A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes.
A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes.
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DOI：
10.1161/circgenetics.111.960930
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发表时间：
2012-02-01
期刊：
影响因子：
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通讯作者：
Roden DM
中科院分区：
文献类型：
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作者：
Kääb S;Crawford DC;Sinner MF;Behr ER;Kannankeril PJ;Wilde AA;Bezzina CR;Schulze-Bahr E;Guicheney P;Bishopric NH;Myerburg RJ;Schott JJ;Pfeufer A;Beckmann BM;Martens E;Zhang T;Stallmeyer B;Zumhagen S;Denjoy I;Bardai A;Van Gelder IC;Jamshidi Y;Dalageorgou C;Marshall V;Jeffery S;Shakir S;Camm AJ;Steinbeck G;Perz S;Lichtner P;Meitinger T;Peters A;Wichmann HE;Ingram C;Bradford Y;Carter S;Norris K;Ritchie MD;George AL Jr;Roden DM
药物诱导的长QT综合征（diLQTS）是一种药物不良反应，对药物使用、开发和监管有重要影响。在这里，我们检验了控制心脏电特性的关键基因的常见变异改变diLQTS风险的假设。在病例对照研究中，我们纳入了176例来自北美和欧洲的欧洲血统diLQTS患者，定义为在使用QT延长药物治疗期间记录的尖端扭转型室性心动过速。对照样本来自207名欧洲血统的患者，这些患者在开始使用QT延长药物治疗期间显示QT延长<50 msec，对照样本来自基于人群的KORA研究的837名对照。受试者在18个候选基因中的1，424个单核苷酸多态性（SNP）处成功地进行了基因分型，包括1，386个标记常见单倍型块的SNP和38个非同义离子通道基因SNP。为了验证，我们使用了一组病例（n=57）和基于人群的欧洲血统对照。已知调节心脏中重要钾电流的SNP KCNE 1 D85 N（rs 1805128）预测diLQTS的优势比为9.0（95%置信区间：3.5-22.9）。该变异等位基因存在于8.6%的病例、2.9%的药物暴露对照和1.8%的人群对照中。在验证队列中，3.5%的病例和1.4%的对照中存在变异等位基因。这种高密度候选SNP方法鉴定了一个关键的钾通道易感性等位基因，该等位基因可能与罕见的药物不良反应尖端扭转型室性心动过速相关。
Drug-induced long QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. Here, we tested the hypothesis that common variants in key genes controlling cardiac electrical properties modify the risk of diLQTS. In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 msec QT lengthening during initiation of therapy with a QT-prolonging drug, and 837 controls from the population based KORA study. Subjects were successfully genotyped at 1,424 single nucleotide polymorphisms (SNPs) in 18 candidate genes including 1,386 SNPs tagging common haplotype blocks, and 38 non-synonymous ion channel gene SNPs. For validation we used a set of cases (n=57) and population-based controls of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval: 3.5–22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed controls, and 1.8% of population controls. In the validation cohort the variant allele was present in 3.5% of cases, and in 1.4% of controls. This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.