GNB3

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 β3 subunit gene ( GNB3 ) induces formation of a splice variant (Gβ3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 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 Bse DI, 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 (χ 2 =22; P =0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolic=105±7, 109±16, and 128±28 mm Hg (mean±SD) for CC , CT , and TT , respectively ( P =0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele ( P =0.006 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 β3 subunit gene in the causation of essential hypertension.

Abstract: Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (≥7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naive youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.

Abstract: Recently, alpha(2)-adrenoceptor activation was shown to play an important role in the vasoconstriction of normal coronary arteries, whereas in the presence of atherosclerosis, the activation of both alpha(1)- and alpha(2)-adrenoceptors reduces coronary blood flow in humans. alpha(2)-Adrenoceptors activate pertussis toxin (PTX)-sensitive G proteins, whereas alpha(1)-adrenoceptors couple to PTX-insensitive G proteins. Thus, the 825T allele of the beta3 subunit of heterotrimeric G proteins, associated with enhanced PTX-sensitive G protein signaling, was expected to determine the alpha(2)-adrenoceptor-, but not the alpha(1)-adrenoceptor-, mediated reduction in coronary blood flow (CBF). Genotyping was performed on 48 individuals. Twelve of the 48 received the alpha(1)-adrenoceptor agonist methoxamine (MTX; 5 mg IC), and 12 received the alpha(2)-adrenoceptor agonist BHT 933 (BHT; 5 mg IC). Twenty-four additional individuals received both MTX and BHT during the same investigational procedure. CBF was calculated on the basis of coronary angiography and intracoronary Doppler flow velocity measurement. Drug-related ischemia was assessed on the basis of ST-segment changes and angina pectoris. In response to BHT, but not to MTX, CBF was reduced to a significantly greater extent in 825T allele carriers (58+/-4%, n=16) than in individuals homozygous for the C825 allele (28+/-4%, n=19, P=0.001). This finding was independent of cholesterol levels, mean arterial blood pressure, and the presence or absence of coronary artery disease. Ischemic events in response to BHT occurred more frequently in 825T allele carriers than in homozygous 825C allele carriers (P=0.01). alpha(2)-Adrenoceptor coronary vasoconstriction is genetically determined and significantly enhanced in GNB3 825T allele carriers.

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 beta3 subunit gene (GNB3) induces formation of a splice variant (Gbeta3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 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 (chi2=22; P=0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolic=105+/-7, 109+/-16, and 128+/-28 mm Hg (mean+/-SD) for CC, CT, and TT, respectively (P=0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele (P=0.006 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 beta3 subunit gene in the causation of essential hypertension.