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The purpose of this study was to characterize the functional consequences of the 393T>C polymorphism of the GNAS1 gene in vivo. PCR-RFLP assays were used to identify GNAS1 and β1-adrenoceptor genotypes. The heart rate (HR), blood pressure, left ventricular fractional shortening (LVFS), and left ventricular ejection fraction (LVEF) were determined in different genotypes through a modified dobutamine stress echocardiography protocol. Our results showed that individuals with homozygous or heterozygous C393 had an increased cardiovascular agonistic response to dobutamine, and the increases from baseline in LVFS at the 3 dosage levels of dobutamine were 19.3% ± 1.0% versus 32.0% ± 2.9%, 36.7% ± 3.1% versus 41.3% ± 4.1%, and 51.7% ± 3.3% versus 58.7% ± 2.6% in T393 homozygotes and C393 homozygotes or heterozygotes, respectively (P = .026). Significant differences were also found between these 2 groups with the increases from baseline in LVEF (P = .007) and SBP (P = .048). In addition, there were significant differences in the increases from atopine in LVFS (P = .011), LVEF (P = .004), and SBP (P = .046) between the T393 homozygotes and C393 homozygotes or heterozygotes. The change of LVEF in C393 homozygous was higher than that in T393 homozygous at the dose of 40 μg/kg/min (28.9% ± 4.0% vs 36.4% ± 2.1%; 95% CI, 18.8%-38.9%; P = .046). These data suggested that the 393T>C polymorphism of GNAS1 was functionally relevant in vivo. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rosiglitazone is one of the thiazolidinedione medicines that is widely used in patients with Type 2 diabetes (T2DM); it acts by activation of peroxisome proliferator-activated receptor-γ. • There are no reports on the influence of genetic variations of UCP2 and ADRB3 on rosiglitazone response in Chinese T2DM patients. • The current study was designed to evaluate the relationship between the genetic polymorphisms of UCP2 –866G/A and ADRB3 Trp64Arg with susceptibility to T2DM development and the therapeutic efficacy of multiple-dose rosiglitazone in Chinese patients with T2DM. WHAT THIS STUDY ADDS • The genetic polymorphisms of UCP2 –866G/A and ADRB3 Trp64Arg are associated with the therapeutic efficacy of multiple-dose rosiglitazone in Chinese T2DM patients. AIMS The aim of this study was to explore the impact of UCP2 and ADRB3 genetic polymorphisms on the therapeutic efficacy of rosiglitazone in Chinese Type 2 diabetes (T2DM) patients. METHODS A total of 199 T2DM patients and 155 healthy volunteers were enrolled to identify UCP2 –866 G/A genotypes, and 273 T2DM patients and 166 controls were genotyped for Trp64Arg of ADRB3 by polymerase chain reaction-restriction fragment length polymorphism assay. Nine patients with GG genotype and 27 with GA+ AA genotype of UCP2 –866 G/A, 11 with Trp64Trp genotype and 25 with Trp64Arg genotype of ADRB3 received oral rosiglitazone as a single-agent therapy (4 mg day−1) for 12 weeks. Serum fasting plasma glucose, postprandial plasma glucose, glycated haemoglobin (HbA1c), fasting serum insulin, postprandial serum insulin (PINS), triglycerol (TG), cholesterol, homeostasis model assessment for insulin resistance, leptin and adiponectin in all T2DM patients were determined before and after rosiglitazone treatment. RESULTS There were no differences in allele frequency of either ADRB3 Trp64Arg or UCP2 –866 G/A between T2DM patients and control subjects. The A allele carriers of UCP2 in the T2DM patients had significantly lower PINS (61.5 ± 34.3 vs. 41.6 ± 28.7 mU l−1, P < 0.01) (37.57, 59.16 vs. 34.82, 49.39) and low-density lipoprotein (LDL)-cholesterol compared with GG genotypes (3.4 ± 1.1 vs. 2.7 ± 1.1 mmol l−1, P < 0.05) (2.64, 3.52 vs. 2.66, 3.15). After rosiglitazone treatment for 12 consecutive weeks, we found that A allele carriers of UCP2 in the T2DM patients had smaller attenuated PINS (−3.82 ± 13.2 vs.−42.1 ± 30.7 mU l−1, P < 0.01) (9.45, 51.31 vs. 0.48, 11.88) and greater attenuated HbA1c (−1.85 ± 1.62 vs.−0.61 ± 0.80, P < 0.05) (0.14, 1.37 vs. 1.10, 2.38) compared with GG genotypes, and ADRB3 Trp64Arg had greater attenuated serum TG (−3.88 ± 2.77 vs.−0.24 ± 1.16 mmol l−1, P < 0.05) (−0.19, 2.74 vs. 1.19, 1.45) and smaller attenuated LDL-cholesterol (1.08 ± 1.36 vs.−0.36 ± 0.99, P < 0.01) (−1.26, 0.78 vs.−1.26, 0.79) as well as reduced enhanced adiponectin (1.57 ± 1.10 vs. 3.15 ± 2.12 mmol l−1, P < 0.05) (1.68, 4.08 vs.