Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes

Ping Yang, Hideaki Kanki, Benoit Drolet, Tao Yang, Jian Wei, Prakash C. Viswanathan, Stefan H. Hohnloser, Wataru Shimizu, Peter J. Schwartz, Marshall Stanton, Katherine T. Murray, Kris Norris, Alfred L. George, Dan M. Roden

Research output: Contribution to journalArticle

Abstract

Background - DNA variants appearing to predispose to drug-associated "acquired" long-QT syndrome (aLQTS) have been reported in congenital long-QT disease genes. However, the incidence of these genetic risk factors has not been systematically evaluated in a large set of patients with aLQTS. We have previously identified functionally important DNA variants in genes encoding K+ channel ancillary subunits in 11% of an aLQTS cohort. Methods and Results - The coding regions of the genes encoding the pore-forming channel proteins KvLQT1, HERG, and SCN5A were screened in (1) the same aLQTS cohort (n=92) and (2) controls, drawn from patients tolerating QT-prolonging drugs (n=67) and cross sections of the Middle Tennessee (n=71) and US populations (n=90). The frequency of three common nonsynonymous coding region polymorphisms was no different between aLQTS and control subjects, as follows: 24% versus 19% for H558R (SCN5A), 3% versus 3% for R34C (SCN5A), and 14% versus 14% for K897T (HERG). Missense mutations (absent in controls) were identified in 5 of 92 patients. KvLQT1 and HERG mutations (one each) reduced K+ currents in vitro, consistent with the idea that they augment risk for aLQTS. However, three SCN5A variants did not alter INa, which argues that they played no role in the aLQTS phenotype. Conclusions - DNA variants in the coding regions of congenital long-QT disease genes predisposing to aLQTS can be identified in ≈ 10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits.

Original languageEnglish
Pages (from-to)1943-1948
Number of pages6
JournalCirculation
Volume105
Issue number16
DOIs
Publication statusPublished - Apr 23 2002

Keywords

  • Arrhythmia
  • Drugs
  • Genetics
  • Long-QT syndrome

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes'. Together they form a unique fingerprint.

  • Cite this

    Yang, P., Kanki, H., Drolet, B., Yang, T., Wei, J., Viswanathan, P. C., Hohnloser, S. H., Shimizu, W., Schwartz, P. J., Stanton, M., Murray, K. T., Norris, K., George, A. L., & Roden, D. M. (2002). Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation, 105(16), 1943-1948. https://doi.org/10.1161/01.CIR.0000014448.19052.4C