Association between a polymorphism in the G protein beta3 subunit gene (GNB3) with arterial hypertension but not with myocardial infarction

OBJECTIVE: A polymorphism at position 825(C-->T) of the G protein beta3 (GNB3) gene was found to be associated with enhanced transmembrane signalling as well as with an increased prevalence of arterial hypertension. The aim of the present study was to further investigate the association of the GNB3 C825T allele status with arterial hypertension in a large population-based sample and its association with specific end organ damage, i.e. myocardial infarction (MI). METHODS: Individuals from a population-based sample (n=2052) and patients suffering from premature MI (age at first MI < or = 60 years, n = 606) were studied by questionnaire as well as by physical examination and biochemical analyses. RESULTS: In the population-based sample, the prevalence of arterial hypertension (blood pressure > or = 160/95 mmHg and/or antihypertensive medication) was higher in individuals with the TT genotype (41.8%) as compared to heterozygote individuals (36.6%) or those with the CC genotype (32.75%) (P = 0.02). This association was predominantly found in men. Moreover, men without antihypertensive medication carrying the TT genotype showed higher diastolic blood pressure than those carrying the CC genotype (86.5 vs. 83.7 mmHg, P = 0.04). However, the genotype distribution and the allele frequencies were similar in both, the population-based and the MI patient sample. Furthermore, neither the age at the time of MI nor the location of the MI were related to the genotype distribution. Similarly, gender and age stratified analyses did not show any association of the GNB3 genotype and MI. CONCLUSIONS: In male individuals from a large population-based sample, the T allele of the GNB3 polymorphism was associated with arterial hypertension. However, the effects of the GNB3 825T allele on blood pressure were small and did not translate to a clinically relevant increase of risk for MI.     

缺血性脑卒中患者G蛋白β3亚单位基因C825T多态性及相关危险因素的研究

目的　观察缺血性脑卒中患者G蛋白 β 3亚单位基因 (GNB3)C82 5T多态性和相关危险因素 ,探讨遗传和环境相互作用在缺血性脑卒中发病机制中的作用。方法　急性缺血性脑卒中患者 72例 ,并按性别、年龄配对设对照组。用聚合酶链反应 (PCR)方法扩增目的基因 ,用限制性内切酶 (BseDI)酶切PCR产物用于基因分型 ,同时观察血压、体重指数、饮酒、膳食、性格等。结果　脑卒中组GNB3C82 5T基因型分布 (基因型频率CC =0 .32 ,CT =0 .5 8,TT=0 .10 )与对照组比较 ,差异有显著性意义 (基因型频率CC =0 .6 5 ,CT =0 .32 ,TT =0 .0 3;χ2 =14 .6 ,P <0 .0 1) ,但在脑卒中患者中有或无原发性高血压亚组之间基因型分布无差异。logistic回归分析显示 ,与脑卒中发病有关联的是收缩压 (SBP)、GNB382 5T等位基因、饮酒和空腹血糖 (FPG)升高。结论　SBP、FPG增高、饮酒和GNB3C82 5T多态性的T等位基因可能是缺血性脑卒中发病的危险因素 ,GNB382 5T等位基因对脑卒中的影响不依赖于血压、饮酒等其他危险因素 ,可能是缺血性脑卒中的独立危险因子。     

G protein beta3 subunit gene 825T allele is associated with increased left ventricular mass in young subjects with mild hypertension.

BACKGROUND: A nucleotide substitution (C-->T) at position 825 of the gene GNB3 encoding the beta3 subunit of heterotrimeric G proteins is associated with alternative splicing and enhanced signal transduction. There is accumulating evidence from different populations that the 825T allele is associated with increased prevalence of hypertension, obesity, and left ventricular hypertrophy. However, it is unclear to what extent the 825T allele has a direct influence on left ventricular structure, independently of the effects of pressure and body mass index. Therefore we explored whether the GNB3 825T allele is associated with increased left ventricular mass index in a selected and homogeneous group of young, never treated, mild hypertensives. PROCEDURES: Young subjects (n = 207, aged 18 to 45 years) were genotyped at the GNB3 825 locus. In each patient, 24-h ambulatory blood pressure (BP) measurement and two-dimensional guided M-mode echocardiography combined with Doppler sonography were performed. RESULTS: The genotype distribution among patients was in Hardy-Weinberg equilibrium. Patients carrying the 825T allele had an increased left ventricular mass index (95.1 +/- 1.5 v 89.7 +/- 1.5 g/m2; P = .01) in comparison to those with CC genotype. The association between left ventricular mass index and 825T allele was independent of gender, age, BP, heart rate, alcohol intake, and physical activity. CONCLUSIONS: In young patients with mild hypertension without heart disease the 825T allele is associated with an increased left ventricular mass index. These hypothesis-generating data suggest that GNB3 825T allele may be considered as one genetic marker predisposing to an increase in left ventricular mass in hypertensives, and justifies larger studies.     

