Prediction of the Risk for Essential Hypertension among Carriers of C825T Genetic Polymorphism of G Protein β3 (GNB3) Gene

Background The guanine nucleotide-binding protein beta polypeptide 3 (GNB3) 825T allele encodes a product that enhances the activation of heterotrimeric G proteins, which is associated with the occurrence of the splice variant Gβ3 s that could play a role in vascular reactivity and hyperproliferation of smooth muscle cells, that makes such proteins attractive candidate gene products for susceptibility to essential hypertension (EH). Objective To predict the risk for EH in individuals with C825T genetic polymorphism of G protein β3 gene. Methods The study consisted of 222 normotensive individuals and 216 hypertensive patients. Individuals were genotyped for C825T genetic polymorphism of G protein β3 gene rs5443 by using restriction fragment length polymorphism. Results Frequencies of C and T alleles were 58.1% and 41.9%, respectively, in the control group compared with 47.7% and 52.3%, respectively, in the hypertensive group. The carriers of rs5443 (T) allele exhibited a significant greater risk for EH compared with the carriers of rs5443 (C) allele (odds ratio = 1.5, 95% confidence interval = 1.2–2.0). Conclusion T allele is a risk factor for EH in the Egyptian population, which may be used as a prognostic and a therapeutic target of prophylaxis.

Genetic Variation in Female BMI Increases with Number of Children Born but Failure to Replicate Association betweenGNβ3Variants and Increased BMI in Parous Females

Objective:As post-pregnancy weight retention in women is a risk factor for obesity later in life, we assessed the changes in magnitude of genetic and environmental variation in BMI due to parity in an Australian female sample, comprising 11,915 female twins and their sisters.Results:Total variance of BMI increased with parity, primarily driven by an increase in nonadditive genetic variance. This finding was of particular interest given Gutersohn et al's (2000) report of recessive association between post-partum weight retention and the 825T allele of theGNβ3gene (rs5443) at 12p13.31. Hence, we attempted to replicate this association and test an additional three SNPs also located near or onGNβ3(rs10744716 (upstream), rs5442 (exon 10), rs5446 (exon 11)) in a sample of 3131 females and 1693 males from 2585 twin families. No association was found between these SNPs among females, even when allowing for a genotype by parity effect. However, a significant association was observed among males for rs10744716 (χ22= 10.22,p= 0.006; effect size = 0.47kg/m2), representing a novel association between a region upstream ofGNβ3and male BMI.

Association between Polymorphisms in Genes Related to Common Adult Diseases and Fetal Growth

A close relationship between size at birth and occurrence of common adult diseases has been reported. As an explanation of this relationship, it has been hypothesized that the thrifty genotypes cause changes in growth efficiency during fetal period and diseases in later life. In the present study, we examined the association of fetal growth with genetic polymorphisms within the IGF2-INS-TH region and in the G protein gene. Analysis of the genes in the IGF2-INS-TH region suggests that thrifty genotype has the effect of accelerating fetal growth, but at the same time a genomic imprinting mechanism is also involved. Analysis of the G protein β3 subunit gene unveiled that the 825T allele in the mother may exert influence on fetal metabolic environment. By extending the analysis to other genomic regions related to common adult diseases using the same technique, the detailed role of genetic polymorphisms may be elucidated.

A Splice Variant ofGNB3and Peripheral Polyneuropathy in Type 1 Diabetes

Abnormalities in G protein-mediated signal transduction could be involved in the pathogenesis of diabetic polyneuropathy (DPN). Here we test whether the GNB3 C825T variant confers susceptibility to DPN in type 1 diabetes (T1D) mellitus. The C825T marker of GNB3 was genotyped in genomic DNA from blood isolated from a total of 213 Russian T1D patients 100 of whom had DPN. Compared to carriers of the wild-type genotypeC/C, diabetic subjects with genotypesT/Thad significantly increased risk to develop DPN (Odds Ratio (OR) of 4.4 (p= 0.001). The adjustment for confounders (age, sex, body mass index, cigarette smoking, and level of reduced glutathione) resulted in increase of the OR value up to 4.72 (p= 8.9 × 10-3). The further adjustment for hypertension abolished the association between the GNB3 C825T variant and DPN (OR = 1.95,p= 0.18). Non-complicated subjects homozygous forT/Tshowed decreased levels of reduced glutathione (T/T: 69 ± 19 vs.C/T: 74 ± 19 vs.C/C: 77 ± 17 μmol/l,p= 0.009). Compared to other GNB3 variants, carriers of theT/Tgenotype had elevated systolic blood pressure (SBP) in complicated (T/T: 115.8 ± 9.1 vs.C/T: 113.3 ± 8.2 vs.C/C: 109.5 ± 8.7 mm/Hg,p= 0.036) and non-complicated T1D patients (T/T: 118.1 ± 8.4 vs.C/T: 116.9 ± 7.9 vs.C/C: 112.1 ± 7.2 mm/Hg,p= 0.02). However, the significance of association between the C825T polymorphism was lost after adjustment for confounding risk factors. In conclusion, the 825T allele of GNB3 is likely to accelerate the development of DPN through primary effects to SBP and hypertension in subgroups of diabetic patients with impaired neurovascular function and advanced oxidative stress.