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

Abstract

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.

Interaction between GNB3 C825T and ACE I/D polymorphisms in essential hypertension in Koreans

“…Another possibility is that the contribution of GNB3 gene to the pathogenesis of EH may be less significant than initially implied in the previous population studies, partly because of ethnicity-specific combination of genetic backgrounds and environmental factors. The frequency of the 825T allele in the present subjects was remarkably higher (50.1%) than that reported in Amerindians (26.5%) and western Europeans (29.6%), 32 but was similar to that described in Taiwan Han Chinese (54.3%), 29 northern Chinese (52%), 25 Canadian Oji-Cree (50.1%) 37 and Japanese populations (49%). 33 On the other hand, the frequency of the 825T allele in our population was much lower than that in Africans (79%), whereas it was slightly higher than the southern Chinese population (43.2%) reported by Siffert et al 37 As for the ACE I/D polymorphism, the D allele of the ACE gene is reportedly associated with the development of EH.…”

“…34 On the contrary, a number of studies of Caucasians have confirmed an association between the 825T allele and EH. 25 In addition, a statistical significant interaction between the 825T allele and obesity was investigated for SBP in the Brazilian population. 35 Interestingly, in contrast to the above findings, the C rather than the T allele was associated with increasing SBP without gender effect in Canadian Oji-Cree.…”

“…The recent reports indicate that the presence of GNB3 825T carriers associated with the increased activity of NHE in hypertensive subjects. 21,23 To date, association studies have shown that the GNB3 825T allele is significantly associated with EH in Africans 24 and Caucasians, 25 and it is also associated with variations in BP. However, the effects of the 825T allele on variations in EH and BP among Asian populations have presented conflicting results.…”

GNB3 gene C825T and ACE gene I/D polymorphisms in essential hypertension in a Kazakh genetic isolate

“…Siffert et al 10 described a C825T polymorphism in G-protein b-3 subunit (GNB3), the gene encoding for the b-3 subunit of heterotrimetric G-proteins, and reported a significant association of the 825T allele with EH in 426 unselected patients in Germany. This genetic finding was supported by other associate study in Europeans, 11 Australian white populations, 12 and Canadian aborigines, 13 but in African Americans 14 have proved conflicting.…”

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.…”