GNB3 Genotype Research Articles

GNB3 and CREB1 gene polymorphisms combined with negative life events increase susceptibility to major depression in a Chinese Han population.

BackgroundMajor depression (MD) is caused by a combination of genetic and environmental factors. In this study we investigated the interaction of variations in the G-protein beta 3 subunit (GNB3) and cAMP response element binding protein 1 (CREB1) genes with negative life events in the pathogenesis of MD. One GNB3 polymorphism (rs5443) and four CREB1 polymorphisms (rs2253206, rs2551941, rs6740584, rs11904814) were investigated based on known associations with MD.Methods512 patients with MD and 513 control subjects were genotyped. The frequency and severity of negative life events were measured by the Life Events Scale (LES). Gene-environment interactions (G×E) were assessed using the generalized multifactor dimensionality reduction (GMDR) method.ResultsDifferences in GNB3 rs5443 allele frequencies and genotype distributions were observed between MD patients and controls. Significant G×E interactions were detected between negative life events and genotypic variation of all five single nucleotide polymorphisms (SNPs). Individuals carrying the T- allele of rs5443 (CC), A- allele of rs2253206 (GG), T- allele of rs2551941 (AA), C- allele of rs6740584 (TT) or G- allele of rs11904814 (TT) conferred susceptibility to MD in subjects only exposed to high-negative life events. However, individuals with the T+ allele of rs5443 (CT, TT) were susceptible to MD when exposed to low negative life events.ConclusionsInteractions between GNB3, CREB1 and negative life events were revealed. Further evidence is provided about the role of the environment in genetic vulnerability to MD.

Association of CLOCK, ARNTL, PER2, and GNB3 polymorphisms with diurnal preference in a Korean population

ABSTRACTPolymorphisms in human circadian genes are potential genetic markers that affect diurnal preference in several populations. In this study, we evaluated whether four polymorphisms in circadian genes CLOCK, ARNTL, PER2, and GNB3 were associated with diurnal preference in a Korean population. In all, 499 healthy subjects were genotyped for four functional polymorphisms in CLOCK, ARNTL, PER2, and GNB3. Composite scale of morningness (CSM) was applied to measure phenotype patterns of human diurnal preference. In addition, three subscale scores, i.e. “morningness,” “activity planning,” and “morning alertness,” were extracted from the CSM. No significant associations were observed between CSM scores and CLOCK (rs1801260) genotype or T allele carrier status, CSM scores and ARNTL (rs2278749) C allele carrier status, and CSM scores and GNB3 (rs5443) genotype or C allele carrier status. However, total CSM scores and scores of its subscales were significantly associated with PER2 (rs934945) genotype (p = 0.010, p = 0.018, and p = 0.005 for total, morningness, and activity planning, respectively) and G allele carrier status (p = 0.003, p = 0.005, and p = 0.002 for total, morningness, and activity planning, respectively). The best model result obtained by performing multifactor dimensionality reduction analysis (2 = 11.2798, p = 0.0008) indicated that interaction among C/T single nucleotide polymorphism (SNP) in ARNTL, C/T SNP in GNB3, and G/A SNP in PER2 synergistically affected the risk associated with diurnal preference toward eveningness. These results suggest that circadian gene PER2 is associated with diurnal preference in healthy Korean population. Although polymorphisms in ARNTL and GNB3 were not significantly associated with diurnal preference, their interactions with the polymorphism in PER2 may synergistically increase the risk of diurnal preference toward eveningness.

GNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study.

Black women are at greater risk for peripartum cardiomyopathy (PPCM). The guanine nucleotide-binding proteins β-3 subunit (GNB3) has a polymorphism C825T. The GNB3 TT genotype more prevalent in blacks is associated with poorer outcomes. We evaluated GNB3 genotype and myocardial recovery in PPCM. A total of 97 women with PPCM were enrolled and genotyped for the GNB3 T/C polymorphism. Left ventricular ejection fraction (LVEF) was assessed by echocardiography at entry, 6 and 12 months postpartum. LVEF over time in subjects with the GNB3 TT genotype was compared with those with the C allele overall and in black and white subsets. The cohort was 30% black, age 30+6, LVEF 0.34+0.10 at entry 31+25 days postpartum. The % GNB3 genotype for TT/CT/CC=23/41/36 and differed markedly by race (blacks=52/38/10 versus whites=10/44/46, P<0.001). In subjects with the TT genotype, LVEF at entry was lower (TT=0.31+0.09; CT+CC=0.35+0.09, P=0.054) and this difference increased at 6 (TT=0.45+0.15; CT+CC=0.53+0.08, P=0.002) and 12 months (TT=0.45+0.15; CT+CC=0.56+0.07, P<0.001.). The difference in LVEF at 12 months by genotype was most pronounced in blacks (12 months LVEF for GNB3 TT=0.39+0.16; versus CT+CC=0.53+0.09, P=0.02) but evident in whites (TT=0.50++0.11; CT+CC=0.56+0.06, P=0.04). The GNB3 TT genotype was associated with lower LVEF at 6 and 12 months in women with PPCM, and this was particularly evident in blacks. Racial differences in the prevalence and impact of GNB3 TT may contribute to poorer outcomes in black women with PPCM.