Human G-protein beta3 subunit variant is associated with serum potassium and total cholesterol levels but not with blood pressure

The activity of a sodium-proton exchanger is enhanced in the patients with essential hypertension and regulated via G-protein, which is a signal transducer between receptors and intracellular effectors. A recent study has revealed that a novel variant (C825T) in exon 10 of the gene encoding the beta3 subunit of heterotrimetric G proteins (GNB3) is a genetic factor predisposing to hypertension in Caucasians. We examined the association between GNB3/ C825T and blood pressure, lipids, electrolytes, and other parameters in a Japanese population. Subjects (n = 352) were selected from the Ohasama Study, the population of which is regarded as from a rural community in Japan. To obtain precise clinical measurements, 24-h ambulatory blood pressure monitoring (ABPM), brain magnetic resonance imaging (MRI), and carotid ultrasonography (CUS) were conducted in this population. In addition, we recruited 762 subjects from outpatients at the Osaka University Medical School to carry out the association study between hypertension and GNB3. The GNB3 genotype distribution did not differ significantly between normotensives and hypertensives in either of the two studies. The T825 allele of GNB3 was not associated with the presence of hypertension, blood pressure level, the number of brain lacunae or carotid wall thickness. However, the serum potassium and total cholesterol levels were significantly higher in subjects with the T allele (P < .005). The T825 allele of GNB3 is associated with increased serum potassium and total cholesterol levels but not with blood pressure in a Japanese population.     

原发性高血压患者中G蛋白β3亚单位基因C825T多态性与复方缬沙坦降压疗效的相关性

目的:探讨原发性高血压(EH)患者中G蛋白β3亚单位基因C825T多态性与EH发生,及复方缬沙坦降压疗效的相关性。方法:80例EH患者(EH组)给予复方缬沙坦1粒/d,治疗4周后,观察其降压疗效。应用直接测序方法对EH组患者和40名健康者(对照组)G蛋白β3亚单位基因C825T作基因分型。结果:EH组中CC和CT+TT基因型频率分别为31.25%和68.75%,对照组中分别为52.50%和47.50%,2组间CT+TT基因型频率差异有统计学意义(P<0.05)。EH组中C和T等位基因频率分别为41.88%和58.12%,对照组中分别为57.50%和42.50%,2组间T等位基因频率差异有统计学意义(P<0.05)。EH组患者中,复方缬沙坦对携带T等位基因者血压的下降幅度与携带C等位基因者比较差异有统计学意义(P<0.05)。结论:G蛋白β3亚单位基因C825T多态性与EH发病有关,携带T等位基因者可能是缬沙坦降压疗效的新的预测因子。     

C825T polymorphism of the GNB3 gene codifying the G-protein beta3-subunit and cardiovascular risk

Hypertension is a common disorder of multifactorial origin that constitutes a major risk factor for cardiovascular 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 variation in blood pressure. A polymorphism (825C/T) in exon 10 of the GNB3 gene, that encodes for the beta3 subunit, has recently been described. The 825T allele is associated with alternative splicing of the gene and formation of a truncated but functionally active beta3 subunit. Carriers of the 825T allele appear to have an increased risk for hypertension, obesity, insulin-resistance and left ventricular hypertrophy. Moreover, 825T allele carriers respond with a stronger decrease in blood pressure to therapy with a thiazide diuretic and with clonidine. GNB3 825T allele may be regarded as a potential genetic marker for a better definition of the risk profile of hypertensive subjects, but further studies are needed to precisely define the impact of T allele on the prognosis of such patients.     