−9.18, 11.40) compared with ADRB3 Trp64Trp. CONCLUSION UCP2 –866 G/A and ADRB3 Trp64Arg polymorphisms are associated with the therapeutic efficacy of multiple-dose rosiglitazone in Chinese T2DM patients. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rosiglitazone is able to increase serum adiponectin levels significantly in Type 2 diabetic patients. • The role of genetic factors that determine the marked interindividual variability in glucose-lowering efficacy of rosiglitazone in Chinese patients is not known. • The current study was designed to evaluate the impact of the adiponectin common allele 45T/G and − 11377C/G polymorphisms on the response to rosiglitazone monotherapy in Chinese patients with Type 2 diabetes (T2D). WHAT THIS STUDY ADDS • The genetic polymorphisms of adiponectin alleles 45T/G and − 11377C/G as well as their common diplotypes are significantly associated with an attenuated fasting plasma glucose, postprandial plasma glucose and homeostasis model assessment for insulin resistance as well as an enhanced adiponectin concentration in Chinese patients with T2D after rosiglitazone treatment. AIMS The aim of the present study was to evaluate the impact of adiponectin allele T45G and C-11377G genetic polymorphisms on efficacy of rosiglitazone in Chinese patients with type 2 diabetes (T2D). METHODS Patients with T2D (n = 255) and 120 healthy volunteers were enrolled to identify 45T/G and –11377C/G genotypes by polymerase chain reaction-restriction fragment length polymorphism assay. Forty-two T2D patients with different 45T/G or –11377C/G genotypes received orally rosiglitazone as a single-dose therapy (4 mg day-1 p.o.) for 12 weeks. Serum triglyceride, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin, fasting serum insulin, postprandial serum insulin, total cholesterol, homeostasis model assessment for insulin resistance (HOMA-IR), low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol (HDL-c) and adiponectin concentration were determined before and after rosiglitazone treatment. RESULTS We showed an attenuated rosiglitazone effect in patients with –11377CG+GG heterozygote genotype on FPG, PPG, HOMA-IR compared with –11377CC homozygote genotype. However, we found an enhanced rosiglitazone effect on serum adiponectin concentration in patients with –11377CC homozygote genotype compared with –11377CG+GG heterozygote genotype ( P = 0.000) and in patients with 45TG + GG heterozygote genotype compared with 45TT homozygote genotype ( P = 0.018). Finally, our results showed that there was an enhanced effect in patients with –11377/45 CGTT diplotype compared with other discovered diplotypes on FPG ( P = 0.001) and PPG ( P = 0.003) after rosiglitazone treatment. CONCLUSIONS These data suggest that the adiponectin allele 45T/G and – 11377C/G polymorphisms are significantly associated with the therapeutic efficacy of multiple-dose rosiglitazone in Chinese patients with T2D. [ABSTRACT FROM AUTHOR]

1. Elevated serum bilirubin levels are caused mainly by liver diseases, haematolysis, genetic defects and drug intake. Unconjugated bilirubin (UCB) is taken up into hepatocytes by human organic anion transporting polypeptide 1B1 (OATP1B1; encoded for by the SLCO1B1 gene). The present study was performed to determine the association between SLCO1B1 gene polymorphisms and serum bilirubin levels in vivo. Moreover, the effects of administration of low-dose rifampicin on serum bilirubin levels in different SLCO1B1 genotypes was examined. 2. Serum bilirubin levels were examined in 42 healthy volunteers who had been analysed for SLCO1B1 genotype (seven, 13, 14 and eight with SLCO1B1 genotypes * 1a/* 1a, * 1b/* 1b, * 1b/* 15 and * 15/* 15, respectively). Among them, 24 subjects (seven, seven, eight and two with SLCO1B1 genotypes * 1a/* 1a, * 1b/* 1b, * 1b/* 15 and * 15/* 15, respectively) were selected to participate in an open-label, two-phase clinical trial. Each was given 450 mg rifampicin orally once daily at 2000 hours for 5 consecutive days. Serum bilirubin concentrations at 0800 hours on the 1st and 6th days were compared between the different SLCO1B1 genotypes. 