[Show abstract][Hide abstract] ABSTRACT: This study investigates whether the interaction between angiotensin-converting enzyme (ACE) inhibitors or beta-blockers and the ACE insertion/deletion (I/D) polymorphism or angiotensin receptor II type 1 (AGTR1) 573C/T polymorphism modifies the risk of myocardial infarction (MI) or stroke. In total, 4097 subjects with hypertension were included in this study. The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model. The risk of MI was reduced in current users of ACE inhibitors with the AGTR1 573CT or CC genotype compared to ACE inhibitors with the AGTR1 573TT genotype (synergy index (SI):0.32; 95% confidence interval (CI): 0.14-0.70). No significant drug-gene interaction was found on the risk of stroke (SI:0.82; 95% CI: 0.44-1.52) or in beta-blocker users. Also, no significant drug-gene interaction was found with the ACE I/D polymorphism. In conclusion, subjects with at least one copy of the AGTR1 573C allele might have more benefit from ACE inhibitor therapy.
Full-text · Article · Apr 2008 · The Pharmacogenomics Journal
[Show abstract][Hide abstract] ABSTRACT: This study investigates whether the interaction between diuretics and alpha-adducin (ADD1) G460W or G-protein beta3-subunit (GNB3) rs2301339 polymorphism modifies the risk of myocardial infarction (MI) or stroke. Data were used from the Rotterdam Study. The drug-gene interaction was determined with a Cox proportional hazard model with adjustment for each drug class as time-dependent covariates. The risk of MI in current users of low-ceiling diuretics with one or two copies of the ADD1 W-allele (hazard ration (HR)=0.92) was similar compared to the expected joint effect of the W-allele and low-ceiling diuretics on a multiplicative scale (1.04 x 0.90=0.94) (synergy index (SI):0.99; 95% confidence interval (CI): 0.43-2.27). No drug-gene interaction was found on the risk of stroke (SI:0.66; 95% CI:0.43-1.27). In addition, a trend towards an interaction was found between current use and the GNB3 rs230119 G/A polymorphism on the risk of MI (SI: 0.51; 95% CI: 0.23-1.15), whereas no interaction on the risk of stroke was found (SI: 0.84; 95% CI: 0.46-1.56).
Full-text · Article · Nov 2007 · The Pharmacogenomics Journal
[Show abstract][Hide abstract] ABSTRACT: To investigate whether the angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen M235T or angiotensin II receptor type 1 573C/T polymorphism modify the risk of atherosclerosis associated with beta-blocker or ACE-inhibitor therapy.
Data were used from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, which started in 1990 and included 7983 subjects of >or= 55 years. In this study, 2216 subjects with hypertension were included. Three subclinical measurements were used for atherosclerosis, i.e. peripheral arterial disease, carotid atherosclerosis and aortic atherosclerosis. The interaction between antihypertensive drugs and genetic polymorphisms on the risk of atherosclerosis was determined with binary logistic regression analysis.
The risk of aortic atherosclerosis associated with long-term (>or=4 years) beta-blocker treatment compared with no use of beta-blockers was higher in subjects with the TT genotype than in subjects with the MM genotype of the AGT gene [synergy index (SI) = 3.36; 95% confidence interval (CI) 1.14, 9.97]. The risk of carotid atherosclerosis associated with long-term ACE-inhibitor treatment compared with no use of ACE-inhibitors was lower in subjects with the TT genotype than in subjects with the MM genotype of the AGT gene (SI = 0.20; 95% CI 0.04, 0.95).
Overall, the risk of atherosclerosis in hypertensives taking a beta-blocker or ACE-inhibitor-based regimen was not strongly modified by any of the three candidate gene polymorphisms.