Abstract 18476: Myocardial Recovery in Peripartum Cardiomyopathy: Effect of the GNB3 C825T Polymorphism in the Multicenter IPAC study

Background: Peripartum cardiomyopathy (PPCM) remains a major cause of maternal morbidity and mortality. Black race is a risk factor for the disorder and although most women recover myocardial function, previous studies suggest less recovery in black women than in whites. The genetic basis of this racial difference in risk and recovery remains unknown. A polymorphism of a G protein beta subunit (GNB3 C825T) in exon 10 has been studied extensively for a potential role in increased risk of hypertension in blacks. We investigated the impact of the GNB3 C825T polymorphism on myocardial recovery in PPCM in the multicenter IPAC study (Investigation of Pregnancy Associated Cardiomyopathy). Method: 97 women with new onset of PPCM were enrolled and genotyped for the GNB3 T/C polymorphism. Myocardial function was assessed by echocardiography at study entry, 2, 6 and 12 months postpartum and LVEF calculated at a core lab. Myocardial recovery in subjects with the GNB3TT genotype was compared to subjects with the GNB3 C allele (CC and CT combined) first for the overall cohort then separately in black and white subsets. Results: Overall the cohort was 30% black, mean age 30 + 6, and LVEF 0.35 + 0.10 at study entry 31 + 25days post-partum. For the overall cohort, the % GNB3 genotype TT/CT/CC =23/41/36 and differed markedly by Race (Black= 52/38/10 versus Whites=10/43/47, p&lt;0.001). In subjects with the GNB3TT genotype, LVEF was similar early postpartum (TT= 0.35 + 0.07; CT+CC= 0.35 + 0.09, p=0.98) but significantly lower at 2 month (TT=0.38 + 0.15; CT+CC= 0.44 + 0.10, p=0.02), 6 months (TT=0.45 + 0.15; CT+CC= 0.53 + 0.08, p=0.002), and 12 months (TT=0.45 + 0.15; CT+CC= 0.56 + 0.07, p&lt;0.001.). The difference in recovery for GNB3 TT subjects was most pronounced in black women (12 months LVEF for GNB3 TT=0.39 + 0.16; versus CT+CC= 0.53 + 0.09, p=0.02) but was still evident in whites ((TT=0.50 + 0.11; CT+CC= 0.56 + 0.06, p=0.04). Conclusion: In IPAC, Women with the GNB3 TT genotype had significantly less myocardial recovery over the first year post-partum, and its impact was particularly evident in black women. The increase prevalence of the GNB3 TT genotype in blacks may contribute to racial differences in myocardial recovery in women with PPCM

Abstract 19037: Impact of the GNB3 C825T Polymorphism on Heart Failure Survival

Introduction: Genetic background can influence heart failure survival and the impact of therapeutics. A polymorphism of a G protein beta subunit, GNB3 C825T, has been investigated extensively for its impact on the genomic risk of hypertension. The T allele is associated with low renin hypertension and increased alpha adrenergic tone. The T allele is more prevalant in African Americans and in the AHeFT trial was associated with a greater impact of therapy with a fixed dose combination of hydralazine and isosorbide dinitrates. We investigated the impact of GNB3 C825T on transplant free survival in systolic heart failure in GRACE (Genetic Risk Assessment of Cardiac Events), a singe center study based in an outpatient heart failure clinic. Methods: 944 subjects with systolic heart failure were enrolled from the Heart Failure Clinic at the University of Pittsburgh and followed for up to 5 years to an endpoint of death or cardiac transplantation. Demographic information was recorded at the time of enrollment and medical therapy reassessed annually. Blood was obtained at entry for DNA banking, and the GNB3 C825T genotype was determined. Transplant free survival was compared by Kaplan Meier log rank assessment. Results: The cohort was 28% female, 13% black, 48% ischemic, mean age 56 + 9, mean LVEF 0.25 + 0.09, and was NYHA class % 1/2/3/4=4%/52%/40%/4%. In terms of the GNB3 genotype the %TT/TC/CC were 16.5%/41.8%/41.7% and the frequency of the T allele differed significantly by race and was more common in Blacks (p&lt;0.001) . During follow up there were 236 (25%) death, and 126 transplants (13%). The T allele was associated with poor transplant free survival (Figure: p=0.025) driven primarily by poorer absolute survival (p=0.017). Conclusions: The GNB3 825T allele was associated with poorer survival in a cohort with chronic heart failure. Its role in racial differences in heart failure outcomes warrants futher investigation.

G-Protein Beta-3 Subunit Genotype Predicts Enhanced Benefit of Fixed-Dose Isosorbide Dinitrate and Hydralazine: Results of A-HeFT

ObjectivesThe purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial). BackgroundGNB3 plays a role in alpha2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans. MethodsA total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets. ResultsThe GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 ± 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 ± 0.06. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H = 0.50 ± 1.6; placebo = −0.11 ± 1.8, p = 0.02), QoL (FDC I/H = 0.69 ± 1.4; placebo = 0.24 ± 1.5, p = 0.04), and event-free survival (hazard ratio: 0.51, p = 0.047), but not in subjects with the C allele (for CS, FDC I/H = −0.05 ± 1.7; placebo = −0.09 ± 1.7, p = 0.87; for QoL, FDC I/H = 0.28 ± 1.5; placebo = 0.14 ± 1.5, p = 0.56; and for event-free survival, p = 0.35). ConclusionsThe GNB3 TT genotype was associated with greater therapeutic effect of FDC I/H in A-HeFT. The role of the GNB3 genotype for targeting therapy with FDC I/H deserves further study.

G protein β3 subunit polymorphism and long-term prognosis of functional dyspepsia.

Background/AimsA link between G protein β3 (GNB3) polymorphism and functional dyspepsia (FD) has been suggested. The aim of this study was to determine the role of GNB3 polymorphism in the long-term prognosis of FD in Koreans.MethodsFD patients and normal healthy controls were recruited from patients who visited our center between December 2006 and June 2007. All of the subjects completed Rome III questionnaires before undergoing upper gastrointestinal endoscopy and colonoscopy. Genomic DNA was extracted for GNB3 genotyping. After 5 years, the subjects were reevaluated using the same questionnaires.ResultsGNB3 825T carrier status was significantly related to FD in Koreans (p=0.04). After 5 years, 61.0% of the initial FD patients and 12.2% of the initial normal subjects were diagnosed with FD (odds ratio [OR], 11.7; 95% confidence interval [CI], 4.3 to 31.1; p<0.001). Regardless of the GNB3 genotype (p=0.798), female sex was strongly correlated with FD after 5 years (OR, 3.3; 95% CI, 1.2 to 9.1; p=0.017).ConclusionsThe T allele of GNB3 is linked to FD in Koreans but does not predict long-term prognosis. Female sex is related to a higher prevalence of FD after 5 years.

The role of G protein gene GNB3 C825TPolymorphism in HIV-1 acquisition, progression and immune activation

BackgroundThe GNB3 C825T polymorphism is associated with increased G protein-mediated signal transduction, SDF-1α-mediated lymphocyte chemotaxis, accelerated HIV-1 progression, and altered responses to antiretroviral therapy among Caucasian subjects. The GNB3 825T allele is highly prevalent in African populations, and as such any impact on HIV-1 acquisition or progression rates could have a dramatic impact. This study examines the association of the 825T polymorphism with HIV-1 acquisition, disease progression and immune activation in two African cohorts. GNB3 825 genotyping was performed for enrolees in both a commercial sex worker cohort and a perinatal HIV transmission (PHT) cohort in Nairobi, Kenya. Ex vivo immune activation was quantified by flow cytometry, and plasma chemokine levels were assessed by cytokine bead array.ResultsGNB3 genotype was not associated with sexual or vertical HIV-1 acquisition within these cohorts. Within the Pumwani cohort, GNB3 genotype did not affect HIV-1 disease progression among seroconverters or among HIV-1-positive individuals after adjustment for baseline CD4 count. Maternal CD4 decline and viral load increase in the PHT cohort did not differ between genotypes. Multi-parametric flow cytometry assessment of T cell activation (CD69, HLA-DR, CD38) and Treg frequency (CD25+FOXP3+) found no differences between genotype groups. Plasma SDF-1α, MIP-1β and TRAIL levels quantified by cytokine bead array were also similar between groups.ConclusionsIn contrast to previous reports, we were unable to provide evidence to suggest that the GNB3 C825T polymorphism affects HIV-1 acquisition or disease progression within African populations. Ex vivo immune activation and plasma chemokine levels were similarly unaffected by GNB3 genotype in both HIV-1-negative and HIV-1-positive individuals. The paucity of studies investigating the impact of GNB3 polymorphism among African populations and the lack of mechanistic studies make it difficult to assess the true biological significance of this polymorphism in HIV-1 infection.

