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 劳累性横纹肌溶解（ER）是一种痛苦的疾病，其特征是快速发作的肌肉细胞坏死和 随后细胞内含量响应运动中的全身循环中泄漏。遗传FAC- TOR在儿科患者，军事新兵和经常发作的运动员中尤为重要 横纹肌溶解；但是，大约一半 缺乏靶向疗法。对反复ER（RER）可能的病因的更深入了解将提供 对其病理生理学的有用洞察力，最终可以转化为治疗和预先的细化 文化策略。这匹马非常适合作为自然发生的模型 肌肉疾病。 RER对纯种（TB）和标准犬（STB）的健康有重大影响 马，与人类患者相同的临床体征和危险因素。有强有力的证据 一种遗传成分，赋予两个品种的敏感性；但是，特定的遗传变异 目前尚不清楚向这种敏感性提供支持。体外鉴定测试的结果表明 在生理和生物化学上与肌肉收缩性缺陷 已知形式的恶性高温。因此，推动该项目的假设是结核病和 STB马是由影响骨骼肌肉收缩力调节的功能遗传变异引起的。 初步基因组关联研究（GWAS）已显着鉴定出七个染色体基因座 与RER相关。该项目的目的是扩展这些初步分析，并确定GE- 通过以下特定目的：1，识别，骨骼肌功能障碍的基础网络变体骨骼肌肉功能障碍 候选基因的敏感性；和2，鉴定RER推定的因果变体。在目标1中 RER敏感性的候选基因将通过GWAS确定，并使用计算优先级 利用对人类和其他物种的横纹肌溶解病理生理学知识的方法。在 AIM 2，将采用对整个基因组序列的分析来识别内部的潜在功能等位基因 这些候选基因在RER病例中以比对照更高的频率发生。高优先级变体将是 用于创建自定义基因分型测定法以基因型我们的整个GWAS队列以及独立的验证 识别真实功能变体的tion队列。预计该提议的工作将确定适中的基因 尽可能促进易感性的重大影响，并将为未来的研究铺平道路 病因变体生理功能的疗程。该项目的结果有望进步 对改变肌肉收缩性和病理生理学的总体理解，因此导致偶数 预防和治疗方案的提高。