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.

Association between single-nucleotide polymorphisms in the endothelial lipase (LIPG) gene and high-density lipoprotein cholesterol levels.

Endothelial lipase (LIPG) is the latest addition to the triglyceride lipase family of genes that includes pancreatic lipase (PL), hepatic lipase (HL), and lipoprotein lipase (LPL). These lipolytic enzymes demonstrate both triglyceride lipase as well as phospholipase activities and are integrally involved in lipid absorption, transport, and metabolism. Several studies have demonstrated that LIPG is important for affecting lipid levels in mice but the data in humans is less complete. To more thoroughly characterize the LIPG gene, we resequenced it from an ethnically diverse population. Thirteen novel single-nucleotide polymorphisms (SNPs) were identified and seven others confirmed. High linkage disequilibrium was found among these SNPs spanning the length of the transcript, allowing interrogation of the entire gene for functional variation. Subjects with either high or low HDL cholesterol were used to investigate its association with LIPG gene variation. Associations were found with the most significant being the intronic variants C+42T/In5 and T+2864C/In8 (P=0.007 and 0.004, respectively). A trend for an association of the same SNPs with fewer myocardial infarctions (P=0.03) was also observed but was not significant after correction for multiple testing. The results of this study provide data linking variation in the human LIPG gene with HDL cholesterol levels as well as further evidence in support of LIPG as a potential target for therapeutic intervention.