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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 b 1 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 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 b 1 adrenergic receptor. For comparison, polymorphisms in the b 2 and b 3 adrenergic receptors were also evaluated. The Ser49Gly polymorphism was significantly associated ( ) with resting P p .0004 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 b 1 adrenergic receptor nor polymorphisms in the b 2 and b 3 adrenergic receptors were associated with resting heart rate. The heritability of heart rate was 39.7% 7.1% (). 5 7 P !10. [ABSTRACT FROM AUTHOR]