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Science 23 August 2002:
Vol. 297. no. 5585, pp. 1333 - 1336
DOI: 10.1126/science.1073569
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Reports

Variant of SCN5A Sodium Channel Implicated in Risk of Cardiac Arrhythmia

Igor Splawski,1* Katherine W. Timothy,2 Michihiro Tateyama,3 Colleen E. Clancy,3 Alka Malhotra,2 Alan H. Beggs,4 Francesco P. Cappuccio,5 Giuseppe A. Sagnella,6 Robert S. Kass,3 Mark T. Keating1*

Every year, ~450,000 individuals in the United States die suddenly of cardiac arrhythmia. We identified a variant of the cardiac sodium channel gene SCN5A that is associated with arrhythmia in African Americans (P = 0.000028) and linked with arrhythmia risk in an African-American family (P = 0.005). In transfected cells, the variant allele (Y1102) accelerated channel activation, increasing the likelihood of abnormal cardiac repolarization and arrhythmia. About 13.2% of African Americans carry the Y1102 allele. Because Y1102 has a subtle effect on risk, most carriers will never have an arrhythmia. However, Y1102 may be a useful molecular marker for the prediction of arrhythmia susceptibility in the context of additional acquired risk factors such as the use of certain medications.

1 Department of Cardiology, Children's Hospital, and Departments of Pediatrics and Cell Biology, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
2 Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
3 Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
4 Division of Genetics, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
5 Department of General Practice and Primary Care,
6 Department of Physiological Medicine, St. George's Hospital Medical School, London SW17 0RE, UK.
*   To whom correspondence should be addressed. E-mail: igor{at}enders.tch.harvard.edu (I.S.); mkeating{at}enders.tch.harvard.edu (M.T.K.)

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