Haruhisa Yanagida

A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis is a pediatric spinal deformity affecting 2–3% of school-age children worldwide. Genetic factors have been implicated in its etiology. Through a genome-wide association study (GWAS) and replication study involving a total of 1,376 Japanese females with adolescent idiopathic scoliosis and 11,297 female controls, we identified a locus at chromosome 10q24.31 associated with adolescent idiopathic scoliosis susceptibility. The most significant SNP (rs11190870; combined P = 1.24 × 10−19; odds ratio (OR) = 1.56) is located near LBX1 (encoding ladybird homeobox 1). The identification of this susceptibility locus provides new insights into the pathogenesis of adolescent idiopathic scoliosis.

Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls. To identify additional AIS-associated loci, we expanded the study by adding X-chromosome SNPs in the GWAS and increasing the size of the replication cohorts. Through a stepwise association study including 1,819 cases and 25,939 controls, we identified a new susceptibility locus on chromosome 6q24.1 in Japanese (P = 2.25 × 10−10; odds ratio (OR) = 1.28). The most significantly associated SNP, rs6570507, was in GPR126 (encoding G protein–coupled receptor 126). Its association was replicated in Han Chinese and European-ancestry populations (combined P = 1.27 × 10−14; OR = 1.27). GPR126 was highly expressed in cartilage, and the knockdown of gpr126 in zebrafish caused delayed ossification of the developing spine. Our results should provide insights into the etiology and pathogenesis of AIS.

Lack of association between adolescent idiopathic scoliosis and previously reported single nucleotide polymorphisms in MATN1, MTNR1B, TPH1, and IGF1 in a Japanese population.

Adolescent idiopathic scoliosis (AIS) is a spinal deformity most commonly arising in apparently healthy girls around puberty. AIS has a strong genetic predisposition. Several genetic associations between AIS and single nucleotide polymorphisms (SNPs) have been reported; common SNPs in the genes for matrilin 1 (MATN1), melatonin receptor 1B (MTNR1B), tryptophan hydroxylase 1 (TPH1), and insulin‐like growth factor 1 (IGF1) are reported to be associated with AIS in Chinese. However, these associations have not been replicated so far. To confirm the associations, we compared these SNPs with AIS predisposition and curve severity in a population of Japanese females consisting of 798 AIS patients and 1,239 controls. All the subjects were genotyped using the PCR‐based Invader assay. We found no association of any of the SNPs with AIS predisposition or curve severity. Considering the statistical power and sample size of the present study, we concluded that these SNPs are not associated with either AIS predisposition or curve severity in Japanese.

Replication study of the association between adolescent idiopathic scoliosis and two estrogen receptor genes.

Adolescent idiopathic scoliosis (AIS) is a common disorder with a strong genetic predisposition. Associations between AIS and common single nucleotide polymorphisms (SNPs) in estrogen receptor genes have been reported. rs9340799 in the gene for estrogen receptor α (ESR1) is reported to be associated with curve severity in Japanese and with AIS predisposition and curve severity in Chinese. In addition, rs1256120 in the gene for estrogen receptor β (ESR2) is reported to be associated with AIS predisposition and curve severity in Chinese. However, the sample sizes of these previous studies were small, and the associations of these SNPs have not been replicated. To examine the association between AIS and estrogen receptor genes, we investigated the association of rs9340799 and rs1256120 with AIS predisposition and curve severity using a large Japanese population, consisting of 798 AIS patients and 637 sex‐matched controls. We found no association of either SNP with AIS predisposition or curve severity in the Japanese population. Considering the statistical power of the present study and the limitations of the previous reports, we conclude that the associations of rs9340799 and rs1256120 with AIS predisposition and curve severity are negative.

Risk factors for complications associated with growing-rod surgery for early-onset scoliosis

Study Design. A retrospective multicenter study. Objective. To identify risk factors for postoperative complications associated with growing-rod (GR) surgery for early-onset scoliosis (EOS). Summary of Background Data. Results and complications of GR surgery for EOS have not been adequately studied. Methods. We evaluated clinical and radiographical results from 88 patients with EOS who underwent GR surgery in 12 spine centers in Japan. The mean age at the time of initial surgery was 6.5 ± 2.2 years (range, 1.5–9.8 yr) and the mean follow-up period was 3.9 ± 2.6 years (range, 2.0–12.0 yr). Risk factors for postoperative complications were analyzed using binomial multiple logistic regression analysis. We considered the potential factors of sex, age, number of rod-lengthening procedures, whether a pedicle screw foundation was used, the uppermost level of the proximal foundation and lowermost level of the distal foundation, Cobb angles of the proximal thoracic, main thoracic, and lumbar curves, and the kyphosis angles in the proximal, main thoracic, thoracolumbar, and lumbar spine. Kaplan-Meier analysis was used to determine the complication-free survival rate of GR surgery as a function of the number of surgical procedures. Results. Complications affected 50 of the patients (57%) and were associated with 119 of 538 surgical procedures, with 86 implant-related failures (72%), 19 infections (16%), 3 neurological impairments (3%), and 11 other complications. The most frequent implant-related failure was dislodged implant (71%) and 95% of the dislodgements occurred at the proximal foundation. Kaplan-Meier analysis demonstrated a linear decrease in complication-free rates as the number of rod-lengthening procedures increased. Binomial multiple logistic regression analysis found the following significant independent risk factors: 6 or more rod-lengthening procedures (odds ratio [OR], 6.534), an increase of every 20° in the proximal thoracic Cobb angle (OR, 3.091), and an increase of every 25° in the lumbar lordosis angle (OR, 2.607) in the preoperative condition. Conclusion. Increases in the upper thoracic scoliotic curve, thoracic kyphosis, and number of rod-lengthening procedures are positively associated with an increased risk of complications after GR surgery for EOS. Level of Evidence: 4

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10(-13); odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.

