Dietary management of neurogenic bowel in adults with spinal cord injury: an integrative review of literature.

OBJECTIVE: To examine the literature for current evidence on the dietary management of neurogenic bowel in adults with spinal cord injuries (SCIs). BACKGROUND: Neurogenic bowel dysfunction presenting as faecal incontinence or constipation is a common occurrence in individuals with SCI. It poses numerous challenges for the management of bowel function and has a significant impact on quality of life following SCI. Dietary management is a common, early treatment strategy as a conservative approach for neurogenic bowel; however, current recommendations rely on expert opinion only. METHODS: An integrative review of the literature using a systematic search was conducted using Medline, Embase, CINAHL, Proquest, and Google Scholar. The selected articles were critically appraised using Critical Appraisal Skills Programme checklists by two independent reviewers. The risk of bias of studies and the quality of evidence for outcomes were assessed using the risk of bias tool and the grading of recommendations, assessment, development, and evaluation system in the Cochrane handbook for systematic review of interventions. RESULTS: Thirteen studies that met the inclusion criteria were identified exploring a variety of diet-related factors: foods, dietary behaviours, and multiple interventions including a diet plan. However, the dietary management strategies used varied significantly between studies, posing challenges to ascertain its efficacy. CONCLUSION: Given the low level of evidence and paucity of data on dietary management of neurogenic bowel, the efficacy of dietary strategies (alone or in combination with others) in managing neurogenic bowel cannot be substantiated from the studies identified. Therefore, more robust studies are warranted to bridge this gap.IMPLICATIONS FOR REHABILITATIONConsumption of ∼15 g dietary fibre is shown to be beneficial in managing neurogenic bowel in SCI.Further research is required to strengthen evidence for fibre recommendations and investigating the potential benefits of traditional and non-traditional dietary approaches.

Abnormal response of the proliferation and differentiation of growth plate chondrocytes to melatonin in adolescent idiopathic scoliosis.

Abnormalities in the melatonin signaling pathway and the involvement of melatonin receptor MT2 have been reported in patients with adolescent idiopathic scoliosis (AIS). Whether these abnormalities were involved in the systemic abnormal skeletal growth in AIS during the peripubertal period remain unknown. In this cross-sectional case-control study, growth plate chondrocytes (GPCs) were cultured from twenty AIS and ten normal control subjects. Although the MT2 receptor was identified in GPCs from both AIS and controls, its mRNA expression was significantly lower in AIS patients than the controls. GPCs were cultured in the presence of either the vehicle or various concentrations of melatonin, with or without the selective MT2 melatonin receptor antagonist 4-P-PDOT (10 µM). Then the cell viability and the mRNA expression of collagen type X (COLX) and alkaline phosphatase (ALP) were assessed by MTT and qPCR, respectively. In the control GPCs, melatonin at the concentrations of 1, 100 nM and 10 µM significantly reduced the population of viable cells, and the mRNA level of COLX and ALP compared to the vehicle. Similar changes were not observed in the presence of 4-P-PDOT. Further, neither proliferation nor differentiation of GPCs from AIS patients was affected by the melatonin treatment. These findings support the presence of a functional abnormality of the melatonin signaling pathway in AIS GPCs, which might be associated with the abnormal endochondral ossification in AIS patients.

Abnormal bone quality versus low bone mineral density in adolescent idiopathic scoliosis: a case-control study with in vivo high-resolution peripheral quantitative computed tomography.

