Elsevier

American Heart Journal

Volume 152, Issue 6, December 2006, Pages 1116-1122
American Heart Journal

Clinical Investigation
Genetics
Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes

https://doi.org/10.1016/j.ahj.2006.08.020Get rights and content

Background

Reduction of drug-induced adverse events may be achievable through a better understanding of the underlying causes of such events. Identifying phenotypes and genotypes that allow event prediction would provide greater safety margins for new therapeutics. Torsades de pointes (TdP) is one such life-threatening adverse event and can arise from excessive lengthening of the QT interval. This study was designed to better understand the role of genetics in the development of TdP and to determine whether genotypes can be used to predict susceptibility and thus reduce adverse events.

Methods

Seven known familial long QT syndrome genes were scanned for sequence variations in 34 patients with TdP. This group of patients is the largest such cohort ever assembled for this type of analysis. The allele frequencies for novel and known polymorphisms in these patients were compared with those in healthy control subjects.

Results

Six novel mutations—4 in ANK2, 1 in KCNQ1, and 1 in SCN5A—were found in the patients with TdP. Two mutations were also found in 595 healthy control subjects, whereas the others were unique to patients with TdP. Two common single nucleotide polymorphisms may be associated with the risk of TdP. The entire ANK2 gene had not been screened in a population this large previously.

Conclusions

Genotypes alone could not be used to completely predict susceptibility to TdP, even when used with phenotypes. The best model using genotypic and phenotypic variables was unable to predict all events. It is unclear what other risk genes or environmental effects might be necessary to predict such cases.

Section snippets

Methods

Genomic DNA was obtained from a small subset of patients enrolled in the DIAMOND studies.17 These studies focused on the effects of dofetilide on 2 populations of patients: 1 with congestive heart failure (CHF) and another with recent myocardial infarction (MI) associated with left ventricular dysfunction. DNA samples were obtained with appropriate informed consent from the patients, and the requests were reviewed by the institutional review boards. Retrospective consent and sample collection

Results

The large number of individuals and the extensive range of sequences analyzed led us to screen for mutations with Transgenomic WAVE denaturing high-performance liquid chromatography. Complete data were obtained from all 34 patients with TdP for 109 of the 112 exons in the 7 genes studied. Exons 1, 11, and 13 in KCNH2 were not amenable to this screening procedure because of their high guanine-cytosine content. Instead, these exons were directly sequenced in 28 patients. DNA from the other 6

Discussion

Although QT prolongation has long been known to be a risk factor for sudden cardiac death, its importance in the general population and how genetic predisposition may affect sudden death have been controversial. Much of this controversy may arise from differences in the populations examined.27 QT is affected by age, sex, BMI, hypertension, diabetes, and other risk factors; therefore, genetic and environmental contributions to both QT and sudden death can vary significantly among different

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