The 825C/T Polymorphism of the G-Protein Subunit β3 Is Not Related to Hypertension

Abstract

Abstract-A polymorphism at position 825 (C3 T) of the cDNA that encodes the ␤3 subunit (GNB3) of the pertussis toxin-sensitive G protein was recently shown to be associated with human hypertension. To verify this finding and to investigate whether this polymorphism could also be associated with coronary heart disease, we analyzed the GNB3 variant in subjects from 2 previously described studies: Projet d'Etude des Gènes de l'hypertension Artérielle Sévère à modérée Essentielle (PEGASE), a case-control study of moderate to severe hypertension (681 cases and 308 controls), and Etude Cas-Témoins de l'Infarctus du Myocarde (ECTIM), a case-control study of myocardial infarction (MI) (564 cases and 633 controls). Genotyping was performed with allele-specific oligonucleotides. Genotype and allele frequencies were in Hardy-Weinberg equilibrium in all groups. Allele and genotype frequencies did not differ significantly between case patients with essential hypertension or MI and control subjects. In the ECTIM study, the 825T allele frequencies in cases and controls from Belfast, Northern Ireland, were 0.31 and 0.30 (Pϭ0.79), respectively; the corresponding frequencies in cases and controls from France were 0.33 and 0.31 (Pϭ0.30), respectively. In the PEGASE study, the 825T allele frequency was 0.35 in female and male cases and 0.31 in male normotensive controls (Pϭ0.12). The odds ratios for hypertension (PEGASE) and MI (ECTIM) associated with T-allele carrying were 1.23 (95% confidence interval, 0.94 to 1.62; Pϭ0.13) and 1.11 (95% confidence interval, 0.88 to 1.39; Pϭ0.37), respectively. There was no association of the GNB3 polymorphism with early onset of hypertension, familial history of hypertension, or blood pressure level. We conclude that the 825C/T polymorphism of the GNB3 gene did not contribute in any important way to the risk of essential hypertension or MI in these studies. 4 have demonstrated that immortalized B lymphoblasts of patients with essential hypertension, which display enhanced NHE-1 activity, also showed increased activity of pertussis toxin-sensitive G proteins. Variations in NHE-1 transcripts could not be detected, 5 and polymorphisms in genes that encode the subunits of trimeric G proteins, such as G␣ i2 , G␣ i3 , G␤ 1 , and G␤ 2 , 6 have been ruled out. Subsequently, Siffert et al 7 were able to localize a polymorphism at position 825 (C3 T) of the cDNA that encodes the ␤3 subunit (GNB3) of the pertussis toxin-sensitive G protein and demonstrated that the 825T allele was significantly associated with hypertension. However, given the expected small effect of susceptibility genes involved in human essential hypertension, a large number of patients must be studied before it can be definitively established that a genotype-phenotype association exists. Therefore, we investigated the 825C/T polymorphism of GNB3 in relation to hypertension and extended our study to patients with coronary heart disease (CHD). Methods PopulationsThe ECTIM Study The PEGASE StudyHypertensive subjects (nϭ681) were recruit...

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

“…36 Published studies on the possible influence of the GNB3 C825T polymorphism reported inconsistent results. The 825T allele was associated with increased blood pressure [40][41][42] or increased risk of hypertension 22,43,44 in Germans, 22,39,42,44 Australian White hypertensive patients 41 and Caribbean or West African Blacks, 43 but not in French, 22 Irish, 22 Japanese 45,46 or African Americans. 47 These discordant findings suggest that ethnic or genetic background, 8 lifestyle or various environmental factors may modulate the potential effect of the C825T allele on blood pressure.…”

“…From the published DNA sequence of the GNB3, 20 we amplified a 268 base pair fragment incorporating the polymorphic site with the use of two primers as described by Siffert et al 21 We previously published the technical procedures, which we implemented for DNA amplification and determination of the genotypes by allele-specific hybridization. 22 …”

Genetics of arterial hypertension and hypotension

“…Several groups have reproduced the original finding that the GNB3 825T allele is associated with hypertension, whereas other groups refuted that finding Schunkert et al 1998;Benjafield et al 1998;Brand et al 1999;Dong et al 1999, to cite but a few). The fact that there is a considerable variance in genotype distribution within different ethnicities (Siffert et al 1999) creates a major problem.…”

Cardiovascular diseases and G-protein β3 subunit gene (GNB3) in the era of genomewide scans

“…In addition, the early studies in Caucasian populations have demonstrated that a distribution of the C825T genotypes among subjects of European origin ensures appropriate epidemiological representation of each variant in population samples of different size. [6][7][8] …”

“…In addition, the early studies in Caucasian populations have demonstrated that a distribution of the C825T genotypes among subjects of European origin ensures appropriate epidemiological representation of each variant in population samples of different size. [6][7][8] In light of these findings, a selection of this candidate by Olszanecka et al 9 in their study on genetic determinants of cardiovascular phenotypes is fully justified. They examined associations of the C825T polymorphism with blood pressures as well as indicators of left ventricular structure and function in two generations of Caucasian families.…”