Full-text · Article · Aug 2007 · British Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Angiotensinogen is an essential component of the renin-angiotensin system. ACE-inhibitors and beta-blockers both have a direct influence on this system. To investigate whether the association between use of ACE-inhibitors or beta-blockers and the risk of myocardial infarction (MI) or stroke is modified by the T-allele of the angiotensinogen M235T polymorphism. In this study, 4097 subjects with hypertension , aged 55 years and older, were included from the Rotterdam Study, a population-based prospective cohort study in The Netherlands, from July 1, 1991 onwards. Follow-up ended at the diagnosis date of MI, stroke, death, or the end of the study period (January 1, 2002). The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model with adjustments for each drug class as time-dependent covariates. The risk of MI was increased in current use of ACE-inhibitors with the MT or TT genotype compared to ACE-inhibitors with the MM genotype (Synergy Index (SI): 4.00; 95% CI: 1.32-12.11). A significant drug-gene interaction was not found on the risk of stroke (SI: 1.83; 95% CI: 0.95-3.54) in ACE-inhibitor users or between current use of beta-blockers and the AGT M235T polymorphism on the risk of MI or stroke. ACE-inhibitor users with at least one copy of the 235T-allele of the AGT gene might have an increased risk of MI and stroke.
Full-text · Article · May 2007 · European Journal of HumanGenetics
[Show abstract][Hide abstract] ABSTRACT: Despite the availability of a variety of effective antihypertensive drugs, inadequate control of blood pressure is common in hypertensive patients. The aim of this study was investigate whether the alpha-adducin G460W polymorphism or angiotensinogen M235T polymorphism has an effect on the mean difference in blood pressure in subjects using antihypertensive drugs. Data from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, was used. This study started in 1990 and included 7983 subjects of 55 years and older. Data from three examination rounds were used. Subjects were included when their blood pressure was elevated at 1 or more examinations and/or a diuretic, beta-blocker, calcium antagonist, or ACE inhibitor was used. A marginal generalized linear model was used to assess the drug-gene interaction. In total, 3025 hypertensives were included. No drug-gene interaction on blood pressure levels was found. The mean difference in systolic blood pressure (SBP) between subjects with the W-allele and GG genotype of the alpha-adducin gene was for diuretic users 1.25 mmHg (95% CI:-2.86 to 5.35), for beta-blockers 0.02 mmHg (95% CI:-3.39 to 3.42), for calcium antagonists -0.70 mmHg (95% CI:-5.61 to 4.21), and for ACE inhibitors -3.50 mmHg (95% CI:-9.02 to 2.02). The mean difference in SBP between subjects with the TT and MM genotype was for diuretic users -2.33 mmHg (95% CI:-8.32 to 3.66), for beta-blocker -0.06 mmHg (95% CI:-4.91 to 4.79), for calcium antagonist 0.59 mmHg (95% CI:-5.95 to 7.13), and for ACE inhibitor -2.33 mmHg (95% CI:-9.66 to 5.01). The G460W polymorphism and the M235T polymorphism did not modify the difference in blood pressure levels among subjects who used diuretics, beta-blockers, calcium antagonists, or ACE inhibitors.
Full-text · Article · Aug 2006 · European Journal of HumanGenetics
[Show abstract][Hide abstract] ABSTRACT: Despite the availability of a variety of effective drugs, inadequate control of blood pressure is common. There are some indications that the angiotensin-converting enzyme (ACE) gene modifies the response to antihypertensive drugs, but the results have been inconclusive.
To investigate whether the insertion/deletion polymorphism of the ACE gene modifies blood pressure differences among subjects using diuretics, beta-blockers, calcium-channel antagonists, or ACE inhibitors.
Data were used from the Rotterdam Study, a population-based, prospective, cohort study in the Netherlands, which started in 1990 and included 7983 subjects aged 55 years or older. Data from 3 subsequent cross-sectional investigations were used, as well. Subjects were included if they had high blood pressure during one or more examinations and/or used monotherapy with a diuretic, beta-blocker, calcium-channel antagonist, or ACE inhibitor. A marginal, generalized, linear model was used to assess the association between the mean difference in systolic/diastolic blood pressure and antihypertensive classes stratified by the 3 genotypes.
In total, 3025 hypertensive individuals were included, and 6500 measurements of blood pressure were taken. The percentages of DD, ID, and II genotypes were 28.3%, 51.4%, and 20.3%, respectively. The mean differences in systolic blood pressure between the II and DD genotypes were 0.23 mm Hg (95% CI -5.48 to 5.94) for diuretics, -2.41 mm Hg (95% CI -6.72 to 1.90) for beta-blockers, 2.12 mm Hg (95% CI -4.64 to 8.89) for calcium-channel antagonists, and -2.01 mm Hg (95% CI -9.82 to 5.79) for ACE inhibitors.
