Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome

Sabine Duchatelet, Lia Crotti, Rachel A. Peat, Isabelle Denjoy, Hideki Itoh, Myriam Berthet, Seiko Ohno, Véronique Fressart, Maria Cristina Monti, Cristina Crocamo, Matteo Pedrazzini, Federica Dagradi, Alessandro Vicentini, Didier Klug, Paul A. Brink, Althea Goosen, Heikki Swan, Lauri Toivonen, Annukka M. Lahtinen, Kimmo KontulaWataru Shimizu, Minoru Horie, Alfred L. George, David Alexandre Trégouët, Pascale Guicheney*, Peter J. Schwartz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Background-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. Methods and Results-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 metaanalysis 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. Conclusions-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.

Original languageEnglish (US)
Pages (from-to)354-361
Number of pages8
JournalCirculation: Cardiovascular Genetics
Issue number4
StatePublished - Aug 2013


  • Association studies
  • Genetics
  • Ion channel
  • Long-QT syndrome
  • Polymorphism
  • Risk factor

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)


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