Dataset Information

Association of Circulating YKL-40 Levels and CHI3L1 Variants with the Risk of Spinal Deformity Progression in Adolescent Idiopathic Scoliosis.

ABSTRACT: The cellular and molecular mechanisms underlying spinal deformity progression in adolescent idiopathic scoliosis (AIS) remain poorly understood. In this study, 804 French-Canadian patients and 278 age- and sex-matched controls were enrolled and genotyped for 12 single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) gene or its promoter. The plasma YKL-40 levels were determined by ELISA. We showed that elevation of circulating YKL-40 levels was correlated with a reduction of spinal deformity progression risk. We further identified significant associations of multiple CHI3L1 SNPs and their haplotypes with plasma YKL-40 levels and scoliosis severity as a function of their classification in a specific endophenotype. In the endophenotype FG3 group, we found that patients harboring the haplotype G-G-A-G-G-A (rs880633|rs1538372|rs4950881|rs10399805|rs6691378|rs946261), which presented in 48% of the cases, showed a positive correlation with the plasma YKL-40 levels (P?=?7.6?×?10-6 and coefficient?=?36). Conversely, the haplotype A-A-G-G-G-G, which presented in 15% of the analyzed subjects, showed a strong negative association with the plasma YKL-40 levels (P?=?2?×?10-9 and coefficient?=?-9.56). We found that this haplotype showed the strongest association with AIS patients in endophenotype FG2 (P?=?9.9?×?10-6 and coefficient?=?-13.53), who more often develop severe scoliosis compared to those classified in the other two endophenotypes. Of note, it showed stronger association in females (P?=?1.6?×?10-7 and coefficient?=?-10.08) than males (P?=?0.0021 and coefficient?=?-9.01). At the functional level, we showed that YKL-40 treatments rescued Gi-coupled receptor signalling dysfunction occurring in primary AIS osteoblasts. Collectively, our findings reveal a novel role for YKL-40 in AIS pathogenesis and a new molecular mechanism interfering with spinal deformity progression.

SUBMITTER: Nada D

PROVIDER: S-EPMC6450973 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Association of Circulating YKL-40 Levels and CHI3L1 Variants with the Risk of Spinal Deformity Progression in Adolescent Idiopathic Scoliosis.

Nada Dina D Julien Cédric C Rompré Pierre H PH Akoume Marie-Yvonne MY Gorman Kristen F KF Samuels Mark E ME Levy Emile E Kost Jason J Li Dawei D Moreau Alain A

Scientific reports 20190405 1

The cellular and molecular mechanisms underlying spinal deformity progression in adolescent idiopathic scoliosis (AIS) remain poorly understood. In this study, 804 French-Canadian patients and 278 age- and sex-matched controls were enrolled and genotyped for 12 single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) gene or its promoter. The plasma YKL-40 levels were determined by ELISA. We showed that elevation of circulating YKL-40 levels was correlated with a reduction of sp ...[more]

PMID: 30952886

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Project description:AimTo evaluate published data on the predictors of progressive adolescent idiopathic scoliosis (AIS) in order to evaluate their efficacy and level of evidence.MethodsSelection criteria(1) study design: randomized controlled clinical trials, prospective cohort studies and case series, retrospective comparative and none comparative studies; (2) participants: adolescents with AIS aged from 10 to 20 years; and (3) treatment: observation, bracing, and other.Search methodOvid MEDLINE, Embase, the Cochrane Library, PubMed and patent data bases. All years through August 2014 were included. Data were collected that showed an association between the studied characteristics and the progression of AIS or the severity of the spine deformity. Odds ratio (OR), sensitivity, specificity, positive and negative predictive values were also collected. A meta-analysis was performed to evaluate the pooled OR and predictive values, if more than 1 study presented a result. The GRADE approach was applied to evaluate the level of evidence.ResultsThe review included 25 studies. All studies showed statistically significant or borderline association between severity or progression of AIS with the following characteristics: (1) An increase of the Cobb angle or axial rotation during brace treatment; (2) decrease of the rib-vertebral angle at the apical level of the convex side during brace treatment; (3) initial Cobb angle severity (> 25(o)); (4) osteopenia; (5) patient age < 13 years at diagnosis; (6) premenarche status; (7) skeletal immaturity; (8) thoracic deformity; (9) brain stem vestibular dysfunction; and (10) multiple indices combining radiographic, demographic, and physiologic characteristics. Single nucleotide polymorphisms of the following genes: (1) calmodulin 1; (2) estrogen receptor 1; (3) tryptophan hydroxylase 1; (3) insulin-like growth factor 1; (5) neurotrophin 3; (6) interleukin-17 receptor C; (7) melatonin receptor 1B, and (8) ScoliScore test. Other predictors included: (1) impairment of melatonin signaling in osteoblasts and peripheral blood mononuclear cells (PBMC); (2) G-protein signaling dysfunction in PBMC; and (3) the level of platelet calmodulin. However, predictive values of all these findings were limited, and the levels of evidence were low. The pooled result of brace treatment outcomes demonstrated that around 27% of patents with AIS experienced exacerbation of the spine deformity during or after brace treatment, and 15% required surgical correction. However, the level of evidence is also low due to the limitations of the included studies.ConclusionThis review did not reveal any methods for the prediction of progression in AIS that could be recommended for clinical use as diagnostic criteria.