Improvement of Non-Steroidal Anti-Inflammatory Drug-Induced Gastrointestinal Symptoms during Proton Pump Inhibitor Treatment: Are G-Protein β3 Subunit Genotype, Helicobacter pylori Status, and Environmental Factors Response Modifiers?

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with significant upper and lower gastrointestinal (GI) morbidity. Aim: To determine the efficacy and safety of pantoprazole versus placebo in controlling GI symptoms during treatment with NSAIDs and to evaluate the influence of potential response modifiers. Methods: 800 patients with GI complaints during NSAID treatment were randomized to pantoprazole 20 mg once daily or placebo for 4 weeks in this double-blind, multicenter trial. Assessments included the difference in cumulated overall symptom load of any GI complaint during treatment (primary endpoint), proportion of days without GI symptoms, and influence of risk factors such as gender, age, alcohol consumption, smoking, Helicobacter pylori status, and GNB3 genotype SNP rs5443 (825C>T) on symptom load. Results: At 4 weeks, cumulated overall symptom load was significantly lower in pantoprazole than placebo recipients [p < 0.0001; intent-to-treat (ITT)]; the effect was statistically significant after 7 days’ treatment. Pantoprazole versus placebo recipients had 54 versus 29% of days without GI symptoms (p < 0.0001; ITT). Neither common risk factors nor GNB3 genotype were significantly associated with therapeutic response, while GNB3 825TT versus CT was associated with a significantly higher baseline symptom load (p < 0.05). Conclusion: In the population studied, treatment with the proton pump inhibitor pantoprazole significantly improves GI symptoms during NSAID therapy, irrespective of the risk factors investigated or GNB3 genotype.

The G-Protein β3 subunit 825 TT genotype is associated with epigastric pain syndrome-like dyspepsia

BackgroundAlthough familial clustering of functional dyspepsia (FD) has been reported, the role of genetics in the susceptibility to FD is still not well understood. Several reports indicate an association between FD and G-protein β3 (GNB3) subunit gene polymorphism (C825T); however, these studies had small sample sizes and the findings are inconclusive. In the present study we clarified the association between GNB3 gene polymorphism and dyspepsia in a large population of Japanese subjects who visited a hospital for annual health check-up.MethodsSubjects with significant upper gastrointestinal findings were excluded. Subjects with dyspeptic symptoms were divided into either a postprandial distress syndrome (PDS) group or an epigastric pain syndrome (EPS) group according to the Rome III criteria. The presence of the GNB3 C825T polymorphism was then evaluated and logistic regression analysis was used to test all variables.ResultsThe GNB3 genotype distribution in subjects without dyspepsia was 191 CC (25.1%), 368 TC (48.4%), and 202 TT (26.5%) and 17 CC (25.0%), 29 TC (42.6%), and 22 TT (32.4%) in subjects with dyspepsia. No significant correlation was found between the GNB3 825TT genotype and dyspepsia. However, the TT genotype was significantly associated with subjects with EPS-like symptoms (odds ratio (OR) = 2.00, 95% confidence interval (CI); 1.07-3.76) compared to the CT/CC genotype adjusted for gender and age. No significant correlation was found between GNB3 polymorphism and PDS-like symptoms (OR = 0.68, 95% CI; 0.31-1.51). With the exclusion of subjects with both EPS- and PDS-like symptoms, only the TT genotype was significantly associated with EPS-like symptoms (OR = 2.73, 95% CI; 1.23-5.91).ConclusionThe homozygous GNB3 825T allele influences the susceptibility to EPS-like dyspepsia.

