Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes

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 ϩ 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 (nϭ92) and (2) controls, drawn from patients tolerating QT-prolonging drugs (nϭ67) and cross sections of the Middle Tennessee (nϭ71) and US populations (nϭ90). 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 ϩ 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 Ϸ10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits. (Circulation. 2002; 105:1943-1948.)

Pharmacogenomics: Challenges and Opportunities

“…Although the length of the QT interval is determined by many ion-channel and other genes, only 1 (HERG [KCNH2]) is the target for QT-prolonging drugs; as a consequence, new drug candidates are now routinely screened for KCNH2-blocking activity (40). Of importance, surveys of patients with drug-induced torsades de pointes occasionally identify predisposing mutations not only in the drug target (the KCNH2 channel) but also in other genes that control the QT interval (41,42); that is, variability in the physiologic control of the QT interval can contribute to variable effects of KCNH2 blockers.…”

“…Because these reactions often occur in an apparently unpredictable fashion, they have been termed "idiosyncratic," and a genetic predisposition is often invoked. Accrual of patient sets in which to test this idea will require multi-center collaborations (46), and the initial focus of genetic analysis has been on a small number of genes chosen because they may be associated with disease susceptibility (41,42,(47)(48)(49)(50).…”

Genomics, heart failure and sudden cardiac death

“…However, the observation that mutations in a number of ion channel genes are responsible for familial or congenital long QT syndrome raised the possibility of the influence of population variants of these genes in the 'acquired' form of long QT syndrome. Yang and colleagues [12] investigated the role of genetic variants in modulating the risk of torsades de pointes and found subclinical long QT syndrome mutations in 10-20% of subjects who develop this arrhythmia. We have proposed the idea of 'repolarization reserve' which suggests that multiple mechanisms contribute to normal repolarization, so that removal of any one of these (by disease, subclinical mutation or polymorphism in an ion channel or other gene) may be without consequence until a drug is added at which point the 'reduced repolarization reserve' becomes evident by marked QT prolongation and torsades de pointes [13].…”

Denaturing high-performance liquid chromatography screening of the long QT syndrome-related cardiac sodium and potassium channel genes and identification of novel mutations and single nucleotide polymorphisms

“…Past research targeted at identifying variations in all LQT genes has demonstrated that 5-15% of patients have minor mutations in these long QT genes (Paulussen et al 2004). In a large-scale screening study of 95 patients, Yang et al (2002) reported that the incidence of SCN5A SNPs was not significantly different between patients and a control group. Although they also identified three novel variations of SCN5A gene in these patients, a causal relationship was not confirmed because functional expression of the mutated channels revealed no alterations in I Na .…”