A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG). METHODS: Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts. RESULTS: We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10-43 for rs11190870, and P=2.94×10-48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes. CONCLUSIONS: Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.

Bone measurements at multiple skeletal sites in adolescent idiopathic scoliosis-an in vivo correlation study using DXA, HR-pQCT and QCT.

Significant correlations for bone mineral density and bone microstructure between spinal and non-spinal skeletal sites (distal radius and proximal femur) in adolescent idiopathic scoliosis (AIS) patients were observed, indicating that proximal femoral DXA and distal radial HR-pQCT could provide valid clinical assessments in patients with AIS. PURPOSE: Low bone mass is an important feature of adolescent idiopathic scoliosis (AIS), which is a complex 3D spinal deformity that affects girls during puberty. However, no clinical imaging modality is suitable for regular monitoring on their spinal bone qualities in rapid growth period. Therefore, we investigated whether bone mineral density (BMD) and bone microstructure at non-spinal sites correlated with BMD and mechanical property in the spine in AIS patients. METHODS: Thirty-two AIS girls (16.7 ± 3.5 years old with mean Cobb angle of 67 ± 11°) who underwent pre-operative spine CT examination for navigation surgery were recruited. Volumetric BMD (vBMD) of lumbar spine (LS) was measured by quantitative computed tomography (QCT), vBMD and bone microstructure of distal radius (DR) by high-resolution peripheral QCT (HR-pQCT) and areal BMDs of total hip (TH) and femoral necks (FN) by dual-energy X-ray absorptiometry (DXA). Biomechanical properties of the DR and LS were estimated by finite element analysis (FEA). Pearson correlation was performed to study the correlation between bone parameters at these three sites. RESULTS: LS vBMD correlated significantly with both FN and TH aBMD (R = 0.663-0.725, both p < 0.01) and with DR microstructural parameters (R = 0.380-0.576, all p < 0.05). Mechanical properties of LS and DR were also correlated (R = 0.398, p = 0.039). CONCLUSIONS: Bone measurement at proximal femur and distal radius could provide an additional predictive power in estimating the bone changes at spine, which is the primary site of deformity in AIS patients. Our result indicated that DXA and HR-pQCT could provide a valid surrogate for spine bone measurements in AIS patients.

Lower Muscle Mass and Body Fat in Adolescent Idiopathic Scoliosis Are Associated With Abnormal Leptin Bioavailability.

STUDY DESIGN: This was a case-control study. OBJECTIVE: This study aimed to investigate the body composition and its correlation with leptin and soluble leptin receptor (sOB-R) levels in girls with adolescent idiopathic scoliosis (AIS) and compared with healthy controls. SUMMARY OF BACKGROUND DATA: Patients with AIS are associated with lower body weight, taller stature, lower body mass index (BMI), and deranged bone quality. Despite the widely reported lower BMI and body weight in girls with AIS, the body composition of these patients was not thoroughly studied with sufficient sample size. Leptin is an important factor in regulating energy and bone metabolism, and has been postulated as one of the etiologic factors of AIS. METHODS: One hundred forty-eight AIS and 116 control girls aged 12 to 14 were recruited. Body composition was measured with bioelectrical impedance analysis. Caloric intake and physical activity level were assessed by food frequency and Baecke questionnaires respectively. Serum total leptin and sOB-R levels were measured with enzyme-linked immunosorbent assay, and free leptin index was calculated. RESULTS: AIS girls had lower body weight and BMI, other anthropometric and sexual maturity parameters were comparable with controls. There were no difference in caloric intake and physical activity levels. After adjustment for physical activity level, AIS girls had lower skeletal muscle mass, lower body fat, and %body fat. Higher sOB-R and lower free leptin index were found in AIS girls after adjusted for age and body weight. Weaker correlations between serum total leptin, FLI, and body composition parameters were observed in AIS girls. CONCLUSION: Results suggested that the lower body weight in AIS girls was contributed by both lower skeletal muscle mass and lower body fat. Altered leptin bioavailability also exists in AIS girls and could lead to lower body weight, lower BMI, and abnormal body composition that were manifested in AIS simultaneously. LEVEL OF EVIDENCE: 4.

