Shimizu Wataru, Moss Arthur J, Wilde Arthur A M, Towbin Jeffrey A, Ackerman Michael J, January Craig T, Tester David J, Zareba Wojciech, Robinson Jennifer L, Qi Ming, Vincent G Michael, Kaufman Elizabeth S, Hofman Nynke, Noda Takashi, Kamakura Shiro, Miyamoto Yoshihiro, Shah Samit, Amin Vinit, Goldenberg Ilan, Andrews Mark L, McNitt Scott
Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan.
J Am Coll Cardiol. 2009 Nov 24;54(22):2052-62. doi: 10.1016/j.jacc.2009.08.028.
The purpose of this study was to investigate the effect of location, coding type, and topology of KCNH2(hERG) mutations on clinical phenotype in type 2 long QT syndrome (LQTS).
Previous studies were limited by population size in their ability to examine phenotypic effect of location, type, and topology.
Study subjects included 858 type 2 LQTS patients with 162 different KCNH2 mutations in 213 proband-identified families. The Cox proportional-hazards survivorship model was used to evaluate independent contributions of clinical and genetic factors to the first cardiac events.
For patients with missense mutations, the transmembrane pore (S5-loop-S6) and N-terminus regions were a significantly greater risk than the C-terminus region (hazard ratio [HR]: 2.87 and 1.86, respectively), but the transmembrane nonpore (S1-S4) region was not (HR: 1.19). Additionally, the transmembrane pore region was significantly riskier than the N-terminus or transmembrane nonpore regions (HR: 1.54 and 2.42, respectively). However, for nonmissense mutations, these other regions were no longer riskier than the C-terminus (HR: 1.13, 0.77, and 0.46, respectively). Likewise, subjects with nonmissense mutations were at significantly higher risk than were subjects with missense mutations in the C-terminus region (HR: 2.00), but that was not the case in other regions. This mutation location-type interaction was significant (p = 0.008). A significantly higher risk was found in subjects with mutations located in alpha-helical domains than in subjects with mutations in beta-sheet domains or other locations (HR: 1.74 and 1.33, respectively). Time-dependent beta-blocker use was associated with a significant 63% reduction in the risk of first cardiac events (p < 0.001).
The KCNH2 missense mutations located in the transmembrane S5-loop-S6 region are associated with the greatest risk.
本研究旨在探讨KCNH2（hERG）突变的位置、编码类型和拓扑结构对2型长QT综合征（LQTS）临床表型的影响。
以往的研究在研究位置、类型和拓扑结构的表型效应时受限于样本量。
研究对象包括来自213个先证者确诊家庭的858例2型LQTS患者，这些患者共有162种不同的KCNH2突变。采用Cox比例风险生存模型评估临床和遗传因素对首次心脏事件的独立影响。
对于错义突变患者，跨膜孔（S5-环-S6）和N端区域的风险显著高于C端区域（风险比[HR]：分别为2.87和1.86），但跨膜非孔（S1-S4）区域并非如此（HR：1.19）。此外，跨膜孔区域的风险显著高于N端或跨膜非孔区域（HR：分别为1.54和2.42）。然而，对于非错义突变，这些其他区域的风险不再高于C端区域（HR：分别为1.13、0.77和0.46）。同样，非错义突变患者在C端区域的风险显著高于错义突变患者（HR：2.00），但在其他区域并非如此。这种突变位置-类型的相互作用具有显著性（p = 0.008）。位于α螺旋结构域的突变患者的风险显著高于位于β折叠结构域或其他位置的突变患者（HR：分别为1.74和1.33）。随时间使用β受体阻滞剂与首次心脏事件风险显著降低63%相关（p < 0.001）。
位于跨膜S5-环-S6区域的KCNH2错义突变与最大风险相关。
