Kääb Stefan, Crawford Dana C, Sinner Moritz F, Behr Elijah R, Kannankeril Prince J, Wilde Arthur A M, Bezzina Connie R, Schulze-Bahr Eric, Guicheney Pascale, Bishopric Nanette H, Myerburg Robert J, Schott Jean-Jacques, Pfeufer Arne, Beckmann Britt-Maria, Martens Eimo, Zhang Taifang, Stallmeyer Birgit, Zumhagen Sven, Denjoy Isabelle, Bardai Abdennasser, Van Gelder Isabelle C, Jamshidi Yalda, Dalageorgou Chrysoula, Marshall Vanessa, Jeffery Steve, Shakir Saad, Camm A John, Steinbeck Gerhard, Perz Siegfried, Lichtner Peter, Meitinger Thomas, Peters Annette, Wichmann H-Erich, Ingram Christiana, Bradford Yuki, Carter Shannon, Norris Kris, Ritchie Marylyn D, George Alfred L, Roden Dan M
Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians University, Munich, Germany.
Circ Cardiovasc Genet. 2012 Feb 1;5(1):91-9. doi: 10.1161/CIRCGENETICS.111.960930. Epub 2011 Nov 18.
Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric 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 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects 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 control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects.
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.
药物性长QT综合征（diLQTS）是一种药物不良反应，对药物的使用、研发及监管具有重要影响。我们检验了如下假设：控制心脏电特性的关键基因中的常见变异会改变diLQTS的风险。
在一项病例对照研究中，我们纳入了176名来自北美和欧洲的具有欧洲血统的diLQTS患者，其定义为在使用延长QT间期的药物治疗期间记录到尖端扭转型室速。对照样本取自207名具有欧洲血统的患者，这些患者在开始使用延长QT间期的药物治疗期间QT间期延长<50毫秒，以及来自基于人群的KORA研究的837名对照受试者。对受试者成功进行了18个候选基因中1424个单核苷酸多态性（SNP）的基因分型，其中包括1386个标记常见单倍型块的SNP和38个非同义离子通道基因SNP。为进行验证，我们使用了一组病例（n = 57）和具有欧洲血统的基于人群的对照受试者。已知可调节心脏中一种重要钾电流的SNP KCNE1 D85N（rs1805128）预测diLQTS的比值比为9.0（95%置信区间，3.5 - 22.9）。变异等位基因在8.6%的病例、2.9%的药物暴露对照受试者和1.8%的人群对照受试者中存在。在验证队列中，变异等位基因在3.5%的病例和1.4%的对照受试者中存在。
这种高密度候选SNP方法鉴定出一个关键的钾通道易感性等位基因，其可能与罕见的药物不良反应尖端扭转型室速相关。
