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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2007 Feb 12;64(1):57–66. doi: 10.1111/j.1365-2125.2007.02848.x

Pharmacogenetic interactions of three candidate gene polymorphisms with ACE-inhibitors or β-blockers and the risk of atherosclerosis

H Schelleman 1,2, O H Klungel 1, J C M Witteman 2, A Hofman 2, C M van Duijn 2, A de Boer 1, B H CH Stricker 2
PMCID: PMC2000614  PMID: 17298481

Abstract

What is already known about this subject

  • To our knowledge, there are no prior studies which investigate whether there is a drug–gene interaction between the three genes involved in the renin–angiotensin system and ACE-inhibitor therapy or β-blocker therapy with these subclinical measurements of atherosclerosis.

  • Some studies have found an effect on blood pressure or stroke/myocardial infarction, although the results are not conclusive.

What this study adds

  • The results do not indicate the presence of a strong drug–gene interaction between the use of ACE-inhibitors or β-blockers and the ACE insertion/deletion, AGT M235T or AGTR1573C/T polymorphism on the overall risk of atherosclerosis.

Aims

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 β-blocker or ACE-inhibitor therapy.

Methods

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 ≥ 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.

Results

The risk of aortic atherosclerosis associated with long-term (≥4 years) β-blocker treatment compared with no use of β-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).

Conclusion

Overall, the risk of atherosclerosis in hypertensives taking a β-blocker or ACE-inhibitor-based regimen was not strongly modified by any of the three candidate gene polymorphisms.

Keywords: antihypertensive drugs, atherosclerosis, pharmacogenetics, polymorphisms

Introduction

Knowledge of pharmacogenetic determinants of the interaction between antihypertensive drugs and the renin–angiotensin system might optimise the effectiveness of therapy.

The renin–angiotensin system plays an important role in vascular homeostasis. The vasoactive peptide angiotensin II is generated by sequential cleavage of angiotensinogen (AGT) by renin and by angiotensin converting enzyme (ACE). Besides regulating blood pressure, angiotensin II also has various actions that can damage blood vessels. For example, angiotensin II stimulates NADH and NADPH activity and thereby raises the oxidative potential of vascular tissue [1, 2]. In addition, it plays a role in the vascular-injury response, since it stimulates leucocyte adhesion to the site of the injury. In addition, it favours superoxide and peroxynitrite formation and proliferation and migration of various cell types towards the luminal site of injury [3]. The cascade of events that follows results, for example, in atherosclerotic plaques. Angiotensin II and some of its constituent peptides also stimulate the synthesis of the plasminogen activator inhibitor 1 (PAI1). Therefore, it is thought that activation of the renin–angiotensin system predisposes to atherosclerosis and thromboembolic events, including myocardial infarction (MI) and stroke [4, 5].

Of the four antihypertensive drug classes mainly prescribed (i.e. diuretics, β-blockers, calcium channel blockers and ACE-inhibitors), only ACE-inhibitors and β-blockers have a direct effect on the renin–angiotensin system, i.e. ACE-inhibitors inhibit the conversion from angiotensin I into angiotensin II and β-blockers inhibit the β-adrenoceptor-mediated release of renin from the kidneys. The objective of this study was to determine whether the risk of atherosclerosis varies between ACE-inhibitor and β-blocker users with different genotypes of genes that are involved in the renin–angiotensin system, i.e. ACE, AGT and angiotensin receptor II type 1 (AGTR1) gene.

Methods

Setting and design

The Rotterdam Study is a prospective, population-based cohort study, which started in 1990. All 10 275 residents of the suburb Ommoord in Rotterdam aged ≥55 years were invited to participate in an extensive home interview and two visits to the research centre. This study was approved by the Medical Ethics Committee of Erasmus University and conducted in compliance with their requirements. In total, 7983 (78%) subjects gave written informed consent and baseline measurements took place until 1993. Information was collected on present health status and medical history, including previous MI and stroke. All reported MIs and stroke at baseline were verified with medical records. Almost all study participants were White (>99%). During a physical examination, blood pressure, weight and height were measured and blood was drawn for DNA extraction. In total, blood samples were available for genotyping of 86% of the cohort. The design of this population-based study has been described elsewhere [6]. A second (1993–1995) and third (1997–1999) cross-sectional assessment were conducted in a similar way. Only atherosclerosis measurements from the third cross-sectional assessment were included, since a limited number of atherosclerosis measurements were performed in the second assessment and pharmacy records were available only as of 1 January 1991, which is later than most of the baseline atherosclerosis assessments. Of 3506 participants, information on at least one measure of atherosclerosis, assessed during the third cross-sectional assessment, was available. We included only individuals with hypertension and defined this as systolic blood pressure (SBP) ≥160 mmHg and/or diastolic blood pressure (DBP) ≥95 mmHg, and/or the use of an antihypertensive drug during follow-up.