BACKGROUND CONTEXT: Adolescent idiopathic scoliosis (AIS) is associated with low bone mass that could persist into early adulthood and is an important prognostic factor for curve progression. Previous studies were confined to areal bone mineral density measurement that was a two-dimensional investigation for a three-dimensional structure. Evaluation of volumetric BMD (vBMD) and other bone quality parameters are important for gaining in-depth understanding of the etiopathogenesis of AIS. PURPOSE: The objective of this study was to carry out direct in vivo measurement of bone quality in AIS using high-resolution peripheral quantitative computed tomography (HR-pQCT) and compare the correlation of bone quality with osteopenia between AIS and control subjects. STUDY DESIGN/SETTING: A case-control study. PATIENT SAMPLE: Newly diagnosed AIS girls (n=112) and non-AIS girls (n=115) between 11 and 13 years. OUTCOME MEASURES: Areal bone mineral density of bilateral femoral necks and HR-pQCT of the nondominant distal radius were performed. METHODS: Areal bone mineral density of femoral necks was measured by dual-energy X-ray absorptiometry. Subjects were classified into the osteopenic (Z score less than or equal to -1) and nonosteopenic (Z score more than -1) groups. Bone quality parameters, including bone morphometry, trabecular bone microarchitecture, and vBMD, were measured by HR-pQCT (XtremeCT; Scanco Medical, Zurich, Switzerland). RESULTS: In AIS, the osteopenic group had lower measurements in cortical area, cortical thickness, average vBMD, compact bone vBMD, trabecular vBMD, trabecular bone volume to tissue volume ratio, and trabecular thickness compared with nonosteopenic AIS subjects. In contrast, among the non-AIS controls, the osteopenic group had lower measurements only in bone morphometry, average vBMD, and compact bone vBMD but not in trabecular vBMD and all other trabecular bone microarchitecture parameters. CONCLUSIONS: This is the first study using HR-pQCT to compare the correlation of bone quality with osteopenia in AIS and non-AIS subjects. It provides new insights and highlights the unique bone quality profile with predominant changes in the trabecular compartment in association with osteopenia being notably only detected in the AIS subjects. Further studies in this area are warranted for defining the metabolic nature and biomechanical sequelae of derangement in bone mass and bone quality and their roles in the etiopathogenesis of AIS.

Abnormal Skeletal Growth in Adolescent Idiopathic Scoliosis Is Associated with Abnormal Quantitative Expression of Melatonin Receptor, MT2.

The defect of the melatonin signaling pathway has been proposed to be one of the key etiopathogenic factors in adolescent idiopathic scoliosis (AIS). A previous report showed that melatonin receptor, MT2, was undetectable in some AIS girls. The present study aimed to investigate whether the abnormal MT2 expression in AIS is quantitative or qualitative. Cultured osteoblasts were obtained from 41 AIS girls and nine normal controls. Semi-quantification of protein expression by Western blot and mRNA expression by TaqMan real-time PCR for both MT1 and MT2 were performed. Anthropometric parameters were also compared and correlated with the protein expression and mRNA expression of the receptors. The results showed significantly lower protein and mRNA expression of MT2 in AIS girls compared with that in normal controls (p = 0.02 and p = 0.019, respectively). No differences were found in the expression of MT1. When dichotomizing the AIS girls according to their MT2 expression, the group with low expression was found to have a significantly longer arm span (p = 0.036). The results of this study showed for the first time a quantitative change of MT2 in AIS that was also correlated with abnormal arm span as part of abnormal systemic skeletal growth.

Quantitative ultrasound for predicting curve progression in adolescent idiopathic scoliosis: a prospective cohort study of 294 cases followed-up beyond skeletal maturity.

Adolescent idiopathic scoliosis (AIS) is prevalent among adolescents and can carry significant morbidities. We evaluated the use of quantitative ultrasound (QUS) for predicting curve progression in patients with AIS. We recruited 294 girls with AIS at a mean age of 13.4 years, and they were prospectively followed beyond skeletal maturity for curve progression. We recorded 3 calcaneal QUS measurements at baseline, namely broadband ultrasound attenuation (BUA), velocity of sound (VOS), and stiffness index (SI). Logistic regression analysis indicated that SI, age, menarchal status, and Cobb angle were significant prognostic factors to be included in the final prediction model. The adjusted odds ratio of curve progression for Z-score of SI≦0 was 2.00 (95% CI: 1.08-3.71). The area under the ROC curve was 0.831 (95% CI: 0.785-0.877). The results of this study indicate that SI was an independent and significant prognostic factor for AIS and could be considered in addition to other prognostic factors when estimating the risk for curve progression and planning treatment for patients with AIS.

Abnormal skeletal growth patterns in adolescent idiopathic scoliosis--a longitudinal study until skeletal maturity.

