Association of a human G-protein β3 subunit variant with hypertension

Hypertension is a common disorder of multifactorial origin that constitutes a major risk factor for cardiovascular events such as stroke and myocardial infarction. Previous studies demonstrated an enhanced signal transduction via pertussis toxin-sensitive G proteins in lymphoblasts and fibroblasts from selected patients with essential hypertension. We have detected a novel polymorphism (C825T) in exon 10 of the gene encoding the p3 subunit of heterotrimeric G proteins (GNB3). The T allele is associated with the occurrence of a splice variant, GNB3–S (encoding Gβ3–s), in which the nucleotides 498–620 of exon 9 are deleted. This in-frame deletion causes the loss of 41 amino acids and one WD repeat domain of the Gβ subunit. By western-blot analysis, Gβ3–s appears to be predominantly expressed in cells from individuals carrying the T allele. Significant enhancement of stimulated GTPγS binding to Sf9 insect cells expressing Gβ3–s together with Ga 2 and Gy5 indicates that this splice variant is biologically active. Genotype analysis of 427 normotensive and 426 hypertensive subjects suggests a significant association of the T allele with essential hypertension.