Polymorphisms in the GNAS Gene as Predictors of Ventricular Tachyarrhythmias and Sudden Cardiac Death: Results From the DISCOVERY Trial and Oregon Sudden Unexpected Death Study.
Polymorphisms in the GNAS Gene as Predictors of Ventricular Tachyarrhythmias and Sudden Cardiac Death: Results From the DISCOVERY Trial and Oregon Sudden Unexpected Death Study.
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DOI：
10.1161/jaha.116.003905
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发表时间：
2016-11-28
影响因子：
5.4
通讯作者：
Siffert W
中科院分区：
文献类型：
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作者：
Wieneke H;Svendsen JH;Lande J;Spencker S;Martinez JG;Strohmer B;Toivonen L;Le Marec H;Garcia-Fernandez FJ;Corrado D;Huertas-Vazquez A;Uy-Evanado A;Rusinaru C;Reinier K;Foldesi C;Hulak W;Chugh SS;Siffert W
基于人群的研究表明，遗传因素导致心脏性猝死（SCD）。在本研究的第一部分，（诊断数据对疾病管理的影响以及遗传多态性与ICD患者室性快速性心律失常的关系[DISCOVERY]试验）进行考克斯回归，以确定编码G蛋白亚基的3个基因中的7个单核苷酸多态性（SNP）在1145例接受植入式心律转复除颤器（ICD）的患者中，GNB 3、GNAQ、GNAS与室性快速性心律失常（VT）相关。在研究的第二部分，进一步研究了来自俄勒冈州SUDS的1335名受试者中与VT显著相关的SNP，这是一项分析SCD原因的基于社区的研究。在DISCOVERY试验中，GNAS基因中的2个SNP的基因型在前瞻性筛选中名义上是显著的，并且当在事后分析中被视为隐性性状时与VT显著相关（c.393C>T中TT vs CC/CT：HR 1.42 [CI 1.11 - 1.80]，P=0.005; c.2273C>T中TT vs CC/CT：HR 1.57 [CI 1.18 - 2.09]，P=0.002）。任一SNP中的TT基因型与HR 1.58（CI 1.26 - 1.99）相关（P=0.0001）。在俄勒冈州SUDS队列中，在加性（P=0.039，OR=1.21 [CI 1.05 - 1.45]）和隐性（P=0.01，OR=1.52 [CI 1.10 - 2.13]）遗传模型下观察到GNAS c.393 C>T与SCD相关的显著证据。 GNAS包含2个与ICD患者VT风险增加相关的SNP，其中1个在基于社区的SCD病例人群中成功复制。据我们所知，这是ICD VT监测确定的基因变异作为SCD替代参数的第一例，并在一般人群中得到证实。 URL：http://www.clinicaltrials.gov。唯一标识符：NCT 00478933。
Population‐based studies suggest that genetic factors contribute to sudden cardiac death (SCD). In the first part of the present study (Diagnostic Data Influence on Disease Management and Relation of Genetic Polymorphisms to Ventricular Tachy‐arrhythmia in ICD Patients [DISCOVERY] trial) Cox regression was done to determine if 7 single‐nucleotide polymorphisms (SNPs) in 3 genes coding G‐protein subunits (GNB3, GNAQ, GNAS) were associated with ventricular tachyarrhythmia (VT) in 1145 patients receiving an implantable cardioverter‐defibrillator (ICD). In the second part of the study, SNPs significantly associated with VT were further investigated in 1335 subjects from the Oregon SUDS, a community‐based study analyzing causes of SCD. In the DISCOVERY trial, genotypes of 2 SNPs in the GNAS gene were nominally significant in the prospective screening and significantly associated with VT when viewed as recessive traits in post hoc analyses (TT vs CC/CT in c.393C>T: HR 1.42 [CI 1.11‐1.80], P=0.005; TT vs CC/CT in c.2273C>T: HR 1.57 [CI 1.18‐2.09], P=0.002). TT genotype in either SNP was associated with a HR of 1.58 (CI 1.26‐1.99) (P=0.0001). In the Oregon SUDS cohort significant evidence for association with SCD was observed for GNAS c.393C>T under the additive (P=0.039, OR=1.21 [CI 1.05‐1.45]) and recessive (P=0.01, OR=1.52 [CI 1.10‐2.13]) genetic models. GNAS harbors 2 SNPs that were associated with an increased risk for VT in ICD patients, of which 1 was successfully replicated in a community‐based population of SCD cases. To the best of our knowledge, this is the first example of a gene variant identified by ICD VT monitoring as a surrogate parameter for SCD and also confirmed in the general population. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00478933.