Lack of an Association of GNB3 C825T Polymorphism and Blood Pressure in Patients with Rheumatoid Arthritis

G-protein beta 3 subunit (GNB3) C825T (rs5443) single nucleotide polymorphism (SNP) has been implicated as a risk factor for essential hypertension in the general population. The effects of this SNP may be more prominent in subjects with endothelial dysfunction (ED). Rheumatoid arthritis (RA) is associated with ED and has a high prevalence of hypertension. Thus far, this SNP has not been studied in RA patients. We genotyped 383 RA patients and 432 controls. GNB3 C825T was identified using real-time polymerase chain reaction (PCR) and melting curve analysis. There were no differences in the frequencies of the GNB3 C825T genotype and alleles between RA and controls. Within RA patients, prevalence of hypertension did not differ across genotypes. The TT versus CC+CT contrast yielded an adjusted odds ratio (OR) of 0.92 (95% CI: 0.49 to 1.76, p = 0.813), the contrast of TT+CT versus CC an adjusted OR of 2.17 (95% CI: 0.885 to 5.30, p = 0.091), whereas that of the T allele versus C allele an adjusted OR of 1.11 (95% CI: 0.76 to 1.61, p = 0.604). Systolic and diastolic blood pressure levels were not significantly different across the three genotypic groups. No significant interaction was observed between GNB3 825C/T polymorphism and serum endothelin levels. Data from the present study suggest that the T825 variant of the G protein β3 subunit gene is unlikely to constitute major susceptibility loci for essential hypertension in Caucasian RA patients. Further larger studies are required to confirm our findings and assess the interaction of rs5443 with environmental factors.     

G蛋白β_3亚单位基因C825T多态性影响缬沙坦的降压疗效

目的探讨G蛋白β3亚单位基因C825T多态性与缬沙坦的降压疗效的关系。方法采用聚合酶链反应限制片段长度多态性方法检测147例健康人(对照组)和321例高血压病患者(高血压组)的G蛋白β3亚单位C825T多态性,其中102例高血压病患者口服缬沙坦4周。结果高血压组G蛋白β3亚单位C825T多态性中基因型频率(CC28.7%、CT 52.0%、TT 19.3%)、等位基因频率(C 54.7%、T 45.3%)与对照组基因型频率(CC 27.2%、CT 46.9%、TT25.9%)、等位基因频率(C 50.7%、T 49.3%)比较无显著性差异;缬沙坦对CT[(18.29±11.17)mm Hg,1 mm Hg=0.133 kPa]、TT[(25.63±22.68)mm Hg]、CT+TT[(19.25±13.20)mm Hg]基因型患者降低收缩压的作用强于CC基因型[(11.33±9.15)mm Hg,P<0.05];对CT[(15.03±9.35)mm Hg]、CT+TT[(14.50±9.23)mm Hg]基因型患者降低舒张压的作用强于CC基因型[(8.81±5.60)mm Hg,P<0.05]。结论G蛋白β3亚单位基因C825T多态性与缬沙坦的降压疗效相关,而与原发性高血压无关。     

有高血压史的脑梗死患者G蛋白β3亚基基因C825T多态性研究

目的 探讨G蛋白β3亚基（G proteinβ3 subunit,GNB3）基因C825T多态性与原发性高血压和有高血压病史脑梗死发病的关系。方法采用聚合酶链反应限制性片段长度多态性分析对110名40岁以上的健康成年人和92例原发性高血压、80例有高血压史的脑梗死患者GNB3基因C825T多态性进行检测,记录性别、年龄、糖尿病史、吸烟史、饮酒史,并测定体质指数、腰臀比、总胆固醇( total cholesterol,TC)、三酰甘油（triglyceride,TG）、高密度脂蛋白胆固醇（high-density lipoprotein cholesterol,HDL-C）和空腹血糖浓度。采用多变量logistic回归分析筛选与高血压患者脑梗死发病相关的因素。结果 3组人群GNB3基因C825T多态性分布均符合Hardy -weinberg遗传平衡定律。在有高血压史的脑梗死患者中CC、CT和TT等3种基因型频率分别为33％、57％和20％,在原发性高血压患者中分别为33％、42％和25％,健康对照组中分别为26％、54％和20％,无显著差异(x2=4.030,P=0.402);3组人群中825T等位基因频率分别为39％、40％和47％,无显著差异(x2=0.367,P=0.832)。多变量logistic回归分析显示,TC[优势比（odds ratio,OR）10.810,95％可信区间(confidence interval,CI)2.645 ～ 44.136,P=0.000]、TG( OR 5.453,95% CI 1.662～17.881,P=0.005)、HDL-C(OR0.181,95％CI 0.041～0.795,P=0.027)、血糖（OR2.386,95％ CI 1.062 ～5.363,P=0.035）、糖尿病（OR7.156,95％CI1.271～40.291,P=0.026）是脑梗死的独立危险因素,而GNB3基因型和等位基因未进入模型。结论 GNB3基因C825T多态性可能与脑梗死和原发性高血压无关。     

