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

ABSTRACT: 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.

SUBMITTER: Duchatelet S

PROVIDER: S-EPMC3864834 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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

Duchatelet Sabine S Crotti Lia L Peat Rachel A RA Denjoy Isabelle I Itoh Hideki H Berthet Myriam M Ohno Seiko S Fressart Véronique V Monti Maria Cristina MC Crocamo Cristina C Pedrazzini Matteo M Dagradi Federica F Vicentini Alessandro A Klug Didier D Brink Paul A PA Goosen Althea A Swan Heikki H Toivonen Lauri L Lahtinen Annukka M AM Kontula Kimmo K Shimizu Wataru W Horie Minoru M George Alfred L AL Trégouët David-Alexandre DA Guicheney Pascale P Schwartz Peter J PJ

Circulation. Cardiovascular genetics 20130715 4

<h4>Background</h4>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.<h4>Methods and results</h4>In a matched case-control study including 112 patient duos with LQTS from France, Italy, and Japan, 25 polymorphisms were genotyped based on ...[more]

PMID: 23856471

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Project description:BackgroundInsight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration.MethodsPatients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death.ResultsA total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%).ConclusionsThe present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Dataset Information

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

Publications

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

Similar Datasets

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