Duchatelet Sabine, Crotti Lia, Peat Rachel A, Denjoy Isabelle, Itoh Hideki, Berthet Myriam, Ohno Seiko, Fressart Véronique, Monti Maria Cristina, Crocamo Cristina, Pedrazzini Matteo, Dagradi Federica, Vicentini Alessandro, Klug Didier, Brink Paul A, Goosen Althea, Swan Heikki, Toivonen Lauri, Lahtinen Annukka M, Kontula Kimmo, Shimizu Wataru, Horie Minoru, George Alfred L, Trégouët David-Alexandre, Guicheney Pascale, Schwartz Peter J
INSERM, UMR S956, Paris, France.
Circ Cardiovasc Genet. 2013 Aug;6(4):354-61. doi: 10.1161/CIRCGENETICS.113.000023. Epub 2013 Jul 15.
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 and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS.
In a matched case-control study including 112 patient duos with LQTS 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 2 relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation: 1 with cardiac events and 1 asymptomatic and untreated. The findings were then validated in 2 independent founder populations totaling 174 symptomatic and 162 asymptomatic patients with LQTS, 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 patients with LQTS. This finding is a step toward a novel approach for risk stratification in patients with LQTS.
长QT综合征（LQTS）具有显著的临床异质性，即使在携带相同突变的家庭成员中，临床结局也可能从猝死到无症状不等。我们研究了基因变异作为LQTS患者心脏事件风险修饰因子的作用。
在一项匹配病例对照研究中，纳入了来自法国、意大利和日本的112对LQTS患者，基于25种多态性与健康人群QTc间期的关联或其在肾上腺素能反应中的作用进行基因分型。这些配对由两名携带相同杂合KCNQ1或KCNH2突变的亲属组成：一名有心脏事件，一名无症状且未接受治疗。然后在两个独立的奠基人群中进行验证，共有174例有症状和162例无症状的LQTS患者，并进行了荟萃分析。在联合发现和复制队列中，KCNQ1 rs2074238 T等位基因与症状风险降低显著相关[比值比（OR）0.34（0.19 - 0.61）；P < 0.0002]且与较短的QTc相关（P < 0.0001）。
我们提供的证据表明，KCNQ1 rs2074238多态性是一种独立的风险修饰因子，次要T等位基因可保护LQTS患者预防心脏事件。这一发现朝着LQTS患者风险分层的新方法迈出了一步。
