Long QT Syndrome: Population, Genetic & Cardiac Studies

描述（由申请人提供）：拟议的研究是一项多学科、多中心、合作研究，旨在继续调查长QT综合征（LQTS）的临床、心脏和遗传方面的问题。LQTS是一种遗传性通道病，伴延迟心室复极和发作性危及生命的室性心动过速，表现为晕厥和猝死。本研究项目将研究LQT1和LQT2这两种最常见的LQTS的表型和基因型风险因素以及生物物理电生理风险机制。这个为期五年的项目将：1)继续收集：a)在LQTS Registry美国部分登记的基因型确定的LQT1和LQT2受试者的整个生命周期的详细年度临床数据，b)根据自由ECG-QTc标准对LQT1和LQT2突变可能携带者的LQTS Registry受试者的血液样本进行彻底的基因分型，以扩大确定的LQT1和LQT2基因型受试者的数量；2)对已知和新的LQT1和LQT2基因突变进行综合基因分型，确定：a)注册表中所有LQT1或LQT2突变患者；b)在10-15%患有这两种LQTS的受试者中，这些基因中可能存在两个或多个离子通道突变；3)对鉴定的LQT1和LQT2突变进行均匀的哺乳动物表达研究，确定突变对离子通道电流的生物物理电生理功能影响；4)利用基因型和表型协变量以及生物物理电生理功能数据对LQT1和LQT2突变个体进行危及生命的心律失常事件风险分层，以更好地识别这两种遗传性LQTS疾病患者的心律失常风险机制。从功能上讲，该项目有六个部分：临床中心对多代LQT1和LQT2受试者进行随访；用于细胞系制备/储存的遗传病理学实验室；用于基因型研究的功能基因组学中心；用于细胞电生理研究的离子通道表达中心；生物统计科参与复杂的事件时间分析；以及用于集中数据管理和项目协调的协调和数据中心。我们的中心假设是，在LQT1和LQT2基因型患者中，离子通道突变的位置和突变的生物物理功能障碍效应是与临床协变量和LQTS治疗无关的心律失常相关心脏事件的重要危险因素。这一综合表型-基因型研究项目对提高对心律失常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：识别编码功能失调离子通道的突变LQTS基因与危及生命的室性心动过速之间的关系，应该为复极障碍中涉及的遗传和电生理因素提供更完整的知识。这些关于心室复极改变的研究将有助于对伴有缺血性和非缺血性心肌病的获得性心脏疾病以及qt延长药物相关的心源性猝死机制提供重要的新见解。这种知识的增强将导致更有效的策略，以预防广泛的遗传性和获得性心脏疾病中的猝死，并具有重大的公共卫生效益。

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.