The adjusted mean difference in diastolic and systolic blood pressure among diuretic, beta-blocker, calcium-channel antagonist, or ACE inhibitor users was not modified by the ACE insertion/deletion polymorphism.
Full-text · Article · Mar 2006 · Annals of Pharmacotherapy
[Show abstract][Hide abstract] ABSTRACT: Hypertension is a major public health
hazard, because of its high prevalence and strong positive
association with cardiovascular diseases. Suboptimal blood
pressure control is the number one attributable risk for
death in the Western world, despite the possibilities to
treat hypertension. Higher pre-treatment blood pressure
levels are associated with a greater antihypertensive drug
response, but this relation is not specific to a particular
antihypertensive drug or drug class nor can it be predicted
from patients characteristics. Therefore, the selection of
the most appropriate pharmacological treatment for an
individual patient is a matter of trial and errors.
Pharmacogenetics aims to understand how genetic variations
contribute to the variation in response to medication. In
this thesis, we investigated whether five of these drug-gene
interactions modified the effect of antihypertensive drugs on
blood pressure, atherosclerosis, and the risk of myoc!
ardial infarction (MI) and stroke in daily practise. The five
candidate gene polymorphisms were: the angiotensin converting
enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT)
M235T, angiotensin II receptor type 1 (AGTR1) 1166A/C or
573C/T, a-adducin (ADD1) G460W, and Î²3-subunit of the
G-protein (GNB3) 825C/T polymorphism.
The results of this thesis suggests the presences of two
drug-gene interactions i.e. the interaction between the use
of ACE-inhibitors and AGT M235T polymorphism on the risk of
MI and the interaction between the use of diuretics and the
GNB3 825C/T polymorphism on systolic blood pressure.
[Show abstract][Hide abstract] ABSTRACT: Despite the availability of effective antihypertensive drugs, there is a large variation in response to these drugs. This study investigates whether polymorphisms in the angiotensin converting enzyme (I/D), angiotensinogen (M235T), alpha-adducin (G460W), angiotensin II type 1 receptor (1166A/C), or G protein beta(3)-subunit (825C/T) gene modify the mean difference in blood pressure levels among diuretics, beta-blockers, or ACE-inhibitors users. Data were used from the Doetinchem Cohort Study, and blood pressure data were collected from GPs (1987-1997). A marginal generalized linear model (GEE) was used to assess the gene-drug interaction on the mean difference in systolic/diastolic blood pressure. In total, 625 hypertensive individuals were included with a total of 5262 measurements of blood pressure. Only the interaction between diuretic use and the GNB3 825C/T polymorphism was significant (C allele versus TT systolic blood pressure (SBP): 4.33 mmHg [95% CI: 0.14-8.54]). Thus, the mean SBP level among diuretic users may be modified by the GNB3 825C/T polymorphism.
Full-text · Article · Jan 2006 · The Pharmacogenomics Journal
[Show abstract][Hide abstract] ABSTRACT: We investigated whether the insertion/deletion (I/D) polymorphism of the ACE gene modified the adherence to ACE inhibitors as measured by the discontinuation of an ACE inhibitor, or addition of another antihypertensive drug.
This was a cohort study among 239 subjects who started ACE inhibitor therapy. A Cox proportional hazard model was used to calculate relative risk (RR).
During follow-up there was no significant difference between subjects with the DD, ID or II genotype (DD vs II; RR = 1.17, 95%CI: 0.78, 1.77 and ID vs II; RR = 1.06, 95%CI: 0.73, 1.55) in adherence.
The I/D polymorphism of the ACE gene does not influence the adherence to ACE inhibitors.
Full-text · Article · May 2005 · British Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Recent meta-analyses have indicated that the dopamine transporter gene (DAT1) and the dopamine receptor genes D4 (DRD4) and D5 (DRD5) are associated with attention-deficit hyperactivity disorder (ADHD), although single studies frequently failed to show significant association. In a family-based sample of 236 Dutch children with ADHD, we have investigated the previously described variable number of tandem repeat (VNTR) polymorphisms and two additional microsatellites at the DAT1 and DRD4 loci. DRD5 was investigated using the microsatellite that was previously found to be associated. Transmission disequilibrium tests (TDTs) did not show preferential transmission of alleles or two-marker haplotypes to affected offspring. These data suggest that DAT1, DRD4, and DRD5 do not contribute substantially to ADHD in the Dutch population.
