Genetic bases of exercise induced rhabdomyolysis

运动诱发横纹肌溶解症的遗传基础

• 批准号: 9327541
• 负责人: Samantha K Beeson
• 金额: $ 4.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-05 至 2021-06-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327541
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Alleles; Animal Model; Automobile Driving; Biochemical; Biochemistry; Biological Assay; Blood Circulation; Ca(2+)-Transporting ATPase; Candidate Disease Gene; Clinical; Code; Cohort Studies; Computing Methodologies; Contracture; Custom; Defect; Diagnosis; Diet; Dihydropyridine Receptors; Domestic Animals; Electrolytes; Equus caballus; Etiology; Exercise; Exertion; Extravasation; Frequencies; Functional disorder; Future; Gender; Gene Frequency; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genotype; Goals; Health; Heritability; Human; In Vitro; Inborn Genetic Diseases; Individual; Investigation; Ion Channel; Knowledge; Lead; Malignant hyperpyrexia due to anesthesia; Membrane; Military Personnel; Modeling; Muscle; Muscle Cells; Muscular Atrophy; Mutation; Myoglobinuria; Myopathy; Necrosis; Pain; Patients; Performance; Physiological; Polygenic Traits; Population; Predisposition; Prevention; Prevention strategy; Proteins; Recruitment Activity; Recurrence; Regulation; Rhabdomyolysis; Risk; Risk Factors; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Skeletal Muscle; Strenuous Exercise; Structure; Suggestion; Temperament; Testing; Translating; Untranslated RNA; Validation; Variant; Work; activity marker; base; candidate identification; case control; cell injury; clinical phenotype; cohort; enzyme deficiency; follow-up; gene function; genetic variant; genome wide association study; insight; muscle metabolism; next generation sequencing; novel; pediatric patients; protein function; receptor binding; response; risk variant; study population; targeted treatment; treatment strategy; ward; whole genome

PROJECT SUMMARY Exertional rhabdomyolysis (ER) is a painful condition characterized by rapid-onset muscle cell necrosis and subsequent leakage of intracellular contents into the systemic circulation in response to exercise. Genetic fac- tors are especially important in pediatric patients, military recruits, and athletes with recurrent episodes of rhabdomyolysis; however, approximately half of these cases fail to receive a definitive diagnosis, leading to a lack of targeted therapy. A deeper understanding of the possible etiologies of recurrent ER (RER) will provide useful insight into its pathophysiology, which could eventually translate to the refinement of treatment and pre- vention strategies. The domestic horse is uniquely suited to serving as a naturally occurring model for exer- tional muscle disease. RER has a major impact on health in Thoroughbred (TB) and Standardbred (STB) horses, with many of the same clinical signs and risk factors as in human patients. There is strong evidence for a genetic component conferring RER susceptibility in both breeds; however, the specific genetic variants con- tributing to this susceptibility are currently unknown. Results from in vitro contracture tests are suggestive of a defect in muscle contractility in RER-susceptible horses that is physiologically and biochemically distinct from known forms of malignant hyperthermia. Therefore, the hypothesis driving this project is that RER in TB and STB horses is caused by functional genetic variants affecting the regulation of skeletal muscle contractility. Preliminary genome-wide association studies (GWAS) have identified seven chromosomal loci significantly associated with RER. The goal of this project is to expand on these preliminary analyses and identify the ge- netic variants underlying RER skeletal muscle dysfunction through the following specific aims: 1, Identification of candidate genes for RER susceptibility; and 2, Identification of putative causal variants for RER. In aim 1 candidate genes for RER susceptibility will be determined via GWAS and prioritized using computational methods that capitalize on knowledge of rhabdomyolysis pathophysiology for humans and other species. In aim 2, analysis of whole genome sequence will be employed to identify potentially functional alleles within these candidate genes that occur at higher frequency in RER cases than controls. High-priority variants will be used to create a custom genotyping assay to genotype our entire GWAS cohort as well as independent valida- tion cohorts to identify the true functional variants. The proposed work is expected to identify genes of moder- ate to major effect contributing to RER susceptibility and will pave the way for future studies focused on as- sessment of the physiologic function of causative variants. Results from this project are expected to advance overall understanding of altered muscle contractility and RER pathophysiology and therefore lead to the even- tual improvement of prevention and treatment regimes.

项目摘要 间歇性横纹肌溶解症（ER）是一种疼痛性疾病，其特征是快速发作的肌细胞坏死， 随后响应于运动，细胞内内容物渗漏到体循环中。遗传因素 对于反复发作的儿科患者、新兵和运动员， 横纹肌溶解症;然而，这些病例中约有一半未能得到明确的诊断， 缺乏针对性治疗。对复发性ER（RER）可能病因的深入了解将提供 有益的洞察其病理生理学，这最终可以转化为治疗和预处理的完善， 预防战略。国内马是唯一适合作为一个自然发生的模型exer- 肌肉疾病。RER对纯种马（TB）和标准马（STB）的健康有重大影响 马，具有许多与人类患者相同的临床体征和风险因素。有强有力的证据表明， 遗传成分赋予RER易感性在两个品种;然而，特定的遗传变异， 导致这种易感性的原因目前尚不清楚。体外挛缩试验的结果表明， RE易感马的肌肉收缩性缺陷，在生理和生化上不同于 已知的恶性高热因此，推动这一项目的假设是，结核病和 STB马是由影响骨骼肌收缩力调节的功能性遗传变异引起的。 初步的全基因组关联研究（GWAS）已经确定了七个染色体位点显着 与RER有关。本项目的目标是在这些初步分析的基础上进行扩展，并确定通用的 通过以下特定目的研究RER骨骼肌功能障碍的遗传变异：1、鉴定 RER易感性的候选基因;和2，鉴定RER的假定的因果变异。在aim 1中 RER易感性的候选基因将通过GWAS确定，并使用计算优先级， 利用人类和其他物种横纹肌溶解症病理生理学知识的方法。在 目的2，全基因组序列分析将用于鉴定 这些候选基因在RER病例中出现的频率高于对照组。高优先级变体将是 用于创建定制的基因分型检测，以对我们整个GWAS队列进行基因分型， 以识别真正的功能变体。这项工作有望确定现代人的基因， 的主要影响，有助于RER的敏感性，并将铺平道路，为未来的研究重点是作为- 致病变异体生理功能的评估。预计该项目的成果将进一步提高 全面了解肌肉收缩力和粗面内质网病理生理学的改变，从而导致均匀的 切实改进预防和治疗制度。