Project description:BackgroundA misbalance in forces is proposed for causing adolescent idiopathic scoliosis (AIS). AIS is therefore correlated to adjacent musculoskeletal pathologies. Its concomitance with idiopathic pectus deformities (PD) is underexposed. This systematic review analyzes the clinical significance and predictive factors of PD-associated AIS.MethodsA search was performed in PubMed, UpToDate, Embase, and Cochrane. A study was included if it: assessed the association between PD and scoliosis (category I), reported a prevalence of scoliosis in PD patients (category II), or addressed other topics about PD-associated AIS (category III). Studies in category I discussing predictive factors were appraised using the Quality in Prognosis Studies tool. Because of heterogeneity among the studies, predictive factors were analyzed according to a best evidence synthesis. A mean prevalence of scoliosis in PD patients was calculated using category I and II. Category III was narratively reviewed.ResultsForty-eight studies were included (I:19, II:21, III:8). Category I comprised 512 patients with PD-concomitant scoliosis. Thirteen studies reported predictive factors, of which 15 concerned the prevalence of scoliosis in PD patients and 12 Cobb Angle (CA) change after PD correction. Compared with AIS, PD seems to develop earlier in adolescence, and PD with concomitant AIS was more frequently reported in older patients. Evidence remained conflicting regarding the association between the severity of PD and that of scoliosis. As opposed to at a younger age, late PD correction is not associated with a postoperative increase of CA. Limited evidence showed that patients with a high CA undergoing PD correction do not experience an increase in CA, though, strong evidence indicated that it would not lead to a decrease in CA. The mean probable prevalence of AIS in PD patients was 13.1%.ConclusionCurrent literature confirms the association between PD and AIS in patients with an indication for PD correction.Level of evidence: III.

Project description:BackgroundPrediction of curve progression risk in adolescent idiopathic scoliosis (AIS) remains elusive. Prior studies have revealed the potential for three-dimensional (3D) morphological parameters to prognosticate progression, but these require specialized biplanar imaging equipment and labor-intensive software reconstruction. This study aimed to formulate a deep learning model with standing posteroanterior (PA) X-rays at first clinic visit to differentiate between progressive (P) and non-progressive (NP) curves.MethodsFor this retrospective cohort study, we identified patients presenting with AIS between October 2015 to April 2020 at our tertiary referral centre. Patients with mild curvatures (11 - 30o) who were skeletally immature (Risser sign of ≤2) were recruited. Patients receiving biplanar X-ray radiographs (EOS™) were divided between a training-cross-validation cohort (328 patients) and independent testing cohort (110 patients). Another 52 patients receiving standard PA spinal X-rays were recruited for cross-platform validation. Following 3D reconstruction, we designated the major curve apex upon PA X-rays as the region of interest (ROI) for machine learning. A self-attentive capsule network was constructed to differentiate between curves manifesting P and NP trajectories. A two-stage transfer learning strategy was introduced to pre-train and fine-tune the model. Model performance (accuracy, sensitivity, specificity) was compared to that of traditional convolutional neural networks (CNNs) and a clinical parameter-based logistic regression model.Findings3D reconstruction identified that apical rotation of the major curve and torsion were significantly different between P and NP curve trajectories. Our predictive model utilizing an ROI centered on the major curve apex achieved an accuracy of 76.6%, a sensitivity of 75.2% and a specificity of 80.2% upon independent testing. Cross-platform performance upon standard standing PA X-rays yielded an accuracy of 77.1%, a sensitivity of 73.5% and a specificity of 81.0%. Errors in prediction occurred when the degree of apical rotation / torsion was discrepant from that of the subsequent curve trajectory but could be rectified by considering serial X-rays. Performance was superior to that of traditional CNNs as well as clinical parameter-based regression models.InterpretationThis is the first report of automated prediction of AIS curve progression based on radiomics and deep learning, towards directing treatment strategy at first visit. Patients predicted to be at-risk of progression may be counselled to receive early bracing with enforcement of treatment compliance. Over-treatment may be avoided in curves deemed to be non-progressive. Results need to be consolidated in larger sample populations of different ethnicities.FundingThe Society for the Relief of Disabled Children (SRDC).

Dataset Information

Association of Circulating YKL-40 Levels and CHI3L1 Variants with the Risk of Spinal Deformity Progression in Adolescent Idiopathic Scoliosis.

Publications

Association of Circulating YKL-40 Levels and CHI3L1 Variants with the Risk of Spinal Deformity Progression in Adolescent Idiopathic Scoliosis.

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