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

描述(由申请人提供)： 房颤是最常见的心律失常，影响着200多万美国人。房颤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，死亡率增加近两倍有关。有越来越多的证据表明房颤是遗传成分，在离子通道和信号分子中已经描述了房颤的突变，但这种突变很少见。全基因组关联研究(GWAS)已经发现了许多常见的变异，这些变异可能导致广泛的疾病。2007年，冰岛人的房颤基因分析确定了染色体(CHR)4q25上的房颤易感区域，这一发现在我们的孤独AF1人群中重复。1虽然CHR 4q25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名房颤患者的初步GWAS。由于房颤可能存在许多其他遗传变异，Ellinor、Benjamin和Heckbert博士组织了由来自12项研究的研究人员组成的Charge-AF联盟，这些研究涉及8000多名房颤患者和8.6万名非房颤患者。患有孤立性房颤且无器质性心脏病证据的受试者房颤的家族聚集性特别高。在前期工作中，我们使用来自五项研究的病例进行了孤立性房颤的GWA；总共有1335例孤立性房颤病例和12844例参考受试者。在CHR 4q25，有77个单核苷酸多态(SNPs)存在P&lt；5x10-8。在CHR 1q21上发现了第二个新的基因座；最显著的SNP，rs13376333，是钾通道KCNN3的内含子。在对原始和复制队列的荟萃分析中，rs13376333的优势比为1.52(P=1.8x10-21)。KCNN3是电压非依赖性钙激活钾通道家族的一员，在许多可兴奋组织中表达，包括脑40和心脏；41，42然而，这些通道在心脏中的作用尚不清楚。我们建议通过以下具体目标扩展我们的工作：目标1-通过精细定位KCNN3基因座，将左房RNA水平与KCNN3基因相关联，以及确定KCNN3中的多谷氨酰胺重复序列是否与房颤相关，确定KCNN3基因的遗传变异是否与房颤风险相关。目的2-鉴定和鉴定房颤患者中KCNN3基因的突变和罕见变异。目的3-确定与KCNN3功能相关的保守的、非编码的调控元件。目的4-鉴定两个KCNN3功能改变的小鼠的心脏表型。我们相信，我们的多学科转换方法集成了现有的GWA、细胞电生理学和动物模型系统，是唯一适合进行该项目的方法。了解房颤的分子决定因素将为房颤的发病机制提供深入的认识，并最终为预防和治疗这种病理性心律失常的新疗法提供靶点。

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.