STUDY DESIGN: A cross-sectional and prospective longitudinal study on the anthropometric parameters and growth pattern of girls with adolescent idiopathic scoliosis (AIS). OBJECTIVE: To investigate the growth pattern of girls with AIS with different severities, using cross-sectional and prospective longitudinal data set in comparison with age-matched healthy controls. SUMMARY OF BACKGROUND DATA: AIS occurs in children during their pubertal growth spurt. Although there is no clear consensus on the difference in body height between girls with AIS and healthy controls, it is generally thought that the development and curve progression in girls with AIS is closely associated with their growth rate. There is no concrete prospective longitudinal study to document clearly the growth pattern and growth rate of subjects with AIS . METHODS: A total of 611 girls with AIS and 296 healthy age-matched controls were included in the study and among them, 194 girls with AIS and 116 healthy controls were followed up until skeletal maturity. The girls with AIS were grouped into moderate (AIS20) and severe curve (AIS40) groups on the basis of maximum curve magnitude at skeletal maturity. Clinical data and detailed anthropometric parameters were recorded. In the cross-sectional analysis, the groups of subjects were compared within different age groups (from the age of 12-16 yr). In the longitudinal study, linear mixed modeling with respect to age or years since menarche was employed to formulate the growth trajectory of different anthropometric parameters. RESULTS: In the cross-sectional analysis, the girls with AIS were generally taller, with longer arm span and lower body mass index than the healthy controls. The girls with AIS40 were found to be significantly shorter in height (P = 0.006) and arm span (P = 0.025) at the age of 12 years but caught up and overtook the control group at the age of 14 to 16 years. In the longitudinal study, the average growth rate of arm span in girls with AIS40 was significantly higher than that in girls with AIS20 (> 30%) (P = 0.004) and controls (> 70%) (P = 0.0004). The age of menarche of girls with AIS40 was significantly delayed by 5.9 months and 3.8 months when compared with the control group and girls with AIS20, respectively (P < 0.05). CONCLUSION: The growth patterns of girls with AIS with confirmed curve severities were significantly different from healthy age-matched controls. Girls with severe AIS had delayed menarche with faster skeletal growth rate during the age of 12 to 16 years. Monitoring the rate of change of arm span of girls with AIS could be an important additional clinical parameter in helping predict curve severity in girls with AIS.

Genetic epidemiology and heritability of AIS: A study of 415 Chinese female patients.

Recent familial segregation studies supported a multifactorial genetic model for the etiology of adolescent idiopathic scoliosis (AIS). However, the extent of quantitative genetic effects, such as heritability, have not been fully evaluated. This genetic epidemiology study examined the sibling recurrent risk and heritability of AIS in first-degree relatives of 415 Chinese female patients, which is up to now the largest cohort. They were first diagnosed by community screening program and compared to 203 age-matched normal controls. Out of the total 531 sibs of AIS cases, 94 sibs had scoliosis (sibling recurrence risk = 17.7%). The prevalence of AIS among male and female sibs of an index case were 11.5% (95% CI = 7.5-15.5) and 23.0% (95% CI = 18.1-27.9), respectively. Female sibs of an index case had an increased risk of 8.9-fold (95% CI = 3.2-34.4) for developing AIS. These recurrent risks were significantly higher than the risk in the control group (p < 0.0001). Overall, heritability was estimated to be 87.5 ± 11.1%. The results confirmed the prevailing impression of strong genetic influence on the risk of AIS. Here we provided a large-scale study for the genetic aggregation estimates in an Asian population for the first time. The finding also positioned AIS among other common disease or complex traits with a high heritability.

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.

Low-intensity pulsed ultrasound enhances posterior spinal fusion implanted with mesenchymal stem cells-calcium phosphate composite without bone grafting.

