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.

项目概要 劳力性横纹肌溶解症 (ER) 是一种疼痛性疾病，其特征是快速发作的肌细胞坏死和 随后，由于运动，细胞内内容物渗漏到体循环中。遗传因素 对于患有反复发作的儿科患者、新兵和运动员来说，这些变化尤其重要 横纹肌溶解症;然而，大约一半的病例未能得到明确的诊断，导致 缺乏针对性治疗。更深入地了解复发性 ER (RER) 的可能病因将有助于 对其病理生理学的有用见解，最终可以转化为治疗和预治疗的改进。 发明策略。家养的马特别适合作为自然发生的运动模型。 肌肉疾病。 RER 对纯种马 (TB) 和标准马 (STB) 的健康产生重大影响 马具有许多与人类患者相同的临床症状和危险因素。有强有力的证据表明 赋予两个品种 RER 易感性的遗传成分；然而，特定的遗传变异 目前尚不清楚导致这种易感性的原因。体外挛缩试验的结果表明 RER 易感马的肌肉收缩力缺陷在生理和生化上与 已知形式的恶性高热。因此，推动该项目的假设是 TB 和 RER 马匹 STB 是由影响骨骼肌收缩性调节的功能性遗传变异引起的。 初步全基因组关联研究（GWAS）已鉴定出七个显着的染色体位点 与 RER 相关。该项目的目标是扩展这些初步分析并确定 通过以下具体目标，识别 RER 骨骼肌功能障碍背后的网络变异：1、识别 RER 易感性候选基因； 2、识别 RER 的假定因果变异。目标1 RER 易感性的候选基因将通过 GWAS 确定，并使用计算进行优先排序 利用人类和其他物种横纹肌溶解病理生理学知识的方法。在 目标 2，将利用全基因组序列分析来识别潜在的功能等位基因 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 用于创建定制基因分型测定，对我们整个 GWAS 队列进行基因分型以及独立验证 化队列来识别真正的功能变异。拟议的工作预计将鉴定现代基因 吃了对 RER 易感性产生重大影响，并将为未来的研究铺平道路 致病变异生理功能的评估。该项目的成果预计将取得进展 对改变的肌肉收缩力和 RER 病理生理学的全面了解，从而导致均匀- 防治体系不断完善。