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


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 I(Na), 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 approximately 10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits.
Yang
Ping
P
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn 37232, USA.
Kanki
Hideaki
H
Drolet
Benoit
B
Yang
Tao
T
Wei
Jian
J
Viswanathan
Prakash C
PC
Hohnloser
Stefan H
SH
Shimizu
Wataru
W
Schwartz
Peter J
PJ
Stanton
Marshall
M
Murray
Katherine T
KT
Norris
Kris
K
George
Alfred L
AL
Roden
Dan M
DM
D000483:Alleles; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects; D016466:CHO Cells; D027682:Cation Transport Proteins; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology; D016171:Torsades de Pointes / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D015222:Sodium Channels; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG