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Value of DNA methylation in predicting curve progression in patients with adolescent idiopathic scoliosis.

ABSTRACT: BACKGROUND:There is considerable discordance in the curve progression of adolescent idiopathic scoliosis (AIS) patients between monozygotic (MZ) twins, indicating that nongenetic factors must be involved in the curve progression of AIS patients. Epigenetic processes may constitute one of these factors and have not yet been investigated in relation to curve progression in AIS patients. METHODS:The genome and methylome of peripheral monocytes were compared between MZ twins discordant for curve progression. Sets of differentially methylated sites were validated using the MassARRAY platform of Sequenome on additional samples. RESULTS:In the discovery study, we found evidence suggesting a lack of differences at the genome sequence level and the presence of epigenetic differences related to the curve progression of AIS patients. The top 4 differentially methylated CpG sites associated with curve severity were tested, and only site cg01374129 (CpG site located at chr8:122583383, Hg19) was confirmed in two replication cohorts. The methylation levels of site cg01374129 were significantly lower in the progression group than in the nonprogression group. Cox regression analysis demonstrated that hypo-methylation of site cg01374129 was an independent prognostic factor for curve severity. Site cg01374129 methylation as a marker achieved a sensitivity of 76.4% and a specificity of 85.6% in differentiating between samples from patients with and without curve progression (AUC?=?0.827; 95% CI: 0.780 to 0.876). CONCLUSION:Increased curvature is associated with decreased methylation at site cg01374129. Our results indicate that methylation of site cg01374129 may therefore serve as a promising biomarker in differing between patients with and without curve progression.

SUBMITTER: Meng Y

PROVIDER: S-EPMC6197569 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Value of DNA methylation in predicting curve progression in patients with adolescent idiopathic scoliosis.

Meng Yichen Y Lin Tao T Liang Shulun S Gao Rui R Jiang Heng H Shao Wei W Yang Fu F Zhou Xuhui X Zhou Xuhui X

EBioMedicine 20180918

<h4>Background</h4>There is considerable discordance in the curve progression of adolescent idiopathic scoliosis (AIS) patients between monozygotic (MZ) twins, indicating that nongenetic factors must be involved in the curve progression of AIS patients. Epigenetic processes may constitute one of these factors and have not yet been investigated in relation to curve progression in AIS patients.<h4>Methods</h4>The genome and methylome of peripheral monocytes were compared between MZ twins discordan ...[more]

PMID: 30241917

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Project description:BackgroundThe Proximal Femur Maturity Index (PFMI) can be used to assess skeletal maturity on existing whole-spine radiographs without additional radiation. However, the relationship between the PFMI at the initiation of bracing for adolescent idiopathic scoliosis (AIS) and subsequent curve progression remains unknown. This study aimed to investigate the relationship between the PFMI and curve progression, and the predictability of risks to adulthood curve progression and surgical thresholds based on the PFMI grade at brace initiation.MethodsThis was a prospective study of 202 patients with AIS who were prescribed underarm bracing according to the Scoliosis Research Society criteria and had good brace-wear compliance. The patients were followed from brace initiation until complete skeletal maturity. Longitudinal data on the coronal Cobb angle and skeletal maturity assessments using Risser staging, Sanders staging, the distal radius and ulna classification, and the PFMI were collected. Each patient was assessed on whether the major curve progressed to ≥40° (adulthood deterioration) and ≥50° (the surgical threshold). Logistic regressions were used to predict probabilities of curve progression to the 2 thresholds, adjusted for factors that were significant in univariate analyses.ResultsThe PFMI correlated with the other skeletal maturity indices (r s [Spearman rank correlation] = 0.60 to 0.72, p < 0.001 for all). The pre-brace PFMI grade correlated with progression to ≥40° (r rb [rank-biserial correlation] = -0.30, p < 0.001) and to ≥50° (r rb = -0.20, p = 0.005). Based on regression models (p < 0.001) adjusted for the pre-brace major Cobb angle and curve type, brace initiation at PFMI grades 2 and 3 for a curve of ≥30° had predicted risks of 30% (95% confidence interval [CI], 4% to 55%) and 12% (95% CI, 7% to 17%), respectively, for progression to the surgical threshold. Brace initiation at PFMI grade 5 had 0% progression risk.ConclusionsThe PFMI can be used for predicting curve progression and prognosticating brace outcomes in AIS. Patients with brace initiation at PFMI grade 4 for a curve of <30° or at grade 5 were unlikely to progress to the adulthood deterioration or surgical threshold. In comparison, skeletally immature patients initiating bracing at a PFMI grade of ≤3 for a major curve of ≥30° had a higher risk of progression despite compliant brace wear.Level of evidencePrognostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Project description:There is no consensus on the definition of a structural proximal thoracic curve (PTC) and the indications for fusion. As such, we assessed a single institute's experience in the management of large PTCs (>35 degrees) in patients with adolescent idiopathic scoliosis (AIS) who were either fused or not fused. A retrospective radiographic analyses of 30 consecutive AIS patients with double thoracic curves who underwent PSF with a minimum of 2 years' follow-up were included for review. The patients were divided into two groups: group 1 (n = 15 patients) with fusion extended up to T2 or T3 and group 2 (n = 15) with fusion limited to T5 or below. Shoulder balance was assessed according to clavicular angle, first-rib difference, and radiographic shoulder height difference (SHD). PTCs were defined based on a Cobb angle of >35, the presence of apical rotation, and a positive T1 tilt. The decision to fuse the PTC was based on curve magnitude only, with those between 35 and 45 degrees undergoing a selective fusion of the main thoracic curve (MTC), with both curves fused if the PTC was more than 45 degrees. In group 1, there were eight females and seven males. Their ages ranged between 12 and 33 years, with a mean of 16.2 ± 5.5 years. Postoperatively, the mean PTC correction was 45.6%, which statistically differed from preoperative status (p = 0.001). No statistical difference was noted in T1 tilt and the first-rib difference from preoperative to postoperative follow-up (p > 0.05). However, the clavicular angle and SHD were increased significantly at the immediate postoperative interval (p < 0.05) but demonstrated no significant changes between the initial and the last follow-up values (p > 0.05). Group 2 consisted of one male and 14 females. The mean age was 16.4 ± 4 years (range: 11 to 28 years). The mean spontaneous PTC correction was 28.3% and remained essentially unchanged at the end of the follow-up. The improvement in the curve from preoperative status was highly statistically significant (p = 0.001). All radiographic shoulder parameters exhibited a significant increase in the immediate postoperative period and at last follow-up, and shoulder balance improvement was not noted on follow-up. Although both groups were not statistically similar with regards to the preoperative PTC, AVR, apical vertebral translation, and shoulder parameters, no significant difference could be found in PTC or shoulder parameters between both groups at last follow-up (p > 0.05). Our study illustrates important observations that should be considered in defining the PTC for fusion consideration. Spontaneous correction of the PTC occurs in structural curves greater than 35 degrees and less than 45 degrees, and this correction is maintained over time. Despite that correction, radiographic shoulder parameters are expected to slightly increase. Nonfusion strategy may be appropriate for PTCs between 35 and 45 degrees. After fusion of both the MTC and the PTC, the radiographic shoulder parameters did not significantly differ. Preoperative radiographic shoulder parameters are not predictive of postoperative shoulder imbalance.

