RESUMEN
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.
Asunto(s)
Cromosomas Humanos Par 9/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Escoliosis/genética , Adolescente , Animales , China , Proteínas de Unión al ADN/metabolismo , Embrión no Mamífero/metabolismo , Embrión no Mamífero/patología , Estudio de Asociación del Genoma Completo , Humanos , Japón , Luciferasas , Oportunidad Relativa , Escoliosis/patología , Factor de Transcripción YY1/metabolismo , Pez CebraRESUMEN
STUDY DESIGN: Posterolateral lumbar fusions were performed in nicotine-exposed, New Zealand white rabbits. Animals that developed a pseudarthrosis were then regrafted with no graft, autograft, or osteogenic protein-1 (OP-1). OBJECTIVES: To establish a model of pseudarthrosis repair and to evaluate the ability of OP-1 to induce fusion in this model. SUMMARY OF BACKGROUND DATA: OP-1 has been shown to have a 100% fusion rate in an established rabbit fusion model, even in the presence of nicotine, which is known to inhibit fusion. METHODS: Forty-four New Zealand white rabbits underwent posterolateral lumbar fusion with iliac crest autograft. To maximize the incidence of pseudarthroses, nicotine was administered to all rabbits. At 5 weeks, the spines were explored, and all pseudarthroses were redecorticated and grafted with no graft, autograft, or OP-1. At 10 weeks, the rabbits were killed and fusions masses were assessed with manual palpation, radiography, computed tomography, and/or histology. RESULTS: Nine rabbits (20%) were lost to complications. Thirty-four (94%) had pseudarthroses on exploration at 5 weeks. By manual palpation at 10 weeks, 1 of 10 (10%) pseudarthroses that received no graft fused, 5 of 12 (42%) pseudarthroses that received autograft fused, and 9 of 11 (82%) pseudarthroses that received OP-1 fused. Computed tomography and histology further characterized the fusion masses. CONCLUSIONS: This study establishes a model for treatment of pseudarthroses. OP-1, which has previously been shown to have 100% fusion rate in animal models, outperformed autograft and induced fusion in 82% of rabbits.