| Background1. Genetic factor can influence the variability in metoprolol's therapeutic result and adverse effect, many studies focused on the effect ofβ-adrenergic receptor, which a small part of the variability could be derived from.2. Besides P-adrenergic receptor, the polymorphisms in angiotensin-converting enzyme (ACE) and a-adrenergic receptor may affect the antihypertensive response to metoprolol, little is known about their relation.3. The level of triglyceride (TG) in plasma is determined by enzyme involved in its metabolism, the relationship between the elevated TG induced by metoprolol and the polymorphisms of those enzyme is unclear.4. Metoprolol is metabolized by CYP2D6, a few of studies investigated the influence of CYP2D6*10 polymorphism on metoprolol's therapeutic result and adverse effect.ObjectivesThe aim of the present study was to investigate:1 the association of the polymorphism of ACE and a-adrenergic receptor and proteins in endothelial and smell muscle cells and metoprolol's therapeutic result; and 2 the association of the polymorphism of enzyme involved in TG metabolism and the elevated TG induced by metoprolol; and 3 the influence of CYP2D6*10 polymorphism on metoprolol's therapeutic result and adverse effect.MethodsNinety-seven patients with essential hypertension, who visited the FUWAI hospital (from May 2006 to March 2007), received metoprolol (95/100mg once daily) as monotherapy for 8 weeks. Twenty-four hour ambulatory blood pressure monitoring and dynamic electrocardiogram were performed before and after treatment, some biochemical index was measured to assess the influence of metoprolol on metabolism during treatment.The following single nucleotide polymorphisms (SNPs) were determined by polymerase chain reaction with restriction fragment length polymorphism or gene sequencing:angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) G1566T, angiotensin receptor I (AGTR1) C961T and A1166C, a 1D adrenergic receptor A1903T, endothelial nitric oxide synthase (eNOS) Glu298Asp, theβ1-subunit of the large-conductance, Ca2+-dependent K+(BK) channel (KCNMB1) E65K, Lipoprotein lipase (LPL) HindⅢand S447X, Low density lipoprotein receptor (LDL) C16370T, apolipoprotein (APOA5) A-1131G, PLIN C114829T, CYP2D6 C188T.Results1. Association of gene polymorphisms with cardiovascular to metoprolol1.1 ACE gene I/D had an effect on difference in 24-hour average heart rate during the treatment, patients with ACE geneⅡpolymorphism showed greater reduction in 24-hour average HR than those with ID or DD polymorphisms (8.7±8.2 beats/min vs 5.5±6.3 beats/min,P= 0.045).1.2 eNOS Glu298Asp influenced the difference in 24-hour average systolic blood press (SBP) and daytime SBP and nocturnal SBP, in patients with GG genotype the fall was 3.3±11.3 mmHg,3.7±11.9 mmHg and 3.8±14.9 mmHg, while in GT and TT genotypes the fall was 8.4±8.7 mmHg,5.9±6.2 mmHg and 9.9±8.6 mmHg (P value was 0.021,0.045 and 0.024).1.3 The other polymorphisms had no association with the changes in BP and heart rate.2. Association of gene polymorphisms with the elevated TG induced by metoprolol1.1 PLIN C1229T influenced the difference in TG during the treatment, patients with TT genotype had the greatest increase in TG than those with CT or CC genotype (1.40±3.21 mmol/L,0.26±1.07 mmol/L and 0.23±1.02 mmol/L, P= 0.045); and changes of heart rate in clinic were influenced by this polymorphism, the difference in TT was-4.0±8.6 beats/min, in CT was 6.8±8.6 beats/min and in CC beats/min was 7.12±9.28 beats/min, P=0.046.1.2 The other polymorphisms had no association with the changes in TG.3. The influence of CYP2D6*10 on TG and cardiovascular to metoprololA tendency had been observed that the difference in daytime diastolic blood pressure (DBP) was classified by this polymorphism, the reduction was 6.9±6.8 mmHg in CC genotype group,3.9±6.2 mmHg in CT genotype group, and 5.6±6.3 mmHg in TT genotype group. Statistical difference was observed between CT and TT genotype group, P=0.045.Conclusions1. ACE gene I/D had an effect on difference in 24-hour average heart rate during the treatment with metoprolol.2. eNOS Glu298Asp (G/T) influenced the difference in 24-hour average systolic blood press (SBP) and daytime SBP and nocturnal SBP.3. PLIN C11482T influenced the difference in TG and heart rate induced by metoprolol.4. CYP2D6*10 maybe a genetic marker for change in daytime DBP induced by metoprolol.
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