G-Protein β3 Subunit Gene ( GNB3 ) Variant in Causation of Essential Hypertension

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 β3 subunit gene ( GNB3 ) induces formation of a splice variant (Gβ3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 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 Bse DI, 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 (χ ² =22; P =0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolic=105±7, 109±16, and 128±28 mm Hg (mean±SD) for CC , CT , and TT , respectively ( P =0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele ( P =0.006 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 β3 subunit gene in the causation of essential hypertension.