STUDY DESIGN: Experimental study on the effect of low-intensity pulsed ultrasound (LIPUS) on rabbit spinal fusion with mesenchymal stem cell (MSC)-derived osteogenic cells and bioceramic composite. OBJECTIVE: To investigate the efficacy of LIPUS in enhancing fusion rate and bone formation with porous tricalcium phosphate (TCP) bioceramic scaffold impregnated with MSCs without any bone grafts. SUMMARY OF BACKGROUND DATA: The goal of spinal fusion in the corrective spinal surgery for spinal deformities is to achieve solid bony fusion between selected vertebral segments. Previous studies with bone morphogenetic proteins and genetically manipulated materials revealed significant difficulties in actual clinical application. Alternative such as LIPUS has been shown to be effective in enhancing healing of fracture and nonunion clinically. Its potential for enhancing spinal fusion warrants further in-depth study. METHODS: Posterolateral intertransverse processes spinal fusion at the L5 and L6 levels were evaluated in New Zealand white rabbit model. The animals were divided into three groups with (A) TCP alone, (B) TCP with differentiated MSCs, and (C) TCP with differentiated MSCs and LIPUS treatment. At week 7 postoperation, manual palpation, peripheral quantitative computed tomography, and histomorphometric assessments were performed. RESULTS: At week 7 postoperation, a statistically significant increase in clinical fusion by manual palpation was observed in group C animals treated with LIPUS (86%) in comparing with groups A (0%) and B (14%) without LIPUS. With peripheral quantitative computed tomographic analysis, the bone volume of group C fusion mass was significantly larger than the other two groups. Group C fusion also had better osteointegration length between host bone and implanted composite and more new bone formed in the TCP implants. Importantly, all the group C animals had osteochondral bridging--early stage of bony fusion histologically. Endochondral ossification was observed at the junction between the cartilaginous and osseous tissues at the intertransverse processes area. Quantitative analysis showed that the fusion mass in group C had significantly smaller gap and larger area of cartilaginous tissue between the transverse processes. CONCLUSION: The present study showed that the combination of synthetic biomaterials, autologous differentiated MSCs, and LIPUS could promote clinical fusion in rabbit posterior spinal fusion model. The mechanism was likely to be mediated through better osteointegration between the host bone and implanted materials and enhanced endochondral ossification at the fusion site.

Abnormal bone quality in adolescent idiopathic scoliosis: a case-control study on 635 subjects and 269 normal controls with bone densitometry and quantitative ultrasound.

STUDY DESIGN: A case-control study comparing bone quality in Adolescent Idiopathic Scoliosis (AIS) with normal controls. OBJECTIVE: To evaluate bone quality with quantitative ultrasound (QUS) in AIS and normal controls so as to detect any derangement in bone quality among AIS subjects. SUMMARY OF BACKGROUND DATA: AIS is characterized by complex spinal deformities. Despite its high prevalence and clinical impact in adolescents, etiology of AIS remains unknown but one possible mechanism is related to derangement of bony mechanical stability, as quantified by bone mineral density (BMD) and bone quality. AIS is known for its association with osteopenia, but little is known about the bone quality in AIS. With technological advancement, QUS can provide objective measurement of bone quality. In this study, we sought to compare bone quality in AIS with normal controls using QUS in addition to the conventional BMD measurement. METHODS: Six hundred thirty-five AIS girls and 269 age-matched normal girls were investigated. Broadband ultrasound attenuation (BUA), velocity of sound (VOS), and stiffness index (SI) were measured over the nondominant calcaneus using QUS. The results were correlated with anthropometric measurement, radiologic assessment, and BMD of both hips. RESULTS: The z-score of BMD at the femoral neck of AIS subjects (-0.47 ± 0.97) was significantly lower than that of normal controls (-0.12 ± 1.01, P < 0.001). Crude comparison showed that BUA, VOS, and SI of AIS group were 3.8% (P < 0.01), 0.5% (P = 0.042), and 6.9% (P < 0.01) lower than controls, respectively. After controlling confounding from maturity, body weight, body height, and BMD with multiple linear regression analysis for both mild (Cobb's angle ≤ 25°) and severe (Cobb's angle > 25°) curves, BUA and SI were found to be statistically significantly lower in AIS as compared with controls (P < 0.05). CONCLUSION: In addition to higher prevalence of osteopenia, AIS patients were also found to have deranged bone quality. These might contribute to the etiopathogenesis of spinal deformities in AIS.