Pemberton osteotomy for developmental dysplasia of the hip in older children.

The authors reviewed the results of the Pemberton osteotomy as treatment of developmental dysplasia of the hip in 17 hips treated after 7 years of age. Twelve hips required one or more concomitant surgical procedures. The average age at the time of the osteotomy was 9.3 years, and the average follow-up was 9.4 years. Using modified McKays clinical criteria, 14 hips were classified as excellent or good. Using Severins radiographic classification, 13 hips met class I-II criteria. Two patients who preoperatively showed Kalamchi and MacEwens group IV severe avascular necrosis, plus two patients whose necessary acetabular coverage was not achieved by the Pemberton osteotomy without femoral varus osteotomy, were found to meet Severins class III-IV criteria. Pemberton osteotomy can be an effective procedure for older children in whom progressive acetabular development is not expected, although this osteotomy may have to be combined with other operative procedures.

Postoperative distal adding-on and related factors in Lenke type 1A curve.

Study Design. A retrospective, multicenter study. Objective. To investigate the occurrence of and factors related to postoperative adding-on in Lenke type 1A curve. Summary of Background Data. Although several studies have investigated factors associated with adding-on in Lenke type 1A curve, these factors have not been elucidated in a large study population. Methods. This study included 112 patients who were followed more than 2 years after undergoing selective posterior thoracic fusion surgery for Lenke Type 1A curve (8 males, 104 females; mean age at surgery, 16.1 yr; mean follow-up, 3.6 yr). The lower instrumented vertebra (LIV) was T12 in 22 patients, L1 in 55, L2 in 32, and L3 in 3. Distal to the main thoracic curve, the end vertebra, neutral vertebra, stable vertebra (SV), and the last vertebra touching the central sacral vertical line (last touching vertebra, LTV) were determined. The occurrence and factors associated with distal adding-on were investigated. Results. The mean Cobb angle and apical translation of the main thoracic curve were 54.6° ± 9.6° and 53.1 ± 20.4 mm before surgery, and 14.2 ± 7.4 and 16.2 ± 12.7 at follow-up, respectively. Distal adding-on was observed in 21 patients (18.8%) at follow-up. Univariate analyses identified several factors significantly associated with adding-on, including the preoperative proximal thoracic curve, the apical translation of the main thoracic curve, Miyanjis subclassification, the postsurgical proximal and main thoracic curves, the postsurgical apical translation of the main thoracic curve, the correction rate of the main thoracic curve and the clavicle angle immediately after surgery and at follow-up, and the difference in levels between the LIV and the end vertebra, neutral vertebra, LTV, and stable vertebra. Logistic regression analysis showed that the apical translation of the main thoracic curve immediately after surgery (apical translation >25 mm, odds ratio: 10.7, 95% confidence interval: 3.1–37.0, P = 0.001) and the difference in levels between LIV and LTV (LIV-LTV) (LIV-LTV <0, odds ratio: 6.7, 95% confidence interval: 1.9–23.9, P = 0.003) were significantly associated with adding-on. Conclusion. Since the residual apical translation of the main thoracic curve and the lowest instrumented vertebra more cranial to the last touching vertebra were significantly associated with adding-on, surgeons may need to obtain the maximum reduction of the apical translation of the main thoracic curve and to extend the LIV at least to the LTV to avoid postoperative adding-on. Level of Evidence: N/A

Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3.

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, affecting around 2% of adolescents worldwide. Genetic factors play an important role in its etiology. Using a genome-wide association study (GWAS), we recently identified novel AIS susceptibility loci on chromosomes 10q24.31 and 6q24.1. To identify more AIS susceptibility loci relating to its severity and progression, we performed GWAS by limiting the case subjects to those with severe AIS. Through a two-stage association study using a total of ∼12,000 Japanese subjects, we identified a common variant, rs12946942 that showed a significant association with severe AIS in the recessive model (P = 4.00×10−8, odds ratio [OR] = 2.05). Its association was replicated in a Chinese population (combined P = 6.43×10−12, OR = 2.21). rs12946942 is on chromosome 17q24.3 near the genes SOX9 and KCNJ2, which when mutated cause scoliosis phenotypes. Our findings will offer new insight into the etiology and progression of AIS.

Metatarsal lengthening by callus distraction for brachymetatarsia.

Twelve metatarsal lengthening procedures by callus distraction were performed in seven patients with brachymetatarsia. The mean age at the time of the surgery was 12.0 years (range, 11.1–14.5 years). The mean duration of follow-up was 5.2 years (range, 1.2–13.5 years). The bones were lengthened at a rate of 0.7 mm/day by a mean of 20 mm (range, 15–30 mm), which was 45% of their original length (range, 37–61%). The mean healing index was 73 days/cm (range, 41–98 days/cm). Corrective shortening osteotomy was performed in one case in which the metatarsophalangeal joint was dislocated due to excessive lengthening. In 10 of the remaining 11 cases, joint stiffness, narrowing of the joint space and some degree of plantar subluxation of the metatarsophalangeal joint were observed during distraction, but these were gradually resolved without either elongation of the tendon or metatarsophalangeal joint fixation with Kirschner wire.