G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine: results of A-HeFT.
G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine: results of A-HeFT.
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G 蛋白 beta-3 亚基基因型预测固定剂量硝酸异山梨酯和肼苯达嗪的益处增强：A-HeFT 的结果。
DOI：
10.1016/j.jchf.2014.04.016
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
Feldman,ArthurM
中科院分区：
文献类型：
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作者：
McNamara,DennisM;Taylor,AnneL;Tam,SWilliam;Worcel,Manuel;Yancy,ClydeW;Hanley-Yanez,Karen;Cohn,JayN;Feldman,ArthurM
本研究的目的是评价鸟嘌呤核苷酸结合蛋白(G蛋白)、β-3亚单位(GNB3)基因在非裔美国人心力衰竭试验(A-HEFT)中对硝酸异山梨酯和肼丙嗪固定剂量组合(FDC I/H)疗效的影响。存在C825T多态，T等位基因与增强的α-肾上腺素能张力有关，在非裔美国人中更为普遍。方法对350名参加遗传子研究(GRAHF[非裔美国人心力衰竭的遗传风险评估])的受试者进行C825T多态基因分型。结果GRAHF患者中60%为男性，25%为缺血性，97%为纽约心脏协会功能III级，年龄为57±13岁，平均合格左心室射血分数为0.24±0.06。在GNB3型中，TT型184例(53%)，CT型137例(39%)，CC型29例(8%)。在GNB3TT受试者中，FDC I/H改善了CS(FDC I/H=0.50±1.6；安慰剂−=0.11±1.8，P=0.02)、生活质量(FDC I/H=0.69±1.4；安慰剂I/H=0.24±1.5，P=0.04)和无事件生存(危险比：0.51，P=0.047)，但对C等位基因的受试者(CS，FDC I/H=−0.05±1.7；安慰剂：−=0.09±1.7，P=0.87；QOL，FDC I/H=0.28±1.5；安慰剂：=0.14±1.5，P=0.56；无事件生存，P=0.35。GNB3基因在FDC I/H靶向治疗中的作用值得进一步研究。
ObjectivesThe purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial).BackgroundGNB3 plays a role in alpha2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans.MethodsA total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets.ResultsThe GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 ± 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 ± 0.06. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H = 0.50 ± 1.6; placebo = −0.11 ± 1.8, p = 0.02), QoL (FDC I/H = 0.69 ± 1.4; placebo = 0.24 ± 1.5, p = 0.04), and event-free survival (hazard ratio: 0.51, p = 0.047), but not in subjects with the C allele (for CS, FDC I/H = −0.05 ± 1.7; placebo = −0.09 ± 1.7, p = 0.87; for QoL, FDC I/H = 0.28 ± 1.5; placebo = 0.14 ± 1.5, p = 0.56; and for event-free survival, p = 0.35).ConclusionsThe GNB3 TT genotype was associated with greater therapeutic effect of FDC I/H in A-HeFT. The role of the GNB3 genotype for targeting therapy with FDC I/H deserves further study.