GNB3 C825T Polymorphism and Elevated Blood Pressure

Unlike in Europeans and Africans, the relationship between the human guanine nucleotide binding beta polypeptide 3 (GNB3) C825T gene polymorphism (rs5443) and blood pressures is inconsistent in Asians. The aim of the study was to investigate whether the GNB3 genotype demonstrates different associations with resting blood pressure and body fatness across cardio/respiratory fitness (CRF) levels. A total of 727 Korean women aged 31-60 years (mean, 47.8+/-5.4 years) participated in the study. In subgroup analyses of the obese group, TT individuals had significantly higher values of body weight than CC and CT individuals (p=0.006 and p=0.006, respectively) and body mass index (BMI) (p=0.002 and p=0.011, respectively). TT and CT individuals also tended to have higher CRF values than CC individuals. Regression analyses showed that the association between GNB3 genotype and resting blood pressure remained significant after adjustment for age and menopause, but was not significant after additional adjustment for body fatness. In summary, the findings of this study suggest that body fatness and CRF might modify the GNB3-mediated genetic susceptibility to elevated resting blood pressures in middle-aged Korean women.

Common Variants in the G Protein β3 Subunit Gene and Thyroid Disorders in a Formerly Iodine-Deficient Population

Heterotrimeric G proteins are key mediators of signals from membrane receptors-including the thyroid-stimulating hormone (TSH) receptor-to cellular effectors. Gain-of-function mutations in the TSH receptor and the Galpha(S) subunit occur frequently in hyperfunctioning thyroid nodules and differentiated thyroid carcinomas, whereby the T allele of a common polymorphism (825C>T, rs5443) in the G protein beta3 subunit gene (GNB3) is associated with increased G protein-mediated signal transduction and a complex phenotype. The aim of this study was to investigate whether this common polymorphism affects key parameters of thyroid function and morphology and influences the pathogenesis of thyroid diseases in the general population. The population-based cross-sectional Study of Health in Pomerania is a general health survey with focus on thyroid diseases in northeast Germany, a formerly iodine-deficient area. Data from 3428 subjects (1800 men and 1628 women) were analyzed for an association of the GNB3 genotype with TSH, free triiodothyronine and thyroxine levels, urine iodine and thiocyanate excretion, and thyroid ultrasound morphology including thyroid volume, presence of goiter, and thyroid nodules. There was no association between GNB3 genotype status and the functional or morphological thyroid parameters investigated, neither in crude analyses nor upon multivariable analyses including known confounders of thyroid disorders. Based on the data from this large population-based survey, we conclude that the GNB3 825C>T polymorphism does not affect key parameters of thyroid function and morphology in the general population of a formerly iodine-deficient area.

Body Fatness And Fitness Modulate The Associations Between The Gnb3 Genotype And Resting Blood Pressures In Korean Women

Unlike in Caucasians and black Africans, the relationships between the C825T allele variant in exon 10 of the G protein b3 gene (GNB3) and blood pressures are inconsistent in Asians. PURPOSE: To investigate whether or not the GNB3 genotype is differently associated with resting blood pressures and body fatness across cardio/respiratory fitness (CRF) levels. MTHODS: A total of 727 Korean women aged 31-60 years (mean age, 47.8±5.4 yrs old) voluntarily participated in the study. Body fatness and fitness and resting blood pressure were measured by using standardized protocols. The GNB3 genotype (C825T) was determined by using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: For the obese group with body mass index of ≥25 kg/m2, subgroup analyses showed that TT individuals were younger (P =0.049 & P=0.002, respectively) and had significantly higher values in body weight (P=0.006 & P=0.006, respectively) and BMI (P=0.002 & P=0.011, respectively) than CC and CT individuals. Further, TT and CT individuals tended to have higher values in CRF than CC individuals. Regression analyses showed that the relationships between the GNB3 genotype and resting blood pressures remained significant even after adjustments for age and menopause, but the relationships were no longer significant when additionally controlling for body fatness. CONCLUSION: The findings of this study suggest that both body fatness and CRF might differently influence the genetic susceptibility of the GNB3 genotype to elevated resting blood pressures in middle-aged Korean women. Supported by the Korean Research Foundation funded by the Korean Government (KRF-2005-042-G00025)

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

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. 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. 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. 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.