Top theories for the etiopathogenesis of adolescent idiopathic scoliosis.

BACKGROUND: Despite considerable advances in the past few decades, there is no generally accepted "top theory or theories" of the etiology of adolescent idiopathic scoliosis (AIS). This article aims to provide an overview of the current main hypothetical "concepts" on the etiopathogenesis of AIS. METHODS: An extensive literature review on hypothetical concepts on the etiology and etiopathogenesis of AIS. RESULTS: Concepts of etiopathogenesis in AIS were summarized and highlighted under 6 subgroups: genetics factors, abnormalities in nervous system, abnormal skeletal growth, hormones and metabolic dysfunction, biomechanical factors, and environmental and life style factors. An integrative model on the etiopathogenesis of AIS is proposed. CONCLUSIONS: The current knowledge is still fragmented and many fundamental questions have remained to be answered. In moving forward in the perusal of further advancement of our understanding of the etiopathogenetic mechanisms and future evidence-based prevention and management of AIS, multidisciplinary and multicenter innovative research collaboration is imminently important and necessary. CLINICAL RELEVANCE: With a relatively comprehensive review on the current understanding on the etiology and etiopathogenesis of AIS, the article would help to stimulate further innovative thoughts, research, and especially collaborative research in this area of great interest.

The association of disproportionate skeletal growth and abnormal radius dimension ratio with curve severity in adolescent idiopathic scoliosis.

Abnormal anthropometric measurements during the peripubertal growth spurt have been documented in adolescent idiopathic scoliosis (AIS). Magnetic resonance (MR) imaging studies of the spine have suggested a disproportionate endochondral and membranous ossification in AIS. The present study aimed at investigating whether disproportional ossification and skeletal growth occurred in the peripheral bone of AIS patients using the radius as the target bone. Skeletally mature AIS girls with different severity (n = 290) and age-matched control healthy girls (n = 80) were recruited. The anthropometric parameters were recorded. The midshaft of non-dominant radius was scanned with peripheral quantitative computed tomography (pQCT) and the radius diameter was calculated from the cross-sectional area. Radius dimension ratio was derived from the ratio of radius diameter to radius length. The anthropometric parameters were compared between AIS and control with adjustment for age. The radius dimension ratio was further correlated with curve severity in AIS girls using Pearson's correlation test. The analysis showed that the arm span and radius length were slightly longer in AIS girls. The BMI of AIS girls was significantly lower than the controls. The radius dimension ratio in severe AIS girls was significantly lower than the controls and the ratio of AIS girls correlated with the curve severity (r = -0.120; p = 0.039). The abnormal radius dimension ratio supported the presence of systemic growth abnormalities in AIS. Disproportional endochondral-membranous ossification could explain for the observation. The observation of the association of radius dimension ratio with curve severity provides an important potentially clinically measurable parameter for further longitudinal studies on the prognostication of curve progression in AIS.

[The thoracic spine morphology under magnetic resonance imaging in adolescent idiopathic scoliosis and its clinical significance].

OBJECTIVES: To evaluate and compare thoracic vertebrae morphology between patients with idiopathic and normal adolescents through MRI. METHODS: Two-dimensional sagittal MRI of the spine was performed in 10 normal adolescent, 10 patients with mild idiopathic thoracic scoliosis (Cobb angle 15 degrees - 39 degrees ) and 10 patients with moderate thoracic scoliosis (Cobb angle 40 degrees - 75 degrees ), all of them were female and between 13 - 14 years old. Sagittal imaging was reconstructed on image working station (Easy Vision, Philips Medical Systems, Best, Netherlands). Anterior height, posterior height and width of vertebral body as well as length between spinous process were measured on each thoracic spine. RESULTS: Anterior height, posterior height and width of vertebral body increased from T(1) to T(12) with the values from scoliotic groups larger than normal group. The anterior height/width ratio and anterior/posterior column ratio were also larger in scoliotic group especially at apical area. CONCLUSION: The thoracic vertebrae are higher and slimmer in scoliotic patient than in normal age-matched girls which implied that there is abnormal endochondral ossification on spine during adolescent growth spurt.

