The gain-of-function G389R variant of the β1-adrenoceptor does not influence blood pressure or heart rate response to β-blockade in hypertensive subjects

Mutation scanning of the β₁-adrenoceptor gene has identified a polymorphism, G389R, that markedly affects G-protein coupling of the receptor and resulting cAMP production. We have investigated the effect of this functionally active polymorphism on clinical response to β-adrenoceptor blockade. Two cohorts of untreated hypertensive patients randomly assigned to a β₁-selective β-blocker at the start of antihypertensive therapy were studied retrospectively to see if the G389R polymorphism influenced the response in terms of blood pressure and heart rate. The blood pressure and heart rate responses to treatment were assessed 4 weeks later and compared with the G389R genotype, ascertained by PCR/restriction fragment length polymorphism. The falls in blood pressure and heart rate for the first group (n = 92) by genotype were: GG, 20.1±3.5/13.9±2.7 mmHg (systolic/diastolic blood pressure), 18.4±2.2 beats/min; GR, 20.0±2.2/15.0±1.3 mmHg, 16.5±1.5 beats/min; RR, 20.8±2.3/13.4±1.1 mmHg, 16.0±1.4 beats/min. For the second group (n = 55) the corresponding falls were: GG, 17.0±4.3/11.2±3.4 mmHg, 12.0±3.5 beats/min; GR, 16.6±1.8/14.4±1.1 mmHg, 13.1±2.1 beats/min; RR, 18.0±1.6/13.0±1.4 mmHg, 14.4±1.4 beats/min. The G389R genotype also failed to have a significant effect on pretreatment blood pressure or heart rate in either group. These data suggest that, despite clear functional differences between the G389R receptor variants expressed in vitro, the polymorphism does not affect the haemodynamic response of hypertensive subjects to chronic β₁-adrenoceptor blockade.