title: Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome.
abstract: 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.
  
  
  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 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.
  
  
  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.
authors.affiliation: INSERM, UMR S956, Paris, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Duchatelet
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Peat
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.forename: Myriam
authors.initials: M
authors.lastname: Berthet
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Véronique
authors.initials: V
authors.lastname: Fressart
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Monti
authors.forename: Cristina
authors.initials: C
authors.lastname: Crocamo
authors.forename: Matteo
authors.initials: M
authors.lastname: Pedrazzini
authors.forename: Federica
authors.initials: F
authors.lastname: Dagradi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vicentini
authors.forename: Didier
authors.initials: D
authors.lastname: Klug
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brink
authors.forename: Althea
authors.initials: A
authors.lastname: Goosen
authors.forename: Heikki
authors.initials: H
authors.lastname: Swan
authors.forename: Lauri
authors.initials: L
authors.lastname: Toivonen
authors.forename: Annukka M
authors.initials: AM
authors.lastname: Lahtinen
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Trégouët
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D030541:Databases, Genetic; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000209:etiology / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human
keywords: association studies; genetics; ion channel; long-QT syndrome; polymorphism; risk factor