3. In the 42 volunteers, the mean (±SD) serum UCB in both SLCO1B1* 1b/* 15 and * 15/* 15 groups was significantly higher than that in the SLCO1B1* 1b/* 1b group (11.07 ± 2.31, 13.01 ± 3.87 and 8.21 ± 2.68 µmol/L, respectively; P = 0.009 and P < 0.001). Total bilirum (T.BIL) in both the SLCO1B1* 1b/* 15 and * 15/* 15 groups was significantly higher than that in the SLCO1B1* 1b/* 1b group (16.69 ± 4.09, 20.71 ± 5.12 and 13.06 ± 5.12 µmol/L, respectively; P = 0.029 and P < 0.001). The direct bilirubin (D.BIL) in the SLCO1B1* 15/* 15 group was significantly higher than that in the SLCO1B1* 1b/* 1b group (7.69 ± 1.81 vs 4.85 ± 1.81 µmol/L, respectively; P = 0.001). Rifampicin significantly increased UCB, T.BIL and D.BIL concentrations in 24 healthy volunteers (17.68 ± 5.96 vs 13.95 ± 4.44 µmol/L ( P = 0.040), 5.72 ± 2.01 vs 4.35 ± 1.50 µmol/L ( P = 0.028) and 12.00 ± 4.26 vs 9.61 ± 3.15 µmol/L ( P = 0.035), respectively). However, the extent of the increase in serum bilirubin caused by 450 mg rifampicin for 5 days was not affected by SLCO1B1 genotype. 4. Genetic polymorphism in SLCO1B1 is a major determinant of interindividual variability in the serum bilirubin level. SLCO1B1* 15 carriers had higher baseline serum UCB, T.BIL and D.BIL levels compared with subjects with the SLCO1B1* 1a/* 1a and SLCO1B1* 1b/* 1b genotypes. SLCO1B1* 15/* 15 homozygotes are more susceptible to hyperbilirubinaemia. Serum bilirubin levels could be increased by low-dose rifampicin administration, but the extent of the increase was not associated with SLCO1B1 genotype. [ABSTRACT FROM AUTHOR]

Objectives: The human β1-adrenergic receptor, an important therapeutic target in cardiovascular diseases, has 2 common functional polymorphisms (Ser49Gly and Gly389Arg). Our study aimed to confirm that β1-adrenergic receptor polymorphisms affect the blood pressure response to metoprolol monotherapy in the Chinese population with hypertension.Methods: β1-Adrenergic receptor genotype was determined by polymerase chain reaction–restriction fragment length polymorphism assay for 223 patients with essential hypertension. Sixty-one patients with certain β1-adrenergic receptor diplotypes, 18 for 49Ser389Arg/49Ser389Arg, 15 for 49Ser389Arg/49Gly389Arg, 19 for 49Ser389Gly/49Gly389Arg, and 9 for 49Ser389Gly/49Ser389Gly, were selected from those 61 for measurement of the antihypertensive effect of metoprolol. Patients were given 25 mg metoprolol every 12 hours for 4 weeks. Heart rate and blood pressure were measured weekly for the duration of metoprolol therapy.Results: The descent of systolic blood pressure after metoprolol administration was significantly different among genotype groups (10.4% ± 4.0%, 2.8% ± 4.7%, and 1.1% ± 1.5% for Arg389Arg, Gly389Arg, and Gly389Gly patients, respectively; P < .001). We also found a similar difference in changes of diastolic blood pressure (6.1% ± 4.3%, 2.2% ± 4.2%, and 0.9% ± 4.0%, respectively; P < .001) and mean arterial pressure (8.1% ± 3.5%, 2.5% ± 3.0%, and 1.0% ± 2.5%, respectively; P > .001) for Arg389Arg, Gly389Arg, and Gly389Gly patients. Ser49Gly variance exhibited a smaller contribution to the antihypertensive effect of metoprolol. Systolic blood pressure decreased significantly in Ser49 homozygous patients compared with Ser49Gly patients (8.4% ± 3.2% versus 5.3% ± 5.2%, P = .047). There was a highly significant relationship between diplotype and blood pressure during treatment. Systolic blood pressure significantly decreased in 49Ser389Arg/49Ser389Arg (12.0% ± 3.8%, P < .001) and 49Ser389Arg/49Gly389Arg (8.4% ± 5.5%, P < .001) patients, with the decrease in the former being more pronounced (P = .023). We also found a significant decrease in diastolic blood pressure (6.5% ± 4.7% versus 5.7% ± 3.2%, respectively; both P < .001) and mean arterial pressure (8.8% ± 3.2% versus 6.9% ± 3.7%, respectively; both P < .001) in 49Ser389Arg/49Ser389Arg and 49Ser389Arg/49Gly389Arg patients. However, blood pressure did not change significantly in 49Ser389Gly/49Gly389Arg and 49Ser389Gly/49Ser389Gly patients (all P > .05).Conclusions: β1-Adrenergic receptor polymorphism was associated with different blood pressure responses to metoprolol therapy in patients with essential hypertension. 49Ser389Arg/49Ser389Arg and 49Ser389Arg/49Gly389Arg patients were good responders to metoprolol therapy; 49Ser389Arg/49Ser389Arg patients had a larger systolic blood pressure reduction than 49Ser389Arg/49Gly389Arg patients did. 49Ser389Gly/49Gly389Arg and 49Ser389Gly/49Ser389Gly patients were nonresponders to metoprolol antihypertensive therapy.Clinical Pharmacology & Therapeutics (2006) 80, 23–32; doi:10.1016/j.clpt.2006.03.004 [ABSTRACT FROM AUTHOR]