A Polymorphism in the β1 Adrenergic Receptor Is Associated with Resting Heart Rate

Abstract

Resting heart rate is significantly associated with cardiovascular morbidity and mortality. However, the extent to which resting heart rate is genetically determined is poorly understood, and no genes have been found that contribute to variation in resting heart rate. Because signaling through the beta1 adrenergic receptor is a key determinant of cardiac function, we tested whether polymorphisms in this receptor are associated with resting heart rate. A cohort of >1,000 individuals of Chinese and Japanese descent, from nuclear families, was genotyped for two polymorphisms, resulting in a serine/glycine substitution at amino acid 49 (Ser49Gly) and an arginine/glycine substitution at residue 389 (Arg389Gly), in the beta1 adrenergic receptor. For comparison, polymorphisms in the beta2 and beta3 adrenergic receptors were also evaluated. The Ser49Gly polymorphism was significantly associated (P=.0004) with resting heart rate, independent of other variables, such as body-mass index, age, sex, ethnicity, exercise, smoking, alcohol intake, hypertension status, and treatment with beta blockers. The data support an additive model in which individuals heterozygous for the Ser49Gly polymorphism had mean heart rates intermediate to those of either type of homozygote, with Ser homozygotes having the highest mean heart rate and with Gly homozygotes having the lowest. Neither the Arg389Gly polymorphism in the beta1 adrenergic receptor nor polymorphisms in the beta2 and beta3 adrenergic receptors were associated with resting heart rate. The heritability of heart rate was 39.7% +/- 7.1% (P<10-7).

Genetics of arterial hypertension and hypotension

“…The Ser49Gly polymorphism, however, did not affect blood pressure (Bengtsson et al 2001a,b). In Caucasians, but not in other ethnicities, this result has been confirmed once ) and contradicted by other investigators (Büscher et al 2001;Ranade et al 2002;O'Shaughnessy et al 2000;Sofowora et al 2003).…”

β-Adrenergic receptor gene polymorphisms and hemodynamic response to dobutamine during dobutamine stress echocardiography

“…In addition, our findings are largely consistent with the literature in that b 1 -AR codon 389 genotype does not appear to influence HR response to b-receptor agonists, antagonists or exercise, nor does it appear to affect resting HR. [4][5][6][18][19][20][21] Taken together, these data in myriad patient populations suggest that while the functional effects of the b 1 -AR codon 389 polymorphism have been documented in numerous settings, it seems now it may be clearly concluded that this polymorphism does not affect HR, or its responses to agonists, antagonists or exercise.…”

β-Adrenergic receptor gene polymorphism is a genetic risk factor for cardiovascular disease: a cohort study with hypertensive patients

“…[13][14][15] Several functional analyses have addressed these SNPs; for example, participants with the Gly allele in the Ser49Gly polymorphism of b 1 ADR have been reported to have a lower heart rate. 16 In vitro studies of isoproterenol stimulation showed that Arg389 in b 1 ADR produces higher levels of adenylyl cyclase activity, resulting in enhanced cardiac sensitivity to catecholamines. 17 The Gly16 and Glu27 polymorphisms in b 2 ADR have been associated with sympathetic overactivity, as reflected by high plasma norepinephrine levels.…”