Outcome definition

Atherosclerosis of the lower extremities

SBP at the ankles (posterior tibial artery) was measured in the supine position with a random-zero sphygmomanometer and an 8-MHz continuous wave Doppler probe (Huntleigh 500D; Huntleigh Technology, Luton, UK). The ratio of the SBP at the ankle to that at the arm was calculated to obtain the ankle–arm index (AAI). Peripheral arterial disease was considered present when the ankle-brachial blood pressure index was <0.90 in at least one leg [7]. The sensitivity and the specificity of this cut-off are 90% and 98%, respectively, for an angiographically defined stenosis of ≥50% in a major leg artery [8].

Aortic atherosclerosis

Aortic atherosclerosis was diagnosed by radiographic detection of calcified deposits in the abdominal aorta on a lateral abdominal film [9]. Calcified deposits were graduated on a graded scale (with scores of 0 to 5 corresponding to 0, ≤1, 1–2.5, 2.5–4.9, 5.0–9.9 and ≥10 cm, respectively). Aortic atherosclerosis was considered present if the score was ≥1. In addition, aortic atherosclerosis was divided in degrees of severity, i.e. score of 0, 1–2 and ≥3.

Carotid atherosclerosis

Ultrasonography of both carotid arteries was performed with a 7.5-MHz linear-array transducer and a duplex scanner (ATL Ultra-Mark IV; Advanced Technology Laboratories, Bethesda, MD, USA). The common carotid artery, carotid bifurcation and internal carotid artery were examined on both the left and right sides for the presence of plaques as described previously [10]. A weighted plaque score ranging from 0 to 6 was computed by adding the number of sites at which a plaque was detected, divided by the number of sites for which an ultrasonographic image was available, and multiplied by 6 (the maximum number of sites). Carotid atherosclerosis was considered present if the plaque score was ≥1. Carotid atherosclerosis was also divided in degrees of severity, i.e. plaque score of 0, 1–2, 3 and ≥4.

Exposure definition

Pharmacy records were available for approximately 99% of the cohort as of 1 January 1991. These records include the name of the drug, the day of dispensing, the dosage form, the number of units dispensed, the prescribed daily dose and the Anatomical Therapeutic Chemical (ATC) code of the drug [11]. The exposure of interest included ACE-inhibitors and β-blockers, because of their direct effect on the renin–angiotensin system. The use of these antihypertensive drug classes was divided into three categories, i.e. no use, short-term (0–4 years) and long-term (≥4 years). These categories were chosen because of the expected lag-time between drug exposure and the effect on atherosclerosis.

On the date of atherosclerosis measurement, the cumulative duration of use was calculated for all antihypertensive drug classes for each participant. We first calculated each prescription length by dividing the number of dispensed tablets or capsules by the prescribed daily number. Each refill at the pharmacy which occurred within 7 days after last intake from the previous prescription was considered as a continuous drug episode. For dose–effect associations, we used the defined daily dose (DDD). The DDD is a standardized dosing unit defined as the recommended dosage for the main indication in an adult of 70 kg.

Genotyping

Genomic DNA was extracted from whole blood samples using standard methods, described previously [12]. The I and D allele of the ACE gene were identified on the basis of polymerase chain reaction (PCR) technique according to the method of Lindpainter et al.[13], with some modifications. Because the D-allele in heterozygous samples is preferentially amplified, there is a tendency of misclassification for about 4–5% of the ID to DD genotypes. For this reason, a second PCR was performed with a primer pair that recognizes an insertion-specific sequence (5′-TGG GAC CAC AGC GCC CAC TAC-3′ and 5′-TCG CCA GCC CTC CCA TGC CCA TAA-3′). The reaction yielded a 335-bp amplicon only if the I-allele was present. Two independent investigators read pictures from each gel and all ambiguous samples were analysed a second time.

