Published Online
on January 16, 2006

A more recent version of this article appeared on January 24, 2006

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Submitted on August 3, 2005
Revised on September 15, 2005
Accepted on October 11, 2005

Common Sodium Channel Promoter Haplotype in Asian Subjects Underlies Variability in Cardiac Conduction

Connie R. Bezzina PhD^*, Wataru Shimizu MD, PhD, Ping Yang PhD, Tamara T. Koopmann BSc, Michael W.T. Tanck PhD, Yoshihiro Miyamoto MD, PhD, Shiro Kamakura MD, PhD, Dan M. Roden MD, and Arthur A.M. Wilde MD, PhD

From the Experimental and Molecular Cardiology Group, Department of Experimental Cardiology (C.R.B., T.T.K., A.A.M.W.), Department of Clinical Genetics (C.R.B.), and Department of Clinical Epidemiology and Biostatistics (M.W.T.T.), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Division of Cardiology, Department of Internal Medicine (W.S., S.K.), and Laboratory of Molecular Genetics (Y.M.), National Cardiovascular Center, Suita, Osaka, Japan; and Department of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn (P.Y., D.M.R.).

^* To whom correspondence should be addressed. E-mail: C.R.Bezzina{at}amc.uva.nl.

Background--Reduced cardiac sodium current slows conduction and renders the heart susceptible to ventricular fibrillation. Loss of function mutations in SCN5A, encoding the cardiac sodium channel, are one cause of the Brugada syndrome, associated with slow conduction and a high incidence of ventricular fibrillation, especially in Asians. In this study, we tested the hypothesis that an SCN5A promoter polymorphism common in Asians modulates variability in cardiac conduction.

Methods and Results--Resequencing 2.8 kb of SCN5A promoter identified a haplotype variant consisting of 6 polymorphisms in near-complete linkage disequilibrium that occurred at an allele frequency of 22% in Asian subjects and was absent in whites and blacks. Reporter activity of this variant haplotype, designated HapB, in cardiomyocytes was reduced 62% compared with wild-type haplotype (P=0.006). The relationship between SCN5A promoter haplotype and PR and QRS durations, indexes of conduction velocity, was then analyzed in a cohort of 71 Japanese Brugada syndrome subjects without SCN5A mutations and in 102 Japanese control subjects. In both groups, PR and QRS durations were significantly longer in HapB individuals (P0.002) with a gene-dose effect. In addition, up to 28% and 48% of variability in PR and QRS durations, respectively, were attributable to this haplotype. The extent of QRS widening during challenge with sodium channel blockers, known to be arrhythmogenic in Brugada syndrome and other settings, was also genotype dependent (P=0.002).

Conclusions--These data demonstrate that genetically determined variable sodium channel transcription occurs in the human heart and is associated with variable conduction velocity, an important contributor to arrhythmia susceptibility.

Key words: arrhythmia • conduction • death, sudden • genetics • ion channels

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T. Jared Bunch and Michael J. Ackerman
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