Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes.
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.
Mank-Seymour
Amy R
AR
Pharmacogenomics, Molecular Profiling, Groton, CT, USA.
Richmond
Jodi L
JL
Wood
Linda S
LS
Reynolds
Jennifer M
JM
Fan
Yu-Ti
YT
Warnes
Gregory R
GR
Milos
Patrice M
PM
Thompson
John F
JF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017487:Ankyrins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D020641:Polymorphism, Single Nucleotide; D015222:Sodium Channels / Q000235:genetics*; D016171:Torsades de Pointes / Q000235:genetics*
C498994:ANK2 protein, human; D017487:Ankyrins; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels