10.6%, P < 0.001). Besides, the frequency of allele C was found to be remarkably lower in the patients than the controls (26.4% vs. 30.9%, P < 0.001), with an odds ratio of 0.80 (95% confidential interval = 0.71–0.91). Patients with genotype CC had a remarkably lower age at menarche than patients with genotype TT (12.1 ± 1.7 vs. 12.8 ± 2.4 years, P = 0.02). Patients with genotype TT had a remarkably lower expression level of NUCKS1 than patients with genotype CC (2.8 ± 1.9 vs. 4.3 ± 2.2, P = 0.03). As for curve magnitude, no significant difference was found among patients with different genotypes. Conclusion. Patients with allele T of rs951366 can be more vulnerable to the incidence of AIS as well as a late onset of menarche. Further functional analysis is warranted for a comprehensive knowledge on the contribution of this variant to the development of AIS. Level of Evidence: 4