Association of the G protein beta3 subunit T allele with insulin resistance in essential hypertension

A polymorphism (C825T) in the gene encoding the G protein beta3 subunit (GNB3) has recently been associated with hypertension and obesity in several populations. The aim of the study was to analyse the relationship between this polymorphism and insulin sensitivity, an hypothesised unifying factor for hypertension and obesity. One hundred thirty unrelated patients with essential hypertension, 70 female and 60 male, aged 58 +/- 1 years with systolic blood pressure of 173 +/- 2 mm Hg and diastolic blood pressure of 105 +/- 1 mm Hg, were genotyped for the GNB3 polymorphism by PCR and restriction digestion with BseDI, and classified in two groups according to the genotypes CC and CT + TT. Body mass index (BMI) was significantly higher in patients with the T allele as compared with patients without the T allele (29.3 +/- 0.4 vs. 26.7 +/- 0.6 kg/m2, p<0.001). On the contrary, there were no differences in the level of systolic or diastolic blood pressure among the genotypes. Insulin sensitivity was measured in a subgroup of 35 patients by means of an euglycemic hyperinsulinemic clamp test. In this subgroup, patients with the T allele displayed lower insulin sensitivity index (1.6 +/- 0.3 vs. 2.7 +/- 0.3 mg/kg/min, p = 0.022), higher fasting serum insulin (121 +/- 16 vs. 77 +/- 11 pmol/L, p = 0.032), higher serum glucose 120 min after 75 g load (9.8 +/- 1.2 vs. 7.0 +/- 0.5 mmol/L, p = 0.038), and higher glycosilated haemoglobin (5.7 +/- 0.4 vs. 4.7 +/- 0.2%; p = 0.042) as compared with patients without the T allele. A regression analysis showed that the association between the T allele and insulin sensitivity was independent of BMI (beta coefficient -0.386, p = 0.022). These results suggest a relationship between the 825T allele of GNB3 and insulin resistance in the essential hypertensive patients studied, which seems to be independent of BMI.     

Association between the G protein beta3 subunit 825t allele and radial artery hypertrophy

The GNB3 C825T gene polymorphism has recently been identified and associated with hypertension, obesity and left ventricular hypertrophy. The aim of the study was to determine the relationship between the C825T polymorphism of the gene encoding for the G protein beta3 subunit (GNB3 C825T) and vascular hypertrophy. We studied a cohort of 306 subjects (age 49 +/- 12 years) without evidence of cardiovascular disease and never treated with cardiovascular drugs. Vascular phenotypes were evaluated for the common carotid and radial arteries using high-resolution echo-tracking devices. Genotype frequencies were in agreement with the Hardy-Weinberg equilibrium. For the radial artery, mean wall thickness was significantly higher in subjects carrying the 825T allele than in CC genotype subjects (240 +/- 54 microm for CT genotype and 241 +/- 53 microm for TT genotype vs. 222 +/- 52 microm for CC genotype, p = 0.01). The frequency of the 825T allele was significantly different in subjects with (52%) and without (35%) radial artery hypertrophy (chi(2) = 10.88, p < 0.001). The relative risk of radial artery hypertrophy in subjects carrying the 825T allele compared with those with the CC genotype was 3.02 (95% CI 1.53- 5.95). A logistic regression analysis indicated that the positive and significant association between the 825T allele and radial artery hypertrophy was independent of age, blood pressure, gender and BMI. In contrast, no association between genotypes and carotid artery wall thickening was observed. These results suggest that some genetic characteristics determine in part the patterns of radial artery geometrical changes. As the 825T allele is associated with vascular hypertrophy of a muscular artery but not with structural changes of an elastic artery, we hypothesize that the 825T allele may be a genetic marker of arteriolosclerosis.     

