| Background1.Beta-blockers,which cause reduction of heart rate and blood pressure in vivo, is widely used in cardiovascular diseases.Disturbance of blood lipid is a known but seldom-cared side effect of beta-blocker.2.Efficacy and side-effects of beta-blocker shows inter-individual variability. Gene polymorphisms may partly account for the variability.3.Genetic polymorphisms of the beta receptors or of their G proteins could lead to functionally different products,and may consequently cause individualized response to beta-blocker.ObjectivesThe aim of the present study was to investigate the association of the polymorphisms of beta1,2,3 receptors and G proteins with changes of blood pressure,heart rate or lipid after 8-week treatment with metoprolol in hypertensive patients.Methods1.Men and women,who visited the clinic of Fuwai Hospital(from May 2006 to March 2007) with primary mild to moderate hypertension,were enrolled.The baseline clinical measurements included assessment of symptoms,laboratory examination(including plasma concentrations of triglyceride,total cholesterol, high-density lipoprotein,low-density lipoprotein,glucose,etc),ambulatory blood pressure,Holter electrocardiogram and blood sampling.The patients were randomized to receive treatment either with metoprolol fumarate(95mg Qd) or metoprolol tartrate(100mg Qd).The whole trial period were 8 weeks.At the end of 8 weeks,clinical measurements were repeated.2.The following single nucleotide polymorphism(SNP_S) were determined by polymerase chain reaction with restriction fragment length polymorphism or gene sequencing:β1 receptor Ser49Gly,Gly389Arg;β2 receptor Arg16Gly,Gln27Glu;β3 receptor Trp64Arg;guanine nucleotide binding protein,alpha stimulating (GNAS)T393C;G-Protein beta3 subunit(GNB3) C825T.Results1.Association of gene polymorphisms with cardiovascular response to metoprolol①Metoprolols produced a sustained and significant decrease in the parameters of blood pressure and heart rate.②GNB3 C825T genotype was associated with cardiovascular response to metoprolol.The falls in nocturnal systolic blood pressure(SBP) and nocturnal diastolic blood pressure(DBP) by genotype were:CC 11.1±9.3mmHg, 7.9±5.8mmHg;TC 5.8±12.9mmHg,4.5±8.6mmHg;TT 3.6±13.7mmHg,3.0±7.9 mmHg(nocturnal SBP CC vs TT,P=0.025;nocturnal DBP CC vs TT,P=0.014). Stepwise multiple regression analysis was performed to investigate the significant independent determinants of nocturnal blood pressure after 8-week administration of meteprolol.7 Variables were used:age,gender,height,weight,treatment group, baseline nocturnal blood pressure,GNB3 C825T genotype.Baseline nocturnal blood pressure and GNB3 C825T genotype were the only independent predictors of nocturnal blood pressure after 8-week metoprolol treatment.③The gene polymorphisms ofβ1 receptor Ser49Gly,Gly389Arg;β2 receptor Arg16Gly,Gln27Glu;β3 receptor Trp64Arg and GNAS T393C have no association with the changes of heart rate and blood pressure induced by metoprolol.2.Association of gene polymorphisms with disturbance of blood lipid induced by metoprolol①Metoprolols produced a sustained and significant increase in plasma triglyceride(TG) levels,with no effect on total cholesterol,high-density lipoprotein, low-density lipoprotein. ②β2 Receptor Arg16Gly genotype was associated with the changes in TG levels induced by metoprolol.The increases in TG by genotype were:Arg16Arg 0±0.6mmol/L,Arg16Gly 0.4±1.1 mmol/L,Gly16Gly 0.9±2.5 mmol/L(Arg16Gly vs Arg16Arg P=0.036).Stepwise multiple regression analysis was performed to investigate the significant independent determinants of TG after 8-week administration of meteprolol.7 Variables were used:age,gender,height,weight, treatment group,baseline nocturnal blood pressure,Arg16Gly genotype.Baseline TG levels and Arg16Gly genotype were the only independent predictors of TG after 8-week treatment.③The gene polymorphisms ofβ1 receptor Ser49Gly,Gly389Arg;β2 receptor Gln27Glu;β3 receptor Trp64Arg;GNAS T393C and GNB3 C825T have no association with the increase of TG induced by metoprolol.Conclusions1.GNB3 C825T polymorphism associates with cardiovascular response to metoprolol.The falls in nocturnal blood pressure after administration of metoprolol are different between the genotypes(CC＞TC＞TT).2.The gene polymorphisms ofβ1 receptor Ser49Gly,Gly389Arg;β2 receptor Arg16Gly,Gln27Glu;β3 receptor Trp64Arg and GNAS T393C have no association with cardiovascular response to metoprolol.3.β2 Receptor Arg16Gly polymorphism associates with the increase in TG induced by metoprolol.The increases in TG after metoprolol administration are different between the genotypes(Gly16Gly＞Arg16Gly＞Arg16Arg).4.The gene polymorphisms ofβ1 receptor Ser49Gly,Gly389Arg;β2 receptor Gln27Glu;β3 receptor Trp64Arg;GNAS T393C and GNB3 C825T have no association with the increase of TG induced by metoprolol.
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