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Background: Osteoporosis is a major causative factor of the global burden of disease and disability, characterized by low bone mineral density (BMD) and high risks of fracture. We aimed to identify putative causal proteins and druggable targets of osteoporosis. Methods: This study utilized the largest GWAS summary statistics on plasma proteins and estimated heel BMD (eBMD) to identify causal proteins of osteoporosis by mendelian randomization (MR) analysis. Different GWAS datasets were used to validate the results. Multiple sensitivity analyses were conducted to evaluate the robustness of primary MR findings. We have also performed an enrichment analysis for the identified causal proteins and evaluated their druggability. Results: After Bonferroni correction, 67 proteins were identified to be causally associated with estimated BMD (eBMD) (p < 4 × 10-5). We further replicated 38 of the 67 proteins to be associated with total body BMD, lumbar spine BMD, femoral neck BMD as well as fractures, such as RSPO3, IDUA, SMOC2, and LRP4. The findings were supported by sensitivity analyses. Enrichment analysis identified multiple Gene Ontology items, including collagen-containing extracellular matrix (GO:0062023, p = 1.6 × 10-10), collagen binding (GO:0005518, p = 8.6 × 10-5), and extracellular matrix structural constituent (GO:0005201, p = 2.7 × 10-5). Conclusion: The study identified novel putative causal proteins for osteoporosis which may serve as potential early screening biomarkers and druggable targets. Furthermore, the role of plasma proteins involved in collagen binding and extracellular matrix in the development of osteoporosis was highlighted. Further studies are warranted to validate our findings and investigate the underlying mechanism. [ABSTRACT FROM AUTHOR]

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 metaanalysis 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. [ABSTRACT FROM AUTHOR]

The sunlight exposure questionnaire for use in the Chinese population was constructed based on extensive literature review and item suitability for measuring life-time exposure. The content validity index (CVI) was derived from ratings by, an expert panel to assess the item content and relevance. 650 population-based Chinese women completed the sunlight exposure questionnaire through telephone interview. To assess the questionnaire reliability, 94 women were re-interviewed after 2 weeks. 98.4% of the sunlight exposure questionnaire items were found to have valid CVI (>0.83). The Scree plot and the Principal Components Factor Analysis showed a two-factor construct was appropriate and no questionnaire item needed to be excluded. The questionnaire also had a good test-retest reliability (ICC: 0.59-0.93; k: 0.51-100). This sunlight exposure questionnaire was found to be adequate for measurement of life-time sunlight exposure among Hong Kong Chinese women [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Restrictive impairment is the commonest reported pulmonary deficit in AIS, which improves following surgical operation. However, exact mechanism of how improvement is brought about is unknown. Dynamic fast breath-hold (BH)-MR imaging is a recent advance which provides direct quantitative visual assessment of pulmonary function. By using above technique, change in lung volume, chest wall and diaphragmatic motion in AIS patients before and six months after posterior spinal fusion surgery were measured. Methods: 16 patients with severe right-sided predominant thoracic scoliosis (standing Cobb's angle 50° -82°, mean 60°) received posterior spinal fusion without thoracoplasty were recruited into this study. BH-MR sequences were used to obtain coronal images of the whole chest during full inspiration and expiration. The following measurements were assessed: (1) inspiratory, expiratory and change in lung volume; (2) change in anteroposterior (AP) and transverse (TS) diameter of the chest wall at two levels: carina and apex (3) change in diaphragmatic heights. The changes in parameters before and after operation were compared using Wilcoxon signed ranks test. Patients were also asked to score their breathing effort before and after operation using a scale of 1-9 with ascending order of effort. The degree of spinal surgical correction at three planes was also assessed by reformatted MR images and correction rate of Cobb's angle was calculated. Results: The individual or total inspiratory and expiratory volume showed slight but insignificant increase after operation. There was significantly increase in bilateral TS chest wall movement at carina level and increase in bilateral diaphragmatic movements between inspiration and expiration. The AP chest wall movements, however, did not significantly change. The median breathing effort after operation was lower than that before operation (p < 0.05). There was significant reduction in coronal Cobb's angle after operation but the change in sagittal and axial angle at scoliosis apex was not significant. Conclusion: There is improvement of lateral chest wall and diaphragmatic motions in AIS patients six months after posterior spinal fusion, associated with subjective symptomatic improvement. Lung volumes however, do not significantly change after operation. BH-MR is novel non-invasive method for long term post operative assessment of pulmonary function in AIS patients. [ABSTRACT FROM AUTHOR]