Abstract-Essential hypertensives display enhanced signal transduction through pertussis toxin-sensitive G proteins. The T allele of a C825T variant in exon 10 of the G protein ␤3 subunit gene (GNB3) induces formation of a splice variant (G␤3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequencyϭ0.31 versus 0.25 in control). To confirm and extend this finding in a different setting, we performed an association study in Australian white hypertensives. This involved an extensively examined cohort of 110 hypertensives, each of whom were the offspring of 2 hypertensive parents, and 189 normotensives whose parents were both normotensive beyond age 50 years. Genotyping was performed by polymerase chain reaction and digestion with BseDI, which either cut (C allele) or did not cut (T allele) the 268-bp polymerase chain reaction product. T allele frequency in the hypertensive group was 0.43 compared with 0.25 in the normotensive group ( 2 ϭ22; Pϭ0.00002; odds ratioϭ2.3; 95% CIϭ1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolicϭ105Ϯ7, 109Ϯ16, and 128Ϯ28 mm Hg (meanϮSD) for CC, CT, and TT, respectively (Pϭ0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele (Pϭ0.006 for systolic and 0.0003 for diastolic by ANOVA) than they were in male hypertensives. In conclusion, the present study of a group with strong family history supports a role for a genetically determined, physiologically active splice variant of the G protein ␤3 subunit gene in the causation of essential hypertension.

1. A missense mutation (Trp64Arg) in the beta 3-adrenoceptor (beta 3-AR) gene has been associated with weight gain, insulin resistance and earlier-onset non-insulin-dependent diabetes mellitus (NIDDM), but the strength of these associations varies considerably between populations and the functional significance of Trp64Arg remains unclear. 2. The Trp64Arg mutation was investigated in obese NIDDM (n = 50) and obese non-diabetic (n = 53) subjects by polymerase chain reaction (PCR) amplification of genomic DNA and digestion of the 210 bp product by BstOI. The Arg allele was found in 22.3% of all subjects, but there were no homozygotes for the mutation. Non-diabetic subjects heterozygous for the mutation were more obese and Trp/Arg diabetics had a slightly younger age of onset of NIDDM (47 vs 51 years, respectively), but there were no significant differences in mutation frequency between the two groups. Metabolic parameters (e.g. fasting lipids and glycaemic control) were similar among diabetic subjects with and without the Trp64Arg mutation. 3. In conclusion, the frequency of the Trp64Arg mutation of the beta 3-AR was higher in this obese population compared with some previous studies, but there was no evidence that Trp64Arg confers an increased susceptibility to NIDDM among obese insulin-resistant subjects or that diabetics with the mutation fare worse in terms of lipid or glucose metabolism.