The GNB3 C825T polymorphism affects response to HCV therapy with pegylated interferon in HCV/HIV co-infected but not in HCV mono-infected patients

Response to HCV treatment with pegylated interferon-alpha is variable but might at least in part depend on genetic host factors. The G protein beta3 unit (GNB3) C825T polymorphism has been shown to affect treatment response in HCV mono-infection. Here, we analyzed the impact of the GNB3 genotype in the context of HCV/HIV co-infection. HIV/HCV co-infected (n=112) and HCV mono-infected patients (n=150), receiving therapy with pegylated IFN-alpha/ribavirin, were enrolled into this study. Furthermore, we analyzed 220 healthy and 92 HIV mono-infected patients. GNB3 genotype was defined and correlated with respect to treatment response. GNB3 genotype distribution differed significantly between HIV/HCV co-infected patients and HIV-positive/HCV-negative (p=0.0002) or healthy controls (p=0.03). Patients with a GNB3 CC genotype had significantly lower SVR rates as compared to carriers of a non-CC genotype (52% versus 77%; p=0.018). In a logistic regression analysis the GNB3 genotype and the HCV genotype were significantly associated with response to treatment (p=0.018). In contrast to HIV/HCV co-infected patients, GNB3 genotype did not affect response to treatment in HCV mono-infected patients. The GNB3 825 CC genotype is associated with poor SVR rates in HIV/HCV co-infected patients. This underlines the impact of genetic host factors for treatment response.

No association between The GNB3 C825T Gene Polymorphism and Resting Blood Pressures And Body Fatness In Korean Women

PURPOSE: Unlike in Caucasians and black Africans, the relationship between the GNB3 825T allele and blood pressure is inconsistent in Asians. The aim of the study was to investigate whether or not the GNB3 genotype was associated with resting blood pressure and obesity. METHODS: A total of 404 apparently healthy Korean women (non-obese N=253, obese N=151) aged 24–69 yr (mean 49.6±9.3) participated in the study. Body fatness and fitness and resting blood pressure were measured by using standardized protocols. The GNB3 C825T was genotyped by using polymerase chain reaction with restriction fragment length polymorphism. RESULTS: Univariate analyses of variance showed no significant differences in body fatness and resting blood pressure across the GNB3 genotypes either in the total study population or in the non-obese subgroup or in the obese subgroup. Stepwise linear regression analyses showed that age, cardio-respiratory fitness, and body fatness were related to resting blood pressures (i.e., SBP, DBP, MAP), but the GNB3 genotype was not retained as a predictor in the final models. CONCLUSIONS: The current findings of the study suggest that the GNB3 gene C825T polymorphism might not be associated with either body fatness or resting blood pressure in this study population.

G Protein β3 Polymorphism and Triptan Response in Cluster Headache

Only about 70% of migraine and cluster headache (CH) patients report significant treatment responses to triptans, which are agonists at 5-HT(1B/D) receptors belonging to the family of G protein-coupled receptors. We analyzed whether a common polymorphism in the gene for the G protein beta3 subunit (GNB3 C825T) modulates responder rates to triptans among a cohort of 231 unrelated Caucasian CH patients. A total of 180 CH patients used triptans, of whom 71.1% reported treatment success. The adjusted odds ratio for treatment response to triptans for heterozygous carriers of the GNB3 825T allele was 2.96 (95% confidence interval 1.34-6.56; P=0.0074) vs carriers of the 825CC genotype. The GNB3 genotype status did not affect responses to other acute and preventive therapeutic regimes including oxygen, verapamil, and corticosteroids, i.e., drugs not directly affecting G proteins. We conclude that pain relief by triptans is significantly modulated by a common genetic GNB3 variant.

Serotonin 2A −1438 G/A and G-Protein Beta3 Subunit C825T Polymorphisms in Patients with Depression and SSRI-Associated Sexual Side-Effects