The AGT M235T and AGTR1 573C/T (exon 5) polymorphism were genotyped with TaqMan allelic discrimination Assays-By-Design (Applied Biosystems, Foster City, CA, USA). Forward and reverse primer (antisense strand) sequences were 5′-AGG TTT GCC TTA CCT TGG AAG TG-3′ and 5′-GCT GTG ACA GGA TGG AAG ACT-3′ and the minor groove binding probes were 5′-CTG GCT CCC ATC AGG-3′ (VIC) and 5′-CTG GCT CCC GTC AGG-3′ (FAM) for the AGT gene. Forward and reverse primer sequences were 5′-TGT GCT TTC CAT TAT GAG TCC CAA A-3′ and 5′-CAG AAA AGG AAA CAG GAA ACC CAG TAT A-3′ and the minor groove binding probes were 5′-CTA TCG GGA GGG TTG-3′ (VIC) and 5′-CTA TCG GAA GGG TTG-3′ (FAM) for the AGTR1 gene. The assays utilized 5 ng of genomic DNA and 2-µl reaction volumes. The amplification and extension protocol was as follows: an initial activation step of 10 min at 95°C preceded 40 cycles of denaturation at 95°C for 15 s and annealing and extension at 50°C for 60 s. Allele-specific fluorescence was then analysed on an ABI Prism 7900HT Sequence Detection System with SDS v 2.1 (Applied Biosystems).

Potential confounders

As potential confounders we considered age, gender, diabetes mellitus, SBP, DBP, body mass index, use of coumarins, angina pectoris, history of stroke, history of coronary heart disease, smoking, cholesterol level (total cholesterol/high-density cholesterol), follow-up time, cumulative use of other antihypertensive drugs (i.e. loop diuretics, thiazide diuretics, calcium-antagonists, angiotensin II receptor antagonists, α-blockers, and ACE-inhibitors or β-blockers) and DDD. We adjusted for the combined use of other antihypertensive drug classes by adding each antihypertensive drug class separately in the model for no use, short-term and long-term treatment. The same duration of use categories were used for statin therapy. History of angina pectoris was defined as the use of two or more prescriptions of nitrate. History of coronary heart disease was defined as a history of MI, history of percutaneous transluminal coronary angioplasty and history of coronary artery bypass grafting.

Statistical analysis

Binary logistic regression was used for the end-points: presence of peripheral arterial disease, presence of aortic atherosclerosis and presence of carotid atherosclerosis. Cumulative use of antihypertensive drugs was divided into three mutually exclusive groups, i.e. no, short-term (0–4 years) and long-term treatment (≥4 years). In a sensitivity analysis, cut-off points of 2 and 3 years were also used. Multinomial logistic regression was used for the degrees of severity analysis for the outcomes: aortic and carotid atherosclerosis.

We calculated the synergy index (SI), which is the ratio of the odds ratio (OR) in susceptibles (e.g. in subjects with the II genotype) to the OR in subjects with the DD genotype. To investigate the SI between the ACE I/D polymorphism and ACE-inhibitors, four dummy variables were added to the model, e.g. ACE genotype (ID or II) × ACE-inhibitor (short-term or long-term treatment). The reference group consisted of subjects with the DD genotype, who had a prescription of the antihypertensive drug class in question (short-term or long-term). The OR of the treated subjects was defined as the OR of subjects who used the antihypertensive drug class in question minus the OR in untreated subjects with the same genotype. A SI of 1 means that the OR in the two subgroups are the same and that there is no drug–gene interaction on a multiplicative scale. A SI > 1 means that the joint effect of the gene and drug is larger than expected from the product of their individual effects [14].

Results

In total, there were 2305 subjects with hypertension during follow-up. Data on atherosclerosis and blood samples were available from 2216 (96.1%) subjects. Of these 2216 subjects, 727 were treated with ACE-inhibitors, 1267 with β-blockers and 1556 with antihypertensive drugs from other classes. A subject could contribute to one or more categories of antihypertensive drug classes during follow-up. Table 1 shows the characteristics of the subjects included in the study at the moment of the third cross-sectional assessment.

Table 1.

