Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes
Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes
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DOI：
10.1016/j.ahj.2006.08.020
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发表时间：
2006-12-01
影响因子：
4.8
通讯作者：
Thompson, John F.
中科院分区：
文献类型：
--
作者：
Mank-Seymour, Amy R.;Richmond, Jodi L.;Thompson, John F.
通过更好地了解药物引起的不良事件的根本原因，可以减少药物引起的不良事件。鉴定允许事件预测的表型和基因型将为新疗法提供更大的安全裕度。尖端扭转型室性心动过速（TdP）是一种危及生命的不良事件，可能由QT间期过度延长引起。本研究的目的是更好地了解遗传学的作用，在发展中的TdP，并确定基因型是否可以用来预测易感性，从而减少adverse events.Methods七个已知的家族性长QT综合征基因进行了扫描序列变异34例TdP。这组患者是有史以来为这种类型的分析而聚集的最大的此类队列。结果在TdP患者中发现6个新的突变，其中4个位于ANK2，1个位于KCNQ1，1个位于SCN 5A。在595名健康对照受试者中也发现了两种突变，而其他突变是TdP患者所独有的。两种常见的单核苷酸多态性可能与TdP的风险有关。整个ANK2基因还没有被筛选在一个人口这么大previous.Conclusions基因型不能单独用来完全预测TdP的易感性，即使与表型。使用基因型和表型变量的最佳模型无法预测所有事件。目前还不清楚还有哪些其他风险基因或环境影响可能是预测此类病例所必需的。
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.