Genetic Risk Factors for Severe Scoliosis

严重脊柱侧弯的遗传风险因素

• 批准号: 9279048
• 负责人: Matthew Barrett Dobbs
• 金额: $ 45.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-20 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9279048
• 关键词: Adolescent; Age of Onset; Algorithms; Biochemical; Bioinformatics; Biological Assay; Candidate Disease Gene; Caucasians; Child; Childhood; Chinese People; Clinical; Collagen; Collagen Gene; Complement; DNA; Data; Deformity; Development; Disease; Effectiveness; Engineering; European; Evaluation; FBN1; Family; Gender; Generations; Genes; Genetic; Goals; Idiopathic scoliosis; In Vitro; Knowledge; Methods; Modeling; Multicenter Studies; Muscle; Musculoskeletal; Operative Surgical Procedures; Pathogenesis; Pathology; Pathway interactions; Patients; Population; Predictive Factor; Prevention strategy; Recording of previous events; Recruitment Activity; Risk; Risk Factors; Role; Sample Size; Sampling; Severities; Site; Spinal; Spinal Fusion; Techniques; Testing; Tissues; Transforming Growth Factor beta; Validation; Variant; Zebrafish; base; biobank; cost; exome; exome sequencing; fibrillin-2; follow-up; genetic risk factor; genetic variant; genome-wide; high risk; individualized prevention; mutant; novel; operation; prediction algorithm; prevent; public health relevance; rare variant; scoliosis; screening; sex; treatment strategy; validation studies

 DESCRIPTION (provided by applicant): Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity. To develop personalized prevention strategies for those at high risk and to eliminate screening and treatment of those at low risk of progression, accurate methods of predicting curve progression are needed. Unfortunately, currently available algorithms of curve progression for AIS are inaccurate, possibly because the role of rare genetic factors has been largely unexplored. By focusing on extreme cases with severe scoliosis (curve >40°), we recently completed a genome-wide rare variant burden analysis of exome sequence data of 91 cases and validated a significant enrichment of rare variants in FBN1 (fibrillin-1) and FBN2 (fibrillin-2) in AIS cases compared to controls. Furthermore, evidence of TGF-ß pathway activation was seen in paraspinous muscle of AIS patients with rare FBN1 variants, suggesting the possibility of novel treatments for AIS. However, additional studies are needed to identify the full complement of genetic risk factors for severe scoliosis, and to confirm a role for the TGF-ß pathway in its pathogenesis. The goal of this project is to identify genetic risk factors for sever AIS. Here, we propose a multicenter genome-wide rare variant association study of AIS, focusing on extreme cases of severe scoliosis that are likely enriched for genetic factors of large effect. This study utilizes DNA samples collected from five Bracing in Adolescent Idiopathic Scoliosis Trial (BrAIST) sites, and three new sites. A genome-wide rare variant association study will be performed on exome sequence data from 1000 severe AIS cases, followed by validation of the most highly associated variants/genes in AIS cases of both European and Han Chinese ancestry. Functional studies of AIS-associated rare variants will be evaluated using patient biobanked tissue, in vitro assessment of TGF-ß pathway activation, and generation of zebrafish mutants. Knowledge of the genetic risk factors for severe scoliosis is essential for accurate prediction of curve progression and development of new treatment strategies.

 描述（由申请人提供）：青少年特发性脊柱侧凸（AIS）是最常见的小儿脊柱畸形。为了为高风险患者制定个性化的预防策略，并消除对低进展风险患者的筛查和治疗，需要预测曲线进展的准确方法。不幸的是，目前可用的AIS曲线进展算法是不准确的，可能是因为罕见的遗传因素的作用在很大程度上尚未探索。通过关注严重脊柱侧凸（弯曲>40°）的极端病例，我们最近完成了对91例病例外显子组序列数据的全基因组罕见变异负荷分析，并验证了与对照组相比，AIS病例中FBN 1（BN 1 -1）和FBN 2（BN 2 -2）中罕见变异的显著富集。此外，在具有罕见FBN 1变体的AIS患者的棘旁肌中观察到TGF-β通路活化的证据，表明AIS的新治疗的可能性。然而，需要更多的研究来确定 严重脊柱侧凸的遗传危险因素的完整补充，并确认TGF-β通路在其发病机制中的作用。本项目的目标是确定严重AIS的遗传危险因素。在这里，我们提出了一个多中心的AIS全基因组罕见变异关联研究，重点是严重脊柱侧凸的极端病例，这些病例可能富含大的遗传因素， 效果这项研究利用了从五个青少年特发性脊柱侧凸试验（BrAIST）站点和三个新站点收集的DNA样本。将对来自1000例严重AIS病例的外显子组序列数据进行全基因组罕见变异关联研究，然后验证欧洲和中国汉族血统AIS病例中最高度相关的变异/基因。AIS相关罕见变体的功能研究将使用患者生物库组织、TGF-β途径激活的体外评估以及斑马鱼突变体的产生来评估。了解严重脊柱侧凸的遗传危险因素对于准确预测脊柱侧弯的进展和开发新的治疗策略是必不可少的。