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(Circulation. 2005;112:1242-1244.)
© 2005 American Heart Association, Inc.

Editorial

Genes and Cardiac Repolarization

The Challenge Ahead

Michael Rubart, MD; Douglas P. Zipes, MD

From the Wells Center for Pediatric Research, Indiana University School of Medicine (M.R.), and the Krannert Institute of Cardiology, Indianapolis, Ind (D.P.Z.).

Correspondence to Douglas P. Zipes, Krannert Institute of Cardiology, 1800 N Capitol Ave, Indianapolis, IN 46202. E-mail dzipes@iupui.edu

Key Words: Editorials • sudden death • genetics • ion channels • long-QT syndrome

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Cardiovascular diseases are caused by a combination of environmental and genetic factors.^1,2 Deciphering these genetic factors should provide fundamental new insights into their pathogenesis, diagnosis, prevention, and treatment. Previous large-scale association studies have been able to identify patterns of DNA sequence variations that confer susceptibility to cardiovascular diseases³ or alter pharmacological responsiveness.⁴ The most common type of genetic variant, a single nucleotide polymorphism (SNP), is a difference between chromosomes in the base present at a particular site in the DNA sequence. Nonsynonymous SNPs (ie, those resulting in amino acid substitution) have the potential to alter the functional properties of the protein encoded by the polymorphic gene, thereby giving rise to a distinct phenotype. The simultaneous presence of multiple nSNPs within the same gene (eg, in the gene encoding the human ß₂-adrenergic receptor⁴) or the occurrence of a novel mutation within a polymorphic gene may result in a more complex phenotypic alteration, with each variant individually contributing to its manifestation.

See p 1251

In this issue of Circulation, Crotti and coworkers⁵ provide compelling clinical and genetic evidence that co-inheritance of a novel, low-penetrance mutation in the KCNH2 gene (ie, the gene encoding the pore-forming -subunit of the channel mediating the rapidly activating component of the cardiac delayed-rectifier potassium current, I_Kr) and a common, nonsynonymous single nucleotide polymorphism in the same gene is associated with increased QT_c duration and sudden death from cardiac arrhythmia, whereas heterozygous carriers of either gene variant alone were asymptomatic or exhibited only transient . . . [Full Text of this Article]

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