Determining the Role of the Potassium Channel, KCNN3, in Atrial Fibrillation

确定钾通道 KCNN3 在心房颤动中的作用

• 批准号: 7949382
• 负责人: Patrick Thomas Ellinor
• 金额: $ 50.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7949382
• 关键词: 1q21; 4q25; Action Potentials; Affect; Aging; American; Animal Model; Arrhythmia; Atrial Fibrillation; Biological Models; Calcium-Activated Potassium Channel; Candidate Disease Gene; Cardiac; Cardiovascular Diseases; Cell Line; Cessation of life; Chromosomes; Chromosomes, Human, Pair 16; Clinic; Communities; Complex; Data; Dementia; Development; Disease; Elderly; Electrophysiology (science); Epidemiology; Europe; Family; Framingham Heart Study; Functional RNA; Gap Junctions; Genes; Genetic; Genetic Variation; Genomics; Genotype; German population; Heart; Heart Atrium; Heart Diseases; Heart failure; Human; In Vitro; Individual; Ion Channel; Lead; Left; Maps; Meta-Analysis; Molecular; Mus; Mutation; Neurons; Odds Ratio; Other Genetics; Pathogenesis; Phenotype; Population; Potassium Channel; Predisposition; Proteins; Public Health; RNA; Recording of previous events; Regulatory Element; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Signaling Molecule; Single Nucleotide Polymorphism; Sodium Channel; Stroke; Tissues; United States; Variant; Work; base; cardiovascular disorder risk; cohort; genetic variant; genome wide association study; heart rhythm; human disease; insight; male; member; mortality; mouse model; multidisciplinary; nodal myocyte; novel; offspring; polyglutamine; prevent; public health relevance; sex; transcription factor; translational approach; voltage

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common arrhythmia and affects over 2 million Americans. AF is a major public health burden as it is associated with a five-fold increased stroke risk, a tripling in heart failure risk and nearly two-fold increase in mortality. There is increasing evidence of a genetic component to AF, and mutations for AF have been described in ion channels and signaling molecules, but such mutations are rare. Genome-wide association studies (GWAS) have uncovered many common variants underlying risk for a wide range of diseases. In 2007, a GWAS for AF in Icelanders identified a susceptibility region for AF on chromosome (chr) 4q25, findings that were replicated in our population with lone AF.1 While the chr 4q25 locus is in important development in our understanding of AF, these findings were based on an initial GWAS of only 550 individuals with AF. Since there are likely many other genetic variants for AF, Drs. Ellinor, Benjamin and Heckbert organized the CHARGE-AF consortium consisting of investigators from 12 studies with over 8,000 subjects with AF and 86,000 subjects without AF. Subjects with lone AF and no evidence of structural heart disease have a particularly high familial aggregation of AF. In preliminary work, we performed a GWAS of lone AF using cases from five studies; a total of 1,335 cases with lone AF and 12,844 referent subjects were available. At chr 4q25, 77 single nucleotide polymorphisms (SNPs) had P<5x10-8. A second, novel locus was identified on chr 1q21; the most significant SNP, rs13376333, is intronic to the potassium channel KCNN3. In a meta-analysis of the primary and replication cohorts, rs13376333 had an odds ratio of 1.52 (P=1.8x10-21). KCNN3 is a member of a family of voltage-independent calcium-activated potassium channels expressed in a number of excitable tissues including the brain40 and the heart;41, 42 however, the role of these channels in the heart is less clear. We propose to extend our work through the following specific aims: Aim 1 - Determine if genetic variation in KCNN3 is associated with AF risk by fine mapping the KCNN3 locus, correlating left atrial RNA levels with KCNN3 genotypes, and determining if a polyglutamine repeat in KCNN3 is associated with AF. Aim 2 - Identify and characterize mutations and rare variants in KCNN3 in subjects with AF. Aim 3 - Identify conserved, non-coding regulatory elements associated with KCNN3 function. Aim 4 - Characterize the cardiac phenotypes of two mouse lines with alterations in KCNN3 function. We believe that our multidisciplinary translational approach integrating available GWAS, cellular electrophysiology, and animal model systems, is uniquely suited to pursue this project. Understanding the molecular determinants of AF will provide insights into the pathogenesis of AF, and eventually provide targets for new therapies to prevent and treat this morbid arrhythmia. PUBLIC HEALTH RELEVANCE: Atrial fibrillation is the most common irregular heart rhythm and leads to an increased risk of stroke, heart failure, dementia, and death. In a genetic study, investigators have recently identified a gene, KCNN3, associated with an increased risk of atrial fibrillation. We propose to examine the role of KCNN3 in atrial fibrillation using a combination of human studies from the United States and Europe, cell lines, and mouse models with alterations in KCNN3 function.

