Few studies have examined to what extent genetic variants of the beta2-adrenoceptor (ADRB2) are involved in the development of hypertension with age, although beta2-adrenergic receptor responsiveness declines in older subjects. To investigate this, 10 common single-nucleotide polymorphisms (SNPs) in the promoter and coding regions of the ADRB2 gene were genotyped in an unrelated population consisting of 2 ethnic groups: European American (EA; n=610) and African American (AA; n=420). ADRB2 haplotypes were estimated by expectation maximization (EM) algorithm-based methods. In the general population for EAs and AAs, the variants of the ADRB2 gene, including the individual SNPs and their haplotypes, were not associated with hypertension. However, there was a significant interaction between age and one of the common haplotypes (haplotype 1) in EAs (P=0.01). Haplotype 1 was associated with protection against hypertension in young (< or =50 years of age) but not in old (>50 years of age) EAs (odds ratio, 0.5; 95% confidence interval, 0.27 to 0.91; P=0.02). This age-specific effect was further supported by the observations that young subjects carrying > or =1 copy of haplotype 1 had significantly lower diastolic blood pressure and nearly 2-fold higher ADRB2 binding density than the noncarriers (P<0.05). With aging, their ADRB2 numbers decreased to the level of the noncarriers, along with increased body mass index (7%; P<0.05) and decreased heart rate (7%; P<0.001). Our study suggests that age is an important modifier for the effects of ADRB2 polymorphisms on ADRB2 function and the development of hypertension.