Are volumetric bone mineral density and bone micro-architecture associated with leptin and soluble leptin receptor levels in adolescent idiopathic scoliosis?--A case-control study.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is associated with low bone mineral density (BMD). The underlying etiology and how it may relate to the development of osteopenia remains unknown. Leptin has been postulated as one of the etiologic factors of AIS because of its profound effects on bone metabolism and pubertal growth. Its modulator, soluble leptin receptor (sOB-R), may affect leptin bioavailability and signaling. This study aimed to investigate whether serum leptin and sOB-R levels may be associated with bone quality, and whether these relationships may differ between young adolescent girls with and without AIS. METHODS: This was a case-control study involving 94 newly diagnosed AIS girls (Cobb angle 12-48°) aged 12 to 14 years old and 87 age and gender-matched normal controls. Subjects with BMI>23.0 Kg/m(2) were excluded. Anthropometric measurements including body weight, height, arm span and sitting height were taken. Serum total leptin and sOB-R were assayed with ELISA. Non-dominant distal radius was scanned with High Resolution pQCT for assessing bone quality in terms of bone morphometry, volumetric BMD (vBMD) and trabecular bone micro-architecture. RESULTS: Compared with normal controls, AIS girls had numerically higher sOB-R (p = 0.006), lower average vBMD (p = 0.048), lower cortical vBMD (p = 0.029), higher cortical bone perimeter (p = 0.014) and higher trabecular area (p = 0.027), but none remained statistically significant after the Hochberg-Benjamini procedure. Correlation analysis on serum leptin level indicated that distinctive correlations with trabecular bone parameters occurred only in AIS. CONCLUSION: This study showed that bone quality in AIS girls was deranged as compared with controls. In addition, the distinct differences in correlation pattern between leptin and trabecular bone parameters indicated possible abnormalities in bone metabolism and dysfunction of the leptin signaling pathway in AIS.

Abnormal leptin bioavailability in adolescent idiopathic scoliosis: an important new finding.

STUDY DESIGN: This was a cross-sectional study. OBJECTIVE: The present study aimed to explore the differences in leptin bioavailability between adolescent idiopathic scoliosis (AIS) and healthy age-matched girls in a Chinese Han population. SUMMARY OF BACKGROUND DATA: AIS is a common spinal deformity mainly occurring in girls during the peripubertal period. The development of scoliosis is related to relative anterior spinal overgrowth. AIS girls also have associated lower body mass index (BMI) and lower bone mineral status. Leptin, together with soluble leptin receptor (sOB-R), was shown to play an important role in the regulation of bone and energy metabolism in children. It was hypothesized that leptin and sOB-R are abnormal and associated with deranged growth and anthropometric phenotypes in AIS girls. METHODS: Serum leptin and sOB-R were measured together with documentation of anthropometric parameters and clinical data in 95 AIS girls and 46 healthy matched controls (age 11-16 years). Serum leptin and sOB-R concentrations were measured by enzyme-linked immunosorbent assay and correlated with the different measured parameters. RESULTS: AIS girls had significantly lower BMI and longer arm span than healthy controls. AIS girls were found to have significantly higher sOB-R levels and lower free leptin index (FLI) after adjusting for age and body weight in multivariate regression analysis. Significant correlation was found between sOB-R, FLI, and curve severity in AIS girls. CONCLUSION: This is the first study demonstrating the presence of abnormal leptin bioavailability in AIS girls that might play an important role in the etiopathogenesis of AIS. Further investigation is required to provide a better understanding of the underlying mechanisms, with the aim to explore the potential clinical application as a biomarker for predicting curve initiation or progression in AIS.