Interaction of the ACE D allele and the GNB3 825T allele in myocardial infarction

In polygenetic disorders, such as ischemic heart disease, the investigation of gene-gene interactions rather than determination of single gene effects is crucial to better understand the contribution of genetic factors. The 825T allele of the G-protein ss(3)-subunit gene (GNB3) associated with enhanced G-protein signaling is a candidate to interact with the angiotensin-converting enzyme (ACE) deletion/insertion (D/I) polymorphism to increase the risk for myocardial infarction (MI). The ACE D:/I variant affects the renin-angiotensin system hormones that activate G-protein-coupled receptors. Genotyping at the ACE and GNB3 loci was performed on 585 patients with coronary artery disease with (n=270) or without (n=315) previous MI. Logistic regression analysis demonstrated a significant interaction between the ACE D: allele and the GNB3 825T allele (P<0.001). The odds ratio for MI, associated with the 825T allele, was not increased in the presence of the ACE II genotype (OR 0.5; P=0.09) but was significantly higher in 825T allele carriers with the ACE DI genotype (OR 1.9; P=0.01) and further increased in individuals with the ACE DD genotype (OR 2.4; P=0.02). The highest odds ratio was found in homozygous 825T allele carriers with the ACE DD genotype (OR 7.5; P=0.006). Our data suggest a significant interaction of the GNB3 825T allele with the ACE D allele in MI. These hypothesis-generating data may justify larger prospective studies.     

The 825C/T polymorphism of the G-protein subunit beta3 is not related to hypertension.

A polymorphism at position 825 (C-->T) of the cDNA that encodes the beta3 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 (P=0.79), respectively; the corresponding frequencies in cases and controls from France were 0.33 and 0.31 (P=0.30), respectively. In the PEGASE study, the 825T allele frequency was 0.35 in female and male cases and 0.31 in male normotensive controls (P=0.12). 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; P=0.13) and 1.11 (95% confidence interval, 0.88 to 1.39; P=0.37), 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.     

Molecular genetics of G proteins and atherosclerosis risk

Using a classical candidate gene approach, we have described a common C825T polymorphism in the gene GNB3 which encodes the ubiquitously expressed beta3 subunit of heterotrimeric G proteins. The 825T allele is associated with alternative splicing of the gene and the formation of a truncated but functionally active beta3 subunit which is referred to as Gbeta3s. Expression of the splice variant results in an enhanced G protein activation on stimulation of G protein-coupled receptors. Carriers of the 825T allele show an increased risk for hypertension and left ventricular hypertrophy. Homo- and heterozygous 825T allele carriers respond with a stronger decrease in blood pressure to therapy with a thiazide diuretic than homozygous 825C allele carriers. Moreover, 825T allele carriers appear to have an increased risk for obesity which appears sensible given the established role of G protein signaling in adipogenesis. The highest frequencies of the 825T allele are found in ethnicities with the highest lifestyle-dependent risk for obesity, e.g., black Africans and East Asians. This suggests that the 825T allele fulfills the criteria of a thrifty genotype.     

G-protein beta(3) subunit gene (GNB3) 825T allele is associated with enhanced renal perfusion in early hypertension

The C825T polymorphism of the gene encoding the G-protein beta(3) subunit (GNB3) is associated with increased intracellular signal transduction and arterial hypertension. The aim of the study was to investigate the impact of this polymorphism on early adaptive processes of the left ventricle and renal hemodynamic changes in young normotensive to mildly hypertensive subjects. Ninety-five white male students with normal or mildly elevated blood pressure were genotyped for the GNB3 C825T polymorphism. In each participant, 24-hour ambulatory blood pressure, left ventricular structure and function (2D-guided M-mode echocardiography), renal plasma flow (para-aminohippurate clearance), glomerular filtration rate (inulin clearance), and 24-hour urinary sodium excretion were determined. The GNB3 825T allele was not associated with casual or ambulatory blood pressure, parameters of left ventricular structure or function, glomerular filtration, or 24-hour urinary sodium excretion. However, in T:-allele carriers (CT+TT), renal plasma flow was higher than in CC subjects (CT/TT: 659+/-96 versus CC: 614+/-91 mL/min, P:=0.019). ANOVA disclosed that renal plasma flow was independently influenced by both genotype and blood pressure, with hypertensives having a higher renal plasma flow than normotensive subjects. This was the fact irrespective of the criteria used for the definition of hypertension (World Health Organization or 24-hour ambulatory blood pressure criteria). The GNB3 825T variant is associated with increased renal perfusion in this study. Because early renal hemodynamic changes play a pivotal role in the pathogenesis of essential hypertension, our data suggest a relevance of increased G-protein activation in the pathogenesis of hypertension.     