The occurrence of sexual side-effects from antidepressants is thought to be mediated through serotonin 2A (5HT2A) receptors. It is currently unknown if functional polymorphisms in the 5HT2A receptor or its G-protein second messenger complex are related to sexual dysfunction in patients taking an selective serotonin reuptake inhibitor (SSRI) for depression. The purpose of this study was to determine the relationship of the 5HT2A -1438 G/A and GNB3 C825T single nucleotide polymorphisms with overall sexual well-being and individual components of sexual health as measured by the Changes in Sexual Functioning Questionnaire (CSFQ). We evaluated 89 outpatients (18-40 years of age) at low risk for other causes of sexual dysfunction who were being treated for depression with an SSRI and did not have sexual difficulties before taking the antidepressant. Outcome measures were stratified by 5HT2A and GNB3 genotypes. After controlling for age, gender, anxiety scale scores, and depression scale scores, persons with a GG genotype of the 5HT2A -1438 single nucleotide polymorphisms (SNP) were significantly more likely to be categorized as having sexual dysfunction than persons with a GA or AA genotype (OR=3.6; 95% CI 1.03, 12.6; p=0.046). Furthermore, the 5HT2A -1438 GG genotype was a significant predictor of lower arousal scores (p=0.022) after accounting for other measures. There was no significant relationship between any outcome measure and GNB3 genotype.

Effect of a 12-wk Aerobic Exercise Program on Obesity Indices, Cardiopulmonary Fitness, and Metabolic Syndrome Markers Across the GNB3 C825T Gene Polymorphism in Mid-Life Korean Women

The C825T gene polymorphism, a substitution of cytosine (C) for thymine (T) at the nucleotide 825 of G-protein β3 subunit (GNB3) cDNA, activates a cryptic splice site that results in alternative splicing of exon 9, leading to deletion of 41 amino acids in the β3 subunit of GTP-binding proteins. In cross-sectional human studies, the 825T allele of the GNB3 polymorphism has been associated with hypertension and obesity in black Africans and Caucasians. PURPOSE: The purpose of the present study was to investigate whether the GNB3 genotypes modulated the effect of a 12-wk aerobic exercise program on obesity indices, cardiopulmonary fitness, and metabolic syndrome markers in mid-life Korean women. METHODS: A total of 51 abdominally obese women (waist circumference >80cm) aged 45–65 yrs were invited to participate in this study. Following an overnight fast, obesity indices (i.e., body mass index, percent body fat, waist circumference), cardiopulmonary fitness was determined during the treadmill exercise testing. Fasting glucose and lipoprotein-lipids (TC, HDLC, LDLC, TG), leptin, adiponectin were determined by using the commercial analysis kits. A 75 g of oral glucose tolerance test (OGTT) were peformed by using the standardized procedure. Then, all the subjects participated in a dance sports program for 12 weeks (2 hrs/day, 3 times/week). Following the dance sports program, the same measurements performed at the baseline were conducted. RESULTS: Two-way ANOVA analyses showed that the 12-wk aerobic exercise program resulted in significant improvements in all the measured variables (time effects only) except for SBP, DBP, and TC, while the degrees of the improvements were not dependent upon the GNB3 genotypes (no significant time by genotype interaction). However, both the CT heterozygotes and CC homozygotes tended to have greater reductions in area under curve during the OGTT than the TT homozygotes. Conclusions:The current findings suggest that the degree to which exercise training improves insulin sensitivity (i.e., improved glucose tolerance) may be partially modulated by the GNB3 genotype.

Association between the GNB3 Polymorphism and Blood Pressure in Young Korean Men

The purpose of the current study was to investigate the associations between the GNB3 C825T polymorphism, body fatness and fitness, and blood pressure in a sample of young Korean men. A total of 282 apparently healthy Korean men (nonobese N = 152, obese N = 130) aged 19-33 yr participated in the study. Body fatness and blood pressure were measured by using standardized protocols. The GNB3 C825T was genotyped by using polymerase chain reaction with restriction fragment length polymorphism. Univariate analyses of variance and Bonferroni post hoc tests showed that in the obese group only, TT homozygotes had a lower VO2max (P = 0.015 and 0.043, respectively) but higher resting systolic (P = 0.025 and < 0.001, respectively) and mean arterial blood pressures (P = 0.049 and 0.002, respectively) than CC homozygotes or CT heterozygotes. We further investigated possible interactions between group and genotype and found a significant interaction in SBP only (P = 0.037) between the group and genotype, even when controlling for age, BMI, and VO2max as potential confounding factors. Stepwise regression analyses showed that body mass index and GNB3 genotype were two independent predictors for the variations in systolic blood pressure and heart rate up to by 14.3 and 14.5%, respectively. In addition, waist-to-hip ratio explained an individual variation in mean arterial pressure (MAP) up to by 11.2%. The current findings of the study suggest that increased body fatness along with low cardiorespiratory fitness may magnify the genetic susceptibility of the GNB3 825T allele to elevated blood pressure in this study population.