Project description:PurposeTo investigate whether the predisposition genes previously reported to be associated with the occurrence or curve severity of adolescent idiopathic scoliosis (AIS) play a role in the effectiveness of brace treatment.MethodA total of 312 AIS patients treated with bracing were enrolled in this study. The Cobb angle of the main curve was recorded at the beginning of brace treatment as well as at each follow-up. The patients were divided into two groups according to the outcome of brace treatment (success/failure). The failure of brace treatment was defined as a curve progression of more than 5° compared to the initial Cobb angle or surgical intervention because of curve progression. Single nucleotide polymorphism (SNP) sites in the genes for estrogen receptor α (ERα), estrogen receptor β (ERβ), tryptophan hydroxylase 1 (TPH-1), melatonin receptor 1B (MTNR1B) and matrillin-1 (MATN1), which were previously identified to be predisposition genes for AIS, were selected for genotyping by the PCR-RFLP method. Differences of genotype and allele distribution between the two groups were compared by the χ(2) test. A logistic regression analysis was used to figure out the independent predictors of the outcome of brace treatment.ResultsThere were 90 cases (28.8%) in the failure group and 222 cases (71.2%) in the success group. Patients in the failure group were associated with the genotype GA (50.9 vs. 17.9% p < 0.001) and the G allele (27.1 vs. 12.0%, p < 0.001) at SNP rs9340799 of the ERα gene. Similarly, they were also associated with the genotype AT (33.3 vs. 13.0%, p = 0.002) and the A allele (16.7 vs. 9.6%, p = 0.033) at SNP rs10488682 of the TPH-1 gene. For MTNR1B, the difference of genotype distribution between the two groups was found to be statistically significant, while the difference of allele distribution between the two groups was found to be marginally statistically significant; for the MATN1 and ERβ genes, we found no significant differences of the genotype or allele distribution between the two groups. In the logistic regression analysis, ERα and TPH-1 were demonstrated to be independent factors predictive of bracing effectiveness.ConclusionsERα and TPH-1 might be potential genetic markers that could predict the outcome of brace treatment. Patients with the G allele at the rs9340799 site of the ERα gene and the A allele at the rs10488682 site of the TPH-1 gene are prone to be resistant to brace treatment.

Dataset Information

Value of DNA methylation in predicting curve progression in patients with adolescent idiopathic scoliosis.

Publications

Value of DNA methylation in predicting curve progression in patients with adolescent idiopathic scoliosis.

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