High Blood Press Cardiovasc Prev 2004; 11 (3): 107-112 REVIEW ARTICLE 1120-9879/04/0003-0107/$31.00/0 © 2004 Adis Data Information BV. All rights reserved. G-Protein β 3 -Subunit Gene C825T Polymorphism and Cardiovascular Risk Michelangelo Sartori, Emanuela Parotto, Elisa Pagnin, Francesca Cattelan, Giulio Ceolotto, Italia Papparella, Livia Lenzini, Lorenzo A. Cal` o and Andrea Semplicini Clinica Medica 4, Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy Contents Abstract ............................................................................................................... 107 1. C825T Polymorphism and Hypertension ................................................................................ 108 2. C825T Polymorphism and Left Ventricular Hypertrophy .................................................................. 109 3. C825T Polymorphism and Obesity ..................................................................................... 109 4. C825T Polymorphism and Insulin Resistance ............................................................................ 110 5. C825T Polymorphism and Diabetic Nephropathy ....................................................................... 110 6. Conclusions ........................................................................................................ 111 Hypertension is a common disorder of multifactorial origin that constitutes a major risk factor for cardiovas- Abstract cular events such as stroke and myocardial infarction. The subunits of the heterotrimeric G proteins are attractive candidate gene products for both susceptibility to essential hypertension and interindividual variations in blood pressure. A polymorphism (825C/T) in exon 10 of the GNB3 gene, encoding for the Gβ3 subunit, has recently been described. The 825T allele is associated with alternative splicing of the gene and formation of a truncated but functionally active β3 subunit. Carriers of the 825T allele appear to be at an increased risk of hypertension, obesity, insulin resistance and left ventricular hypertrophy. Moreover, 825T allele carriers respond with a larger decrease in blood pressure to therapy with a thiazide diuretic and with clonidine. The GNB3 825T allele may be regarded as a potential genetic marker for better defining the risk profile of hypertensive patients, but further studies are needed to precisely define the impact of the T allele on the prognosis of hypertensive patients. Both genetic and environmental factors contribute to the patho- brane receptors to intracellular second messengers. [5] G-protein signalling is triggered by ligand-induced conformational changes genesis of essential hypertension. [1] Hypertension is about twice as of intracellular portions of the receptor that promote exchange of common in subjects who have one or two hypertensive parents, guanosine 5′-diphosphate (GDP) for GTP on the Gα subunit of the and many epidemiological studies suggest that genetic factors heterotrimeric G protein. [5] This is followed by dissociation of the account for approximately 30% of the variation in blood pressure GTP-bound Gα from the Gβγ dimer. [6] The dissociated subunits in various populations. [2] Single nucleotide gene polymorphisms, can then interact with effector molecules to propagate the intracel- whose products are involved in blood pressure regulation, have lular signal. [6] been associated with hypertension. [3] In particular, genes coding Many of the actions of vasoconstrictors, such as Ang II, are for G-protein subunits may be involved in the pathogenesis of exerted through Gαq protein, which stimulates phospholipase C, hypertension since their products are the intracellular effectors of inositoltriphosphate, and Ca 2+ mobilisation, leading to smooth many vasoconstrictor hormones, such as angiotensin II (Ang II) muscle cell contraction. [7] and endothelin. [4] Heterotrimeric G proteins, so called for their ability to bind guanosine 5′-triphosphate (GTP) when active, are Siffert et al. [8] described a C825T polymorphism in the GNB3 formed by three different subunits (α, β, γ) and couple transmem- gene encoding the β3 subunit of heterotrimeric G proteins, with