Long QT Syndrome: Population, Genetic & Cardiac Studies

描述(申请人提供)：这项拟议的研究是一项多学科、多中心的合作研究，旨在继续研究长QT综合征(LQTS)的临床、心脏和遗传学方面的问题。LQTS是一种遗传性通道病，具有延迟的心室复极，并以晕厥和猝死表现为发作性危及生命的室性快速性心律失常。本研究项目将调查LQT1和LQT2这两种最常见的LQTS的表型和基因型危险因素以及生物物理电生理危险机制。这一为期五年的项目将：1)继续收集：a)在LQTS注册中心美国部分登记的经基因鉴定的LQT1和LQT2受试者一生中详细的年度临床数据，以及b)根据自由的ECG-QTC标准进行彻底基因分型的可能携带LQT1和LQT2突变的LQTS注册受试者的血液样本，以扩大已识别的LQT1和LQT2基因型受试者的数量；2)对LQT1和LQT2基因的已知和新突变进行全面的基因分型，以确定：a)注册中心中所有LQT1或LQT2突变患者；以及b)在10%-15%的LQTS患者中，这些基因可能存在两个或两个以上的离子通道突变；3)对已发现的LQT1和LQT2突变进行统一的哺乳动物表达研究，以确定突变对离子通道电流的生物物理电生理功能影响；以及4)使用基因型和表型协变量及生物物理电生理功能数据，对LQT1和LQT2突变的患者进行危及生命的心律失常事件的风险分层，以更好地确定这两种遗传性LQTS疾病的心律失常风险机制。在功能上，该项目有六个部分：一个用于多代LQT1和LQT2受试者随访的临床中心；一个用于细胞系准备/存储的遗传病理学实验室；一个用于基因研究的功能基因组学中心；一个用于细胞电生理研究的离子通道表达中心；一个涉及复杂的事件间隔时间分析的生物统计科；以及一个用于集中数据管理和计划协调的协调和数据中心。我们的中心假设是，突变在离子通道中的位置和突变的生物物理功能障碍效应是与LQT1和LQT2基因型患者的临床协变量和LQTS治疗无关的心律失常相关心脏事件的重要危险因素。这一综合的表型-基因研究计划对于更好地洞察致心律失常的风险机制具有重要的临床和基础科学意义。公共卫生相关性：识别编码离子通道功能障碍的突变LQTS基因与危及生命的室性快速性心律失常之间的关系，应能更全面地了解复极障碍涉及的遗传和电生理因素。这些对改变的心室复极的研究将有助于对与缺血性和非缺血性心肌病和延长QT的药物相关的获得性心脏疾病相关的心脏性猝死机制有重要的新见解。这一增强的知识应该导致更有效的战略，以预防广泛的遗传性和获得性心脏病的猝死，并对公共卫生产生有意义的好处。

DESCRIPTION (provided by applicant): The proposed research is a multidisciplinary, multicenter, collaborative study to continue the investigation of the clinical, cardiac, and genetic aspects of the Long QT Syndrome (LQTS) - a heritable channelopathy with delayed ventricular repolarization and episodic life-threatening ventricular tachyarrhythmias manifest by syncope and sudden death. This research project will investigate the phenotype and genotype risk factors and biophysical electrophysiologic risk mechanisms in LQT1 and LQT2 -- the two most common forms of LQTS. This five-year project will: 1) continue to collect: a) detailed annual clinical data throughout the life-span of genotype-identified LQT1 and LQT2 subjects enrolled in the U.S. portion of the LQTS Registry, and b) blood samples on LQTS Registry subjects who are possible carriers of LQT1 and LQT2 mutations by liberal ECG-QTc criteria for thorough genotyping in order to expand the number of identified subjects with LQT1 and LQT2 genotypes; 2) carry out comprehensive genotyping for known and novel mutations in the LQT1 and LQT2 genes to identify: a) all patients with LQT1 or LQT2 mutations in the Registry; and b) the presence of two or more ion-channel mutations that may occur in these genes in 10-15% of subjects with these two forms of LQTS; 3) perform uniform mammalian expression studies of identified LQT1 and LQT2 mutations to determine the biophysical electrophysiologic functional effects of the mutations on ion-channel currents; and 4) Risk stratify affected individuals with LQT1 and LQT2 mutations for life-threatening arrhythmic events using genotype and phenotype covariates and biophysical electrophysiologic functional data to better identify arrhythmic risk mechanisms in patients with these two inherited LQTS disorders. Functionally, the project has six sections: a Clinical Center for follow-up of the multigenerational LQT1 and LQT2 subjects; a Genetic Pathology Lab for cell-line preparation/storage; a Functional Genomics Center for genotype studies; an Ion-channel Expression center for cellular electrophysiological studies; a Biostatistical Section involved in sophisticated time-to-event analyses; and a Coordination and Data Center for centralized data management and program coordination. Our central hypothesis is that the location of the mutation in the ion-channel and the biophysical dysfunctional effects of the mutations are important risk factors in arrhythmic-related cardiac events independent of clinical covariates and LQTS therapies in patients with LQT1 and LQT2 genotypes. This integrated phenotype-genotype research program has important clinical and basic science implications for improved insight into arrhythmogenic risk mechanisms. PUBLIC HEALTH RELEVANCE: Identification of the relationship between mutant LQTS genes that encode for dysfunctional ion channels and life-threatening ventricular tachyarrhythmias should provide more complete knowledge into the genetic and electrophysiologic factors involved in repolarization disorders. These studies into altered ventricular repolarization should contribute important new insights into sudden cardiac death mechanisms associated with acquired cardiac disorders that accompany ischemic and nonischemic cardiomyopathy and QT-prolonging drugs. This enhanced knowledge should lead to more effective strategies for prevention of sudden death in a broad spectrum of genetic and acquired cardiac disorders with meaningful public health benefits.