Characteristics of the study population from the third cross-sectional assessment

Characteristics N = 2216
Age, years 73.74 ± 23.26
Gender, male 915 (41.3%)
Systolic blood pressure, mmHg 153.08 ± 71.13
Diastolic blood pressure, mmHg 82.41 ± 74.13
Body mass index, kg m−2 73.74 ± 7.02
Total cholesterol/HDL, mmol l−1 10.59 ± 23.26
Cardiovascular disease, yes 437 (19.7%)
Stroke, yes 128 (5.8%)
Smoking, current/past/never 329/1110/758
ACE gene, DD/ID/II 570/1130/464
AGT gene, MM/MT/TT 760/963/333
AGTR1 gene, CC/CT/TT 559/995/478
Use of ACE-inhibitors, 0/0–4/≥4 years 1489/495/232
Use of β-blockers, 0/0–4/≥4 years 949/773/494
Use of other antihypertensive drugs 1556 (70.2%)
No antihypertensive drug 197 (8.9%)
Use of statins 489 (32.1%)
Use of coumarins 162 (7.3%)
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All three polymorphisms were in Hardy–Weinberg equilibrium. The ACE genotype could be assessed in 2164 subjects. Of these, 26.3%, 52.2% and 21.4% had the DD, ID and II genotype, respectively. The AGT genotype could be assessed in 2056 subjects, of whom 37% had the MM, 46.8% the MT and 16.2% the TT genotype. With regard to the AGTR1 genotype, 2032 could be genotyped, of whom 27.5% had the CC, 49% the CT and 23.5% the TT genotype, respectively.

ACE I/D polymorphism

Figure 1 shows the association between the use of β-blockers or ACE-inhibitors and ACE I/D polymorphism and the risk of peripheral arterial disease, aortic atherosclerosis and carotid atherosclerosis. Hypertensive subjects not treated with ACE-inhibitors with the ACE II genotype had a similar risk of peripheral arterial disease compared with untreated hypertensive subjects with the DD genotype [OR = 0.89; 95% confidence interval (CI) 0.58, 1.35]. In individuals with the DD genotype who had been treated long-term (≥4 years) with ACE-inhibitors, the risk of peripheral arterial disease was higher compared with untreated subjects with the DD genotype (OR = 2.75; 95% CI 1.30, 5.81). Individuals with the II genotype and treated long-term with ACE-inhibitors had an increased risk of peripheral arterial disease (OR = 1.61; 95% CI 0.67, 3.89) compared with untreated subjects with the DD genotype. The estimate for the risk of peripheral arterial disease in subjects with the II genotype (OR = 1.61) is lower than expected from the joint effect of the DD genotype and ACE-inhibitors on a multiplicative scale (0.89 × 2.75). The interaction between long-term use of ACE-inhibitors and the ACE I/D polymorphism was not significant (SI = 0.66; 95% CI 0.23, 1.87). In addition, in those treated with β-blockers there was no drug–gene interaction with this polymorphism (see Figure 1a).

Figure 1.

Figure 1

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Associations between use of β-blockers or ACE-inhibitors and ACE I/D polymorphism on the risk of peripheral arterial disease (first histogram), aortic atherosclerosis (second histogram) and carotid atherosclerosis (third histogram) (adjusted for all potential confounders)

In individuals with the II genotype who were treated long-term with ACE-inhibitors the risk of aortic atherosclerosis was increased to 4.37 (95% CI 1.11, 17.31) compared with untreated subjects with the DD genotype (see Figure 1b). The risk of subjects with the II genotype and treated long-term with β-blockers was reduced to 0.40 (95% CI 0.18, 0.89) compared with those untreated with the DD genotype (see Figure 1c). For both outcomes no drug–gene interaction was found in those treated with β-blockers or ACE-inhibitors with the ACE I/D polymorphism.

AGT M235T polymorphism

The risk of peripheral arterial disease was increased to 2.19 (95% CI 1.11, 4.29) for individuals treated long-term with ACE-inhibitors with the MT genotype and for those with the TT genotype to 2.55 (95% CI 1.09, 5.98) compared with untreated subjects with the MM genotype (see Figure 2a). However, there was no interaction between ACE-inhibitors or β-blockers and the AGT M235T polymorphism on the risk of peripheral arterial disease.

Figure 2.

Figure 2

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Associations between use of β-blockers or ACE-inhibitors and AGT M235T polymorphism on the risk of peripheral arterial disease (first histogram), aortic atherosclerosis (second histogram) and carotid atherosclerosis (third histogram) (adjusted for all potential confounders). *Drug–gene interaction (P-value < 0.05)

For individuals treated long-term with β-blockers with the TT genotype the risk of aortic atherosclerosis was higher, i.e. 1.28 (95% CI 0.48, 3.46) compared with untreated subjects with the MM genotype. Subjects with the TT genotype and treated with β-blockers had a 3.36 higher risk of aortic atherosclerosis then β-blocker users with the MM genotype (SI = 3.36; 95% CI 1.14, 9.97). However, there was no drug–gene interaction when severe aortic atherosclerosis (score ≥3) was compared with no presence of aortic atherosclerosis (score = 0) (data not shown). In addition, a drug–gene interaction was not found in those treated with ACE-inhibitors.