描述（由申请人提供）： 心房颤动（AF）是最常见的心律失常，影响超过200万美国人。AF是一个主要的公共卫生负担，因为它与中风风险增加五倍，心力衰竭风险增加三倍和死亡率增加近两倍有关。有越来越多的证据表明，房颤的遗传成分，和突变的房颤已被描述在离子通道和信号分子，但这样的突变是罕见的。 全基因组关联研究（GWAS）已经发现了许多常见的变异，这些变异是多种疾病的潜在风险。2007年，冰岛人房颤的GWAS在染色体（chr）4 q25上确定了房颤的易感区域，这一发现在我们的孤立性房颤人群中得到了复制。1虽然chr 4 q25基因座在我们对房颤的理解中处于重要发展阶段，但这些发现是基于仅550名房颤患者的初始GWAS。由于房颤可能存在许多其他遗传变异，Ellinor、Benjamin和Heckbert博士组织了CHARGE-AF联盟，由来自12项研究的研究人员组成，这些研究涉及8,000多名AF受试者和86,000名非AF受试者。孤立性AF受试者和无结构性心脏病证据的受试者具有特别高的AF家族聚集性。在初步工作中，我们使用来自5项研究的病例进行了孤立性AF的GWAS;共有1,335例孤立性房颤病例和12,844例参考受试者可用。在chr 4 q25，77个单核苷酸多态性（SNPs）具有P<5x 10 -8。在chr 1 q21上发现了第二个新的基因座;最重要的SNP rs 13376333是钾通道KCNN 3的内含子。在主要和重复队列的荟萃分析中，rs 13376333的比值比为1.52（P=1.8x10-21）。KCNN 3是一个家族的电压非依赖性钙激活钾通道表达在一些可兴奋的组织，包括大脑40和心脏;41，42然而，这些通道在心脏中的作用不太清楚。我们建议通过以下具体目标扩大我们的工作：目的1 -通过精细定位KCNN 3基因座，将左心房RNA水平与KCNN 3基因型相关联，以及确定KCNN 3中的多聚谷氨酰胺重复序列是否与AF相关。目的2 -鉴定和表征患有AF的受试者中KCNN 3中的突变和罕见变体。目的3 -鉴定与KCNN 3功能相关的保守的非编码调控元件。目的4 -表征KCNN 3功能改变的两个小鼠系的心脏表型。 我们相信，我们的多学科翻译方法整合了现有的GWAS，细胞电生理学和动物模型系统，是唯一适合追求这个项目。了解房颤的分子决定因素将有助于深入了解房颤的发病机制，并最终为预防和治疗这种病态心律失常的新疗法提供靶点。 公共卫生关系： 房颤是最常见的心律不齐，导致中风、心力衰竭、痴呆和死亡的风险增加。在一项遗传学研究中，研究人员最近发现了一种与房颤风险增加相关的基因KCNN 3。我们建议使用来自美国和欧洲的人类研究，细胞系和KCNN 3功能改变的小鼠模型来研究KCNN 3在房颤中的作用。