2015-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/649105摘要：心房顫動(atrial fibrillation)是最常見的心律不整，先前的全基因組關聯性分析研宄(genome-wide association study)已經找到9個與心房顫動有關聯性的單核甘酸變異(single nucleotide polymorphisms; SNPs)，但是這結果並無法解釋所有得到心房顫動的遺傳風險。拷貝數變異(copy number variations)會影響基因的表達、功能以及造成罹病的可能，然而拷貝數變異與心房顫動的遺傳風險關聯性並未被探 討過。因此我們提出一個三年計劃來研宄拷貝數變異與心房顫動之間的關聯性。計畫第一年，我們預 計使用1550位心房顫動病人(實驗組)和3050位正常節律的人(對照組)，以多階段(multi-stage)的方法 來尋找與心房顫動相關的拷貝數變異利用Illumina HumanOmnil-Quad Bead Chip (1,014,075 SNPs)晶片進行全基因組拷貝數分析，所有得到的結果都會經由Real-time PCR進行拷貝數驗證。第二年，我 們會釐清在人類心房組織中拷貝數變異會不會影響基因表現量的改變，以證實和心房顫動相關之拷貝 數變異真的能改變基因的活性，我們同時也會在第二年建立斑馬魚模式平台用來評估電生理表型。接 著第三年，我們會在斑馬魚模式中了解這些與心房顫動相關的目標基因其在各組織器官的表達模式， 同時會建立心房顫動斑馬魚模式，藉由morpholino剔除基因表現或是體外的(in vitro) mRNA過度表達 與心房顫動相關的基因。不僅如此，我們亦會釐清在培養的心房心肌細胞以及大鼠模式中，以快速電 刺激或是機械張力拉扯來模擬心房顫動，並探討會不會影響這些與心房顫動相關基因表達，我們提出 的三年計畫是第一個欲建立斑馬魚心房顫動模式的計劃，並且了解拷貝數變異對於心房顫動機轉之間 的關係。<br> Abstract: AF is the most common sustained cardiac arrhythmia. Previously genome-wide association studies haveidentified single nucleotide polymorphisms (SNPs) in nine genomic regions associated with AF. These locido not fully explain the genetic risk for AF. Copy number variation (CNV) also contributes directly tochanges in gene expression, function and disease susceptibility and its association with AF risk has neverexplored before. We propose a three-year project to explore this issue. First year, we plan to use a multi-stageapproach to identify AF susceptibility CNVs with a total of 1550 AF patients and 3050 normal sinus rhythmcontrols. Genome-wide CNV analysis will be conducted using the Illumina HumanOmni1-Quad BeadChip(1,014,075 SNPs) to generate CNV calls. We will verify these CNV regions by real-time polymerase chainreaction. In the second year, we will determine whether CNVs genotypes affect gene expression in humanatrial samples. We will also establish a zebrafish model as a platform to evaluate the in vivoelectrophysiological phenocopies of AF. In the third year, we will characterize the expression pattern oftargeted AF susceptibility genes in the zebrafish model. We will also establish a zebrafish model of AF bymorpholino knockdown and in-vitro mRNA over-expression of identified AF susceptibility genes. Moreover,we will determine whether in vivo and in vitro rapid pacing or mechanical stretch affects AF gene expressionin the cultured atrial myocytes and rat models. Our three-year’s project will first establish the role of CNVsin determining the susceptibility to AF and first establish a zebrafish model of AF.