Full-text · Article · Jan 2005 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to determine the prevalence, treatment, and control of hypertension, and the determinants of undertreatment in the Dutch population. The study design was cross-sectional. A population-based survey on cardiovascular disease risk factors in the Netherlands from 1996 to 2002 was the setting of the study. A total of 10 820 men and women, aged 30-59 years, were included in the study. The main outcome measures of the study were: Prevalence of hypertension, treatment, and control of hypertension and determinants of undertreatment of hypertension. Hypertension was defined as: systolic blood pressure (SBP) > or =140 mmHg and/or diastolic blood pressure (DBP) > or =90 mmHg, and/or the use of antihypertensive medication. Treated and controlled hypertension was defined as SBP <140 mmHg and DBP <90 mmHg. Multivariate logistic regression was used to assess the determinants of undertreatment. The prevalence of hypertension in men was 21.4% and in women 14.9%, and 17.9% of the hypertensive men and 38.5% of the hypertensive women were receiving antihypertensive medication. Of the untreated hypertensives, 21.9% of the men and 13.6% of the women were eligible for treatment with antihypertensive medication according to Dutch guidelines. Female gender and the use of cholesterol-lowering medication were associated with an increased chance of being treated. Subjects who were physically active, on a low salt diet, and current smokers had an increased chance of being untreated. Taking cholesterol-lowering medication and no asthma or allergy were factors associated with better control of blood pressure. In conclusion, a considerable proportion of hypertensives were untreated and uncontrolled. Therefore, the detection and control of hypertension in the Netherlands needs to improve. Several groups of hypertensives were identified that need additional care and attention.
Full-text · Article · Jun 2004 · Journal of Human Hypertension
[Show abstract][Hide abstract] ABSTRACT: Genetic factors may influence the response to antihypertensive medication. A number of studies have investigated genetic polymorphisms as determinants of cardiovascular response to antihypertensive drug therapy. In most candidate gene studies, no such drug-gene interactions were found. However, there is observational evidence that hypertensive patients with the 460 W allele of the alpha-adducin gene have a lower risk of myocardial infarction and stroke when treated with diuretics compared with other antihypertensive therapies. With regard to blood pressure response, interactions were found between genetic polymorphisms for endothelial nitric oxide synthase and diuretics, the alpha-adducin gene and diuretics, the alpha-subunit of G protein and beta-adrenoceptor antagonists, and the ACE gene and angiotensin II type 1 (AT(1)) receptor antagonists. Other studies found an interaction between ACE inhibitors and the ACE insertion/deletion (I/D) polymorphism, which resulted in differences in AT(1) receptor mRNA expression, left ventricular hypertrophy and arterial stiffness between different genetic variants. Also, drug-gene interactions between calcium channel antagonists and ACE I/D polymorphism regarding arterial stiffness have been reported. Unfortunately, the quality of these studies is quite variable. Given the methodological problems, the results from the candidate gene studies are still inconclusive and further research is necessary.
[Show abstract][Hide abstract] ABSTRACT: DNA pooling methods may enable large-scale association studies in complex disorders. However, interpretation of pooling data is difficult due to PCR-induced stutter bands and differential amplification. Aim of this study was to design an efficient correction method for both artefacts to improve the power of DNA pooling for candidate gene studies in psychiatric disorders. Regression analyses were performed on progressively smaller samples of existing genotypes of 10 di- and tetranucleotide repeat markers. Stutter showed a linear relationship with allele length, while differential amplification varied with both absolute length and size difference of the two alleles from a heterozygote. Stutter and differential amplification could be predicted with > 90% accuracy from 10 heterozygous individuals. A correction method based on marker data from 15 genotypes was tested in a replication study of associations of Celiac disease with markers from the HLA region. Analysis of uncorrected pool patterns could only identify strongly associated alleles. Our correction method, however, also allowed replication of weak associations. Here we present how this method is used in ADHD candidate gene studies in pools of 110 persons. To increase power multiple markers for each gene locus were included.
No preview · Article · Oct 2001 · American Journal of Medical Genetics