2012-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/689469摘要：心電圖上的QT 間距代表了心臟再極化(repolarization)電氣活動時間的長短，QT 過長或過短都很容易造成心律不整或猝死的發生。根據雙胞胎及大規模族群（如Framingham study)研究發現QT 本身受到遺傳因素的影響有30%之多(其他是環境或藥物因素）。過去對於QT 或long QT syndrome 的研究，多侷限於離子通道，而且以exon 區域居多；最近幾年，隨著基因體學的發展和基因晶片的使用，西方國家更進一步闡明：遺傳因素對於QT interval 的影響並不僅侷限於少數家族內的基因突變而已；而是某些特定的基因多型性(SNP)的組合，對於個體QT 長短的影響可達2.5-14msec 之多。如此一來，了解生物體內關鍵SNP 的訊息對其本身QT interval 長短甚至是使用藥物發生心律不整或猝死症的影響和預測，就變得非常重要。然而，在台灣，這方面的訊息與研究都非常的少，而且都是停留在mutation screening 的階段。本研究希望從了解這些影響QT interval 的關鍵SNPs 在台灣小於18 歲族群的真正分布著手，並進而探討在台灣的基因背景下，這些SNPs 和mutation 如何影響QTc >440msec 學童的臨床表現－包括心電圖的變化；QT intervalvariability； heart rate variability；運動心電圖上的micro-T wavealternas 及3-10 年間中長期監控的心電圖變化。方法：(一) 回顧最近幾篇大型GWAS study，所得到的與QT interval 相關的SNPs，並搜尋HapMap project 中，這些SNPs 在中國和日本的可能allelefrequency，並配合我們過去做的幾個study，選出了19 個可能的condidateSNPs；應用TaqMan probe 的原理，在400 位healthy control 上作genotyping 以了解這些SNP 在台灣族群的分布。(二) 藉由中華民國兒童心臟病基金會1999-2008「台北市學童心臟病篩檢計劃」所可能搜集到70 位QT >450msec 的受試者。針對KCNQ1、KCNH2、SCN5A、KCNE1、KCNE2 及NOS1AP 及涵蓋第一階段allelic frequency > 1%的基因做詳細的定序分析；同時這70 位病人亦接受十二導程心電圖、運動心電圖及heart rate variability。(三) 作genotype 與phenotype 間的association study。分析臨床的表現與基因型間的關係，並了解這些受試者QT 隨著年紀的變異情形預期成果：有了這些資料之後，便可以把mutation 和SNP 放在同一個框架下，評估它們與臨床變數及猝死風險因子的相關性；同時因為他們在數年前篩檢時，亦都有心電圖記錄。如此一來，以基因型為基礎的QT 長期變化趨勢，亦可藉此研究而了解。這將會形成未來預防青少年猝死的重要基礎，也是藥物遺傳學的重要起點。<br> Abstract: The QT interval in electrocardiography (ECG), a measure of cardiac repolarization, is a geneticallyinfluenced quantitative trait with 30% heritability. Most of previous studies focused on looking formutations in exon regions of ion channels. However, the vast majority of subjects who are at risk forsudden death do not have such mutations. Several genomewide association studies (GWAS) in Caucasianpopulation had been conducted on QT interval and identified a few novel genetic pathways, like NOS1AP,and intronic SNPs of known ion-channel genes associated with length of QT intervals. However, few ofthese results had been replicated in Asian cohorts.Aim(1) Clarify the allelic frequencies of QT-associated SNPs in Taiwan(2) In children and adolescents with QTc > 440 msec, analyze correlation between genotypes(mutations & QT-associated SNPs) and phenotypes (ECG characteristics & risk of sudden death).(3) Understand the longitudinal changes of QT interval in the pediatric cohort.Methods(1) Based on previous GWAS studies and HapMap project, we plan to pick up 19 SNPs. Withtechnique of TaqMan SNP genotyping, genomic DNA of 400 health controls will be examined.Their minor allelic frequencies (MAF) in the general population will be determined.(2) Identify the potential candidates with QTc>440 msec (estimated 70 persons) in the Taipei cityschool heart survey (1999-2008, supported by Chinese Cardiac Children’s Foundation)(3) For each participant, genotyping (exons of ion-channels genes & SNPs with MAF > 1%), ECG,heart rate variability, QT variability and Treadmill will be done.(4) Annual follow-up of ECG and Holter will be done in the following 2-3 years.(5) Analyze correlation between genotypes and phenotypes (ECG characteristics & risk of suddendeath).Anticipated Results(1) The allelic frequencies of QT-associated SNPs in Taiwan(2) Certain SNPs associated with longer QT interval or electrocardiographic risk factors of SCD.(3) Longitudinal ECG changes on the children with QTc ≧ 440 msec