Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome.
Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome.
复制标题
鉴定KCNQ1多态性，该多态性起着防止长QT综合征心律失常风险的保护性修饰剂。
DOI：
10.1161/circgenetics.113.000023
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发表时间：
2013-08
期刊：
影响因子：
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通讯作者：
Schwartz PJ
中科院分区：
文献类型：
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作者：
Duchatelet S;Crotti L;Peat RA;Denjoy I;Itoh H;Berthet M;Ohno S;Fressart V;Monti MC;Crocamo C;Pedrazzini M;Dagradi F;Vicentini A;Klug D;Brink PA;Goosen A;Swan H;Toivonen L;Lahtinen AM;Kontula K;Shimizu W;Horie M;George AL Jr;Trégouët DA;Guicheney P;Schwartz PJ
长QT综合征（LQTS）的特点是如此惊人的临床异质性，即使在携带相同突变的家庭成员中，临床结果也可以从猝死到无症状。我们研究了遗传变异作为LQTS患者心脏事件风险修饰因子的作用。在一项包括来自法国、意大利和日本的112例LQTS患者二人组的匹配病例对照研究中，根据其与健康人群QTc间期的相关性或其在肾上腺素能反应中的作用，对25种多态性进行了基因分型。二人组由两名携带相同杂合KCNQ 1或KCNH 2突变的亲属组成;一名患有心脏事件，另一名无症状且未经治疗。然后在两个独立的创始人人群中验证了这些发现，共174例有症状和162例无症状LQTS患者，并进行了荟萃分析。在联合发现和复制队列中，KCNQ 1 rs 2074238 T等位基因与症状风险降低0.34 [0.19 - 0.61]（p<0.0002）和QTc缩短（p<0.0001）显著相关。我们提供的证据表明，KCNQ 1 rs 2074238多态性是一个独立的风险修饰因子与次要的T等位基因赋予对LQTS患者的心脏事件的保护。这一发现为LQTS患者的风险分层提供了新的方法。
Long-QT Syndrome (LQTS) is characterized by such striking clinical heterogeneity, that even among family members carrying the same mutation, clinical outcome can range between sudden death to no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in LQTS patients. In a matched case-control study including 112 LQTS patient duos from France, Italy and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of two relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation; one with cardiac events and one asymptomatic and untreated. The findings were then validated in two independent founder populations totaling 174 symptomatic and 162 asymptomatic LQTS patients, and a meta-analysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 [0.19 – 0.61] (p<0.0002) and with shorter QTc (p<0.0001) in the combined discovery and replication cohorts. We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in LQTS patients. This finding is a step toward a novel approach for risk stratification in LQTS patients.