Effects of the C825T polymorphism of the GNB3 gene on body adiposity and blood pressure in fertile and menopausal women: a population-based study

OBJECTIVES: The 825T allele of the GNB3 gene is implicated in adipose distribution, predisposing to obesity and hypertension. Menopause is also considered a condition leading to excess adiposity and hypertension. The aim of the present study was to clarify whether the effects of menopause on body weight and blood pressure are influenced by the C825T polymorphism of the GNB3 gene. METHODS: The study involved 1339 subjects (43% men) aged 18-95 years, genotyped at the GNB3 825 locus, undergoing, in an epidemiological population-based frame, questionnaire, anthropometrics and blood examinations. RESULTS: Mean skinfold thickness (MST), truncal obesity and excess subcutaneous adiposity (MST greater than median) were higher in women than in men. A significant interaction was detected between menopausal status and the C825T polymorphism (Pint > 0.0001). MST, truncal obesity and excess subcutaneous adiposity were lower in CC fertile than menopausal women, but were comparable in TT fertile and menopausal women. In a multivariate logistic model for excess subcutaneous adiposity, the relative risk of menopause was 4.12 (95% confidence interval 2.35-7.22) in CC women but was insignificant in the other two genotypes. In fertile women only, higher systolic blood pressure (SBP) was detected in TT than in CC genotypes. CONCLUSION: An interaction exists between the C825T polymorphism and menopause in controlling body adiposity and blood pressure in women. Adiposity and SBP are higher in menopausal than in fertile women, provided they have the CC genotype. TT fertile women show the same adiposity as those in menopause. Men have the same excess adiposity as menopausal women, independent of the GNB3 genotype.     

GNB3基因C825T多态性与中国高血压患者服用坎地沙坦酯或坎地沙坦酯／氢氯噻嗪复方制剂降压疗效的相关性研究

目的探讨GNB3C825T基因多态性与坎地沙坦酯及复方坎地沙坦酯（坎地沙坦酯＋氢氯噻嗪）降压疗效的相关性。方法62名原发性高血压患者随机分组，分别给予坎地沙坦酯片及坎地沙坦酯＋氢氯噻嗪片治疗8周，定期随访取得血压下降数据。采用聚合酶链式反应．限制性片断长度多态性（PCR-RFLP）方法检测GNB3基因型。利用协方差分析各基因型与两药物降压疗效的关系。结果服用坎地沙坦酯／氢氯噻嗪复方的病人血压下降值明显高于单独服用坎地沙坦酯的病人血压下降值（P〈0．05）。GNB3825T等位基因在入选的高血压病人中频率为45．16％。与多数国人报道结果一致。协方差分析结果显示服用两种药后收缩压和舒张压的下降幅度在GNB3C825T各基因型高血压患者问比较均无统计学差异（P〉0．05）。结论GNB3C825T基因多态性可能与坎地沙坦酯及坎地沙坦酯＋氢氯噻嗪降压疗效不相关。     

Gene-environment interaction and the GNB3 gene in the Atherosclerosis Risk in Communities study

OBJECTIVE: The purpose of this study was to investigate the interaction between the G-protein beta-3 (GNB3) 825C>T polymorphism and physical activity in relation to prevalent obesity and hypertension. RESEARCH METHODS AND PROCEDURES: The GNB3 825C>T genotype was measured in a sample of 14,716 African Americans (AAs) and whites from the Atherosclerosis Risk in Communities (ARIC) study, and logistic regression was used to test for genetic effects and gene-environment interactions. RESULTS: The GNB3 825C>T variant was not independently associated with prevalent obesity or hypertension in either AA or whites. However, we observed a significant interaction (P<0.001) between this variant and physical activity in predicting obesity status in AAs. In AAs who were active, each 825T allele was associated with a 20% lower prevalence of obesity (odds ratio (OR)=0.80, 95% confidence interval (CI)=0.689-0.937, P=0.005), whereas each 825T allele was associated with a 23% greater prevalence of obesity for low-active individuals (OR=1.23, 95% CI=1.06-1.44, P=0.008). We also found a significant interaction between the GNB3 825C>T polymorphism, obesity status and physical activity in predicting hypertension in the AA subjects. AA homozygotes for the 825T allele who were both obese and had a low activity level were 2.7 times more likely to be hypertensive, compared to non-obese, active 825C homozygotes (OR=2.71, 95% CI=1.19-6.17, P<0.02). DISCUSSION: Our findings suggest that the variation within the GNB3 gene may interact with physical activity level to influence obesity status and, together with obesity and physical activity, the GNB3 825C>T variant may influence hypertension prevalence in AAs.     