Trabecular bone micro-architecture and bone mineral density in adolescent idiopathic and congenital scoliosis.

OBJECTIVE: To investigate the microstructure of trabecular bone in adolescent idiopathic scoliosis (AIS) and age-matched congenital scoliosis (CS), and to evaluate the bone mineral status of CS patients compared with normal controls and AIS patients. METHODS: This study included 15 AIS and 16 CS female patients and 35 healthy female adolescents. Corrective surgery was indicated for the AIS and CS patients, from whom iliac crest biopsies were collected during autograft harvesting, and scanned by micro-computer tomography. Bone mineral status was assessed at the lumbar and hip areas in every patient by dual energy X-ray absorptiometry (DEXA). RESULTS: Significantly lower lumbar and femoral neck bone mineral density (BMD) was found in AIS patient compared with normal controls. All BMD and bone mineral content (BMC) parameters were significantly lower in CS patients compared with age-matched normal controls. Under DEXA assessment significant associations between bone volume/tissue volume (BV/TV) and BMD values were observed. In the 3D model, BV/TV was significantly higher in AIS (19.9% ± 3.4%) than in CS (13.3% ± 3.0%, P < 0.05). Significant differences between AIS and CS were also found in trabecular thickness (Tb.Th) and bone surface/bone volume (BS/BV) (155.5 ± 54.9 µm vs. 108.1 ± 17.4 µm and 16.4% ± 3.3% vs. 22.0% ± 3.4% respectively, P < 0.05 in both). CONCLUSION: Lower bone mineral status and weak trabecular bone structure observed in AIS and CS justify further investigation of the bone mineral status in scoliosis of various etiologies.

Lack of association between the promoter polymorphism of the MTNR1A gene and adolescent idiopathic scoliosis.

STUDY DESIGN: A genetic association study to investigate variation of the melatonin receptor 1A (MTNR1A) gene in adolescent idiopathic scoliosis (AIS) patients. OBJECTIVE: To determine whether the MTNR1A gene promoter polymorphism is associated with the predisposition and/or disease severity of AIS. SUMMARY OF BACKGROUND DATA: An involvement of the dysfunction of the melatonin pathway in the etiopathogenesis of AIS has been implicated in several studies. Recently, our group has found that the promoter polymorphism of the melatonin receptor 1B (MTNR1B) gene was associated with the occurrence of AIS. Hence, it is of interest to determine whether the promoter polymorphism of the MTNR1A gene could also associated with the occurrence or curve severity of AIS. METHODS: A total of 226 AIS girls and 277 normal controls were recruited. SNP rs2119882 in the promoter region (-369 bp) of the MTNR1A gene was selected for the present study. Genotyping was performed by PCR-RFLP. Statistical analysis of genotype frequencies between case and control was performed by chi test. One-way ANOVA was used in comparison of mean maximum Cobb angles with different genotypes in case-only analysis. RESULTS: Genotype and allele frequencies were comparable between case and control for SNP rs2119882 (P > 0.05). The mean maximum Cobb angles of different genotypes were similar with each other for SNP rs2119882. CONCLUSIONS: Promoter polymorphism of the MTNR1A gene was not associated with the occurrence or curve severity of AIS. The MTNR1A gene may not be involved in the etiopathogenesis of AIS.

[Effect of genetic polymorphism of MTNR1A gene on adolescent idiopathic scoliosis].

OBJECTIVE: To investigate whether the MTNR1A gene promotor polymorphism (rs2119882) are associated with the occurrence or curve severity of adolescent idiopathic scoliosis (AIS). METHODS: 226 AIS patients and 277 normal controls were recruited. The maximum Cobb angles were recorded in AIS patients. PCR-RFLP was used for the genotyping. RESULTS: The genotype and allele frequency distribution were comparable between AIS and normal control, the mean maximum Cobb angle of different genotypes of rs2119882 were similar with each other among AIS patients. CONCLUSION: The MTNR1A gene promoter polymorphism was neither associated with the occurrence nor the curve severity of AIS.

Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis.

STUDY DESIGN: A genetic association study to comprehensively investigate variations of melatonin receptor 1B gene polymorphism by a set of tagging single nucleotide polymorphisms (tagSNPs) derived from the International Hapmap project. OBJECTIVES: To determine whether melatonin receptor 1B (MTNR1B) gene polymorphisms are associated with the predisposition and/or disease severity of adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Linkage studies suggested a genetic predisposition for AIS. In addition, evidence showed that AIS might be related to melatonin deficiency and dysfunction of melatonin signaling pathway. Locating in one of the chromosomal regions linked to AIS, MTNR1B gene is a potential candidate gene for AIS. METHODS: This study was carried out in 2-stage case-control analysis: 1) initial screening (472 cases and 304 controls) and 2) separate replication test (342 cases and 347 controls) to confirm results in the screening. In the first screening stage, 5 tagSNPs were selected to cover most of the genetic variation in the MTNR1B gene. In the second stage, SNPs showing association in the screening stage were studied in a separate replication sample set to confirm the association. Genotyping was performed by PCR-RFLP. RESULTS: The first stage showed a putative association between rs4753426 and AIS, which was confirmed in the replication sample set. By meta-analysis, the frequency of C allele of this SNP locating in the promoter was significantly higher in the cases than controls (P = 0.006 aftermeta-analysis). Subjects with the CC genotype had an odds ratio of 1.29 for AIS. Another SNP rs741837 in promoter region, being moderate linkage disequilibrium with rs4753426, was also marginally associated with AIS. CONCLUSION: Polymorphisms of the promoter of MTNR1B gene were associated with AIS, but not with the curve severity in AIS patients. This suggested that MTNR1B was an AIS predisposition gene.

Genetic association of complex traits: using idiopathic scoliosis as an example.

Although the exact etiology of adolescent idiopathic scoliosis is still undefined, genetic factors play an important role. Some patients have familial genetic disease that appears to have an autosomal dominant pattern. Linkage studies of these families revealed multiple potential genetic loci that may predispose individuals to the condition. Additional genetic analysis is required to identify the disease-predisposition genes of the loci found in the linkage studies. The initial localization of potential critical loci through large family-based population studies now needs fine mapping by association studies using high-density polymorphic markers (single nucleotide polymorphisms or SNPs). These markers are now available as a result of the Human Genome Project, International HapMap Project, and other genetic diversity projects. The application of this emerging data in a large association study of affected individuals and controls is integral for the identification of putative genes. With these complementary approaches, we will be able to progress with mutational analysis of hopefully a small set of candidate genes in the near future. In this commentary, we illustrate what is possible in the genomic era, and indicate what we should expect from genetic studies in adolescent idiopathic scoliosis, a complex trait disease.

Genetic association study of growth hormone receptor and idiopathic scoliosis.

Although the etiology of scoliosis is multifactorial, genetic factors play an important role. Recent linkage studies on familial idiopathic scoliosis revealed multiple putative predisposition loci. A genetic association study is complementary to linkage studies in defining the genetic basis of complex traits of diseases like idiopathic scoliosis. The onset and progression of adolescent idiopathic scoliosis is a manifestation of aberrant growth in the spine. Meanwhile, a high proportion of patients with adolescent idiopathic scoliosis have additional phenotypes, which suggest systemic growth dys-regulation during puberty. The growth hormone-insulin-like growth factor axis plays the principle role in skeletal growth regulation. Because growth hormone receptor alleles were associated with body stature and response to growth hormone treatment, we hypothesized the growth hormone receptor is a candidate predisposing and disease modifier gene for adolescent idiopathic scoliosis. Five hundred ten girls with adolescent idiopathic scoliosis and 363 normal subjects were recruited. Curve severity, arm span, and bone mineral densities were recorded. Five polymorphisms were studied by polymerase chain reaction-restriction fragment length polymorphism. All the genotype and allele frequencies were comparable between groups. The Cobb angles among patients of different genotypes were similar. The growth hormone receptor did not appear to be a predisposing gene or disease modifier gene of adolescent idiopathic scoliosis.