Yogev Dotan, Basheer Maamoun, Blotnick Simcha, Caraco Yoseph, Muszkat Mordechai
aDepartment of Medicine, Division of Clinical Pharmacology bCentral Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Pharmacogenet Genomics. 2015 Nov;25(11):555-63. doi: 10.1097/FPC.0000000000000174.
The ADRB1 389 polymorphism affects responses to the β-1 adrenergic receptor (β1AR) agonist in vitro. Previous studies on its effect on the response to dobutamine stress echocardiography were conflicting. In addition, sex differences in the response to dobutamine have been suggested. The aim of this study was to determine whether the ADRB1 389 polymorphism affects the hemodynamic response to dobutamine in healthy individuals including men and women.
Healthy individuals were recruited according to their ADRB1 49 and 389 genotypes [15 Arg389Arg, 10 Gly389Arg, and 10 Gly389Gly individuals, (all Ser49Ser), 21 men and 14 women]. Dobutamine was infused at 2, 4, and 6 mcg/kg/min. Standardized exercise was performed during the last minute of each infusion.
Resting heart rate (HR) response to 6 mcg/kg/min dobutamine (ΔHR) was 4.7-fold larger in Arg389Arg than in Gly389Gly [(mean ± SD) 12.95 ± 6.99, 2.75 ± 1.65 bpm, respectively, PANOVA=0.012]. Renin response to dobutamine (ΔRenin) was 3.9-fold greater in Arg389Arg than in Gly389Gly (PANOVA=0.032). Among Arg389Gly heterozygotes, ΔHR and ΔRenin were not significantly different from either homozygote group. In multivariate analysis for ΔHR variance, significant contributions were observed for genotype (P=0.011), baseline HR (P=0.011), and borderline effect for sex (P=0.049).
In healthy individuals, HR and renin responses to dobutamine were more than three-fold greater among ADRB1 Arg389 compared with Gly389 homozygotes. Future studies on the effect of the ADRB1 389 polymorphism on dobutamine stress echocardiography should compare Arg389 and Gly389 homozygotes.
ADRB1 389多态性在体外影响对β-1肾上腺素能受体（β1AR）激动剂的反应。先前关于其对多巴酚丁胺负荷超声心动图反应影响的研究结果相互矛盾。此外，已有研究提示多巴酚丁胺反应存在性别差异。本研究旨在确定ADRB1 389多态性是否影响包括男性和女性在内的健康个体对多巴酚丁胺的血流动力学反应。
根据ADRB1 49和389基因型招募健康个体[15名Arg389Arg、10名Gly389Arg和10名Gly389Gly个体，（均为Ser49Ser），21名男性和14名女性]。以2、4和6微克/千克/分钟的速度静脉输注多巴酚丁胺。在每次输注的最后一分钟进行标准化运动。
在对6微克/千克/分钟多巴酚丁胺的静息心率（HR）反应（ΔHR）方面，Arg389Arg个体比Gly389Gly个体大4.7倍[（均值±标准差）分别为12.95±6.99、2.75±1.65次/分钟，P方差分析=0.012]。对多巴酚丁胺的肾素反应（Δ肾素）在Arg389Arg个体中比Gly389Gly个体大3.9倍（P方差分析=0.032）。在Arg389Gly杂合子中，ΔHR和Δ肾素与任何一个纯合子组相比均无显著差异。在对ΔHR方差的多变量分析中，观察到基因型（P=0.011）、基线HR（P=0.011）有显著贡献，性别有临界效应（P=0.049）。
在健康个体中，与Gly389纯合子相比，ADRB1 Arg389个体对多巴酚丁胺的HR和肾素反应大三倍以上。未来关于ADRB1 389多态性对多巴酚丁胺负荷超声心动图影响的研究应比较Arg389和Gly389纯合子。