825T allele of the G-protein beta3 subunit gene (GNB3) is associated with impaired left ventricular diastolic filling in essential hypertension.

OBJECTIVE: Recently, a novel C825T polymorphism in the gene (GNB3) encoding for the G-protein beta3 subunit was identified. The 825T allele is associated with the generation of a novel splice variant, enhanced intracellular signal transduction, and arterial hypertension. In this study, we investigated the impact of the 825T allele on left ventricular structure and function in mild to moderate essential hypertensive subjects. METHODS: In 34 white patients with established mild to moderate essential hypertension (World Health Organization stage I or II, mean age 52 +/- 9 years) genotype analysis of GNB3 C825T polymorphism, insertion/deletion polymorphism of the ACE gene and 1166 A/C polymorphism of the AT1 receptor gene was performed. In each patient, 24 h ambulatory blood pressure measurement (SpaceLabs 90207) and two-dimensional guided M-mode echocardiography combined with Doppler sonography were performed. RESULTS: In our homogenous study group, the GNB3 825T allele was not associated with casual and 24 h ambulatory blood pressure (CC versus TC/TT: 144 +/- 13/92 +/- 8 versus 151 +/- 14/97 +/- 7 and 143 +/- 11/92 +/- 7 versus 150 +/- 16/ 96 +/- 9 mmHg, respectively) or parameters of left ventricular structure (relative wall thickness: CC versus TC/TT, 0.48 +/- 0.1 versus 0.46 +/- 0.1; left ventricular mass: CC versus TC/TT, 281 +/- 65 versus 299 +/- 80 g). However, transmitral flow variables reflecting left ventricular diastolic filling were impaired in patients expressing the TC/TT genotype (ratio of peak late (A) to early (E) velocities: CC versus TC/TT, 0.95 +/- 0.24 versus 1.2 +/- 0.26, P< 0.02; velocity time integrals A/E: CC versus TC/TT, 0.57 +/- 0.16 versus 0.76 +/- 0.23, P< 0.01) while all co-variables such as age, body mass index, ambulatory blood pressure, heart rate and end-diastolic volume were similar between the two groups. If patients were stratified according to the I/D polymorphism of the ACE gene and the A1166C polymorphism of the AT1 receptor gene, no differences in blood pressure, left ventricular structure or systolic and diastolic function of the left ventricle were found between different genotypes. CONCLUSION: The GNB3 825T allele was associated with impaired left ventricular diastolic filling in hypertensive subjects in this study. Since alterations in left ventricular filling have been identified as an early marker of hypertensive heart disease, the GNB3 C825T polymorphism may influence cardiac adaptation to increased afterload.     

Genetischer Polymorphismus in der G-Protein-β3-Untereinheit, Adipositas und essentielle Hypertonie

Following a classical candidate gene approach we have detected a C825T polymorphism in the gene GNB3 which encodes the G beta 3 subunit of heterotrimeric G proteins. The 825T allele causes alternative splicing of the gene and the generation of a truncated but functionally active splice variant of G beta 3 which is referred to as G beta 3s. Thus, genotyping for the C825T polymorphism is predictive for the activation of certain G proteins in humans. The 825T allele is significantly associated with an increased risk for hypertension in Caucasians, most likely "low renin hypertension" and it accumulates significantly in individuals with a strong family history of hypertension. Highest frequencies of the 825T allele (up to 80%) are found in old ethnicities, e.g. black Africans, African Americans, bushmen, and Australian aborigines. This suggests that enhanced G protein activation represents a thrifty genotype which might have facilitated survival in our ancestors. Frequencies of the 825T allele are significant lower in Asians (approximately 40 to 50%) and Caucasians (30%). More recent studies show that young 825T allele carriers are predisposed for obesity and this association could be confirmed across different ethnicities including young Germans, as well as Chinese and black African individuals. Thus, genotyping at the GNB3 locus represents an ideal tool for preventive medicine in that individuals at risk for obesity and hypertension can be identified early and counteract their genetic predisposition through changes in lifestyle. In individuals with borderline hypertension genotyping can facilitate the decision for medical treatment as a positive test result confirms an inherited form of hypertension.