Department of Cardiology, Contilia Heart and Vessel Centre, St. Marien-Hospital Mülheim, Mülheim, Germany
Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.
J Am Heart Assoc. 2016 Nov 28;5(12):e003905. doi: 10.1161/JAHA.116.003905.
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.
基于人群的研究表明，遗传因素与心脏性猝死（SCD）有关。
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 患者室性心律失常的关系[发现]试验）中，进行 Cox 回归以确定编码 G 蛋白亚单位的 3 个基因中的 7 个单核苷酸多态性（SNP）是否与 1145 名接受植入式心脏复律除颤器（ICD）的患者的室性心动过速（VT）相关。在研究的第二部分中，在俄勒冈州 SUDs 的 1335 名受试者中进一步研究了与 VT 显著相关的 SNP，这是一项基于社区的研究，分析了 SCD 的原因。在发现试验中，GNAS 基因中 2 个 SNP 的基因型在前瞻性筛查中具有名义显著性，并且在事后分析中作为隐性特征与 VT 显著相关（c.393C>T 中的 TT 与 CC/CT：HR 1.42[CI 1.11-1.80]，P=0.005；c.2273C>T 中的 TT 与 CC/CT：HR 1.57[CI 1.18-2.09]，P=0.002）。任一位点的 TT 基因型与 HR 为 1.58（CI 1.26-1.99）（P=0.0001）相关。在俄勒冈州 SUDs 队列中，在加性遗传模型下（P=0.039，OR=1.21[CI 1.05-1.45]）和隐性遗传模型下（P=0.01，OR=1.52[CI 1.10-2.13]），GNAS c.393C>T 与 SCD 显著相关。
GNAS 含有 2 个 SNP，与 ICD 患者 VT 风险增加相关，其中 1 个在 SCD 病例的基于社区的人群中成功复制。据我们所知，这是通过 ICD VT 监测作为 SCD 替代参数识别的基因变异的第一个例子，并且在一般人群中也得到了证实。
