Long QT Syndrome: Population, Genetic & Cardiac Studies

描述（由申请方提供）：拟定的研究是一项多学科、多中心、协作研究，旨在继续研究长QT综合征（LQTS）的临床、心脏和遗传方面-一种遗传性通道病，伴有心室复极延迟和发作性危及生命的室性快速性心律失常，表现为晕厥和猝死。本研究计划将探讨LQT 1和LQT 2--两种最常见的LQTS形式--的表型和基因型风险因素以及生物物理电生理风险机制。这一为期五年的项目将：1）继续收集：a）入组LQTS登记研究美国部分的基因型鉴定的LQT 1和LQT 2受试者的整个生命周期的详细年度临床数据，和B）LQT登记研究受试者的血液样本，这些受试者是通过自由ECG-QTc标准进行彻底基因分型的LQT 1和LQT 2突变的可能携带者，以扩大具有LQT 1和LQT 2基因型的鉴定受试者的数量; 2）对LQT 1和LQT 2基因中的已知和新突变进行全面的基因分型，以鉴定：a）登记研究中具有LQT 1或LQT 2突变的所有患者;和B）在10-15%的具有这两种形式的LQTS的受试者中存在可能发生在这些基因中的两种或更多种离子通道突变; 3）对鉴定的LQT 1和LQT 2突变进行一致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效应;和4）对具有LQT 1和LQT 2突变的受影响个体进行终身风险分层-使用基因型和表型协变量以及生物物理电生理功能数据更好地识别脑卒中风险的威胁性脑卒中事件这两种遗传性LQTS疾病的患者的机制。在功能上，该项目有六个部分：一个临床中心，用于多代LQT 1和LQT 2受试者的随访;一个遗传病理学实验室，用于细胞系制备/储存;一个功能基因组学中心，用于基因型研究;一个离子通道表达中心，用于细胞电生理研究;一个生物统计学部分，参与复杂的时间-事件分析;以及协调和数据中心，用于集中数据管理和程序协调。我们的中心假设是，在离子通道中的突变的位置和突变的生物物理功能障碍的影响是重要的危险因素，在与临床协变量和LQT 1和LQT 2基因型患者的LQTS治疗无关的糖尿病相关的心脏事件。这一综合表型-基因型研究计划对提高对致瘤风险机制的认识具有重要的临床和基础科学意义。 公共卫生相关性：鉴定突变LQTS基因编码功能障碍的离子通道和危及生命的室性快速性心律失常之间的关系，应提供更完整的知识，涉及复极障碍的遗传和电生理因素。这些心室复极改变的研究，应有助于重要的新的见解与获得性心脏疾病，伴随缺血性和非缺血性心肌病和QT延长药物的心脏猝死机制。这一知识的提高应导致更有效的战略，以预防猝死在广泛的遗传性和获得性心脏疾病与有意义的公共卫生利益。

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.