Positional genomic analysis identifies the β₂-adrenergic receptor gene as a susceptibility locus for human hypertension

Background - After genome-wide linkage analyses of blood pressure levels, we resequenced 5 positional candidate genes in a linkage region on chromosome 5 and genotyped selected variants in several family samples from Rochester, Minn. Methods and Results - In a sample of 55 pedigrees containing ≥ 1 sibling-pair(s) discordant for systolic blood pressure, polymorphisms within the β₂-adrenergic receptor gene (Arg16Gly, P=0.009) and the glutathione peroxidase 3 gene (-302G→A, P=0.037; -623A→C, P=0.013) were significantly related to blood pressure levels. In a second sample of 298 nuclear families (n=1283 individuals), the Arg16Gly polymorphism was significantly associated with diastolic blood pressure in family-based analyses (P=0.016) and with both diastolic (P=0.009) and mean arterial blood pressure (P=0.038) in analyses of the parental generation only. Neither polymorphism in the glutathione peroxidase 3 gene was associated with blood pressure levels in this sample. An additional 291 families (n = 1240 individuals) were added to the nuclear family sample, and the Gln27Glu polymorphism in the β₂-adrenergic receptor gene was significantly associated with both systolic (P=0.034) and mean arterial blood pressure (P=0.035) in the parental generation of the combined 589 families. The frequencies of both the Gly16 and Glu27 alleles were higher in hypertensives than in normotensives (0.649 versus 0.604 and 0.490 versus 0.429, respectively), and the odds ratio for the occurrence of hypertension was 1.80 (95% confidence interval, 1.08 to 3.00; P=0.023) for the Glu27 allele. Conclusions - The results of this study provide support for further detailed investigations of the mechanistic pathways by which variations in the β₂- adrenergic receptor gene may influence blood pressure levels.