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. © 2013 American Heart Association, Inc

Duchatelet, S., Crotti, L., Peat, R., Denjoy, I., Itoh, H., Berthet, M., et al. (2013). Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome. CIRCULATION, CARDIOVASCULAR GENETICS, 6(4), 354-361 [10.1161/CIRCGENETICS.113.000023].

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

Crotti, L;Crocamo, C;
2013

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. 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. © 2013 American Heart Association, Inc
Articolo in rivista - Articolo scientifico
Association studies; Genetics; Ion channel; Long-QT syndrome; Polymorphism; Risk factor; Alleles; Case-Control Studies; Cohort Studies; Databases, Genetic; Ether-A-Go-Go Potassium Channels; Female; Gene Frequency; Genotype; Heterozygote; Humans; KCNQ1 Potassium Channel; Long QT Syndrome; Male; Risk Factors; Polymorphism, Single Nucleotide; Cardiology and Cardiovascular Medicine; Genetics (clinical); Genetics
English
354
361
8
Duchatelet, S., Crotti, L., Peat, R., Denjoy, I., Itoh, H., Berthet, M., et al. (2013). Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome. CIRCULATION, CARDIOVASCULAR GENETICS, 6(4), 354-361 [10.1161/CIRCGENETICS.113.000023].
Duchatelet, S; Crotti, L; Peat, R; Denjoy, I; Itoh, H; Berthet, M; Ohno, S; Fressart, V; Monti, M; Crocamo, C; Pedrazzini, M; Dagradi, F; Vicentini, A; Klug, D; Brink, P; Goosen, A; Swan, H; Toivonen, L; Lahtinen, A; Kontula, K; Shimizu, W; Horie, M; George, A; Trégouët, D; Guicheney, P; Schwartz, P
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/138287
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