There was an interaction between long-term treatment with ACE-inhibitors and the angiotensinogen M235T polymorphism on the risk of carotid atherosclerosis (SI = 0.20; 95% CI 0.04, 0.95) (see Figure 2c). There was no trend towards a drug–gene interaction when carotid atherosclerosis was classified in more categories of severity or when severe carotid atherosclerosis (score ≥4) was compared with no presence of carotid atherosclerosis (score = 0) (data not shown).

AGTR1 573C/T (exon 5) polymorphism

With regard to AGTR1 polymorphism, no drug–gene interaction was found in those treated on the risk of peripheral arterial disease (see Figure 3a). There was an increased risk for individuals with the CC genotype and long-term treatment with ACE-inhibitors compared with untreated subjects with the CC genotype (OR = 2.93; 95% CI 1.39, 6.17).

Figure 3.

Figure 3

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Associations between use of β-blockers or ACE-inhibitors and AGTR1 573C/T polymorphism on the risk of peripheral arterial disease (first histogram), aortic atherosclerosis (second histogram) and carotid atherosclerosis (third histogram) (adjusted for all potential confounders)

Also, no drug–gene interaction was found on the risk of aortic atherosclerosis (see Figure 3b). Long-term β-blockers users with the CC genotype had a reduced risk of carotid atherosclerosis compared with those untreated with the CC genotype (OR = 0.32; 95% CI 0.14, 0.71), but no drug–gene interaction in β-blockers or ACE-inhibitor users was found (see Figure 3c).

Discussion

Although some of the individual measurements of atherosclerosis showed a significant drug–gene interaction, there was no consistency between the different atherosclerosis measurements, the different antihypertensive drug classes or different genotype classes. In addition, there was no trend towards a drug–gene interaction when aortic and carotid atherosclerosis was classified in more categories of degree of severity. It is therefore most likely that the drug–gene interactions found were false positive. The data do not suggest that there was a strong drug–gene interaction between ACE I/D, AGT M235T, or AGTR1 573C/T polymorphism and the use of ACE-inhibitors or β-blockers on the risk of atherosclerosis found in daily practice.

In this study, we have used three different subclinical measurements for atherosclerosis. All three measurements have been validated previously. Carotid atherosclerosis as shown on ultrasound, aortic atherosclerosis on abdominal X-ray and lower-extremity atherosclerosis reflected by the AAI are validated measures of atherosclerosis and strongly associated, for example, with the presence of coronary calcification [15], coronary heart disease [16, 17] and stroke [18]. Although carotid plaques and AAI are predictors of stroke, they are less strong predictors than aortic calcification [19].

To our knowledge, no previous study has investigated whether there is a drug–gene interaction between the three candidate gene polymorphisms and ACE-inhibitor therapy or β-blocker therapy with these subclinical measurements of atherosclerosis. Two of the three polymorphisms we have investigated have earlier been investigated on other outcomes. For example, the ACE II genotype is associated with lower tissue and plasma levels of ACE compared with the DD genotype [20, 21]. In a large trial, no drug–gene interaction was found on the risk of cardiovascular disease between the I/D polymorphism and ACE-inhibitor therapy [22]. With regard to the AGT M235T polymorphism, subjects with the TT genotype have in general 10–20% higher plasma AGT concentrations than individuals with the MM genotype [23, 24]. However, Hopkins et al.[25] reported no difference in angiotensin II levels between the genotype groups. Bis et al.[26] have reported that subjects carrying one copy of the T-allele who used ACE-inhibitors might have a reduced risk of (nonfatal) stroke compared with users of other antihypertensive drugs, but this interaction was not found on MI. Only with regard to the AGTR1 573C/T polymorphism is no information available on plasma levels or on the risk of MI or stroke. Benetos et al.[27] found a significantly greater reduction in carotid-femoral pulse wave velocity with the AGTR1 1166A/C (exon 5) polymorphism in 40 patients treated with ACE-inhibitors. The distance between the AGTR1 1166A/C polymorphism and the 573C/T polymorphism is about 500 base pairs.

A limitation of this study is that we had only a limited number of pretreatment atherosclerosis measurements and were therefore unable to measure the progression/reduction of atherosclerosis. In addition, subjects included in the Rotterdam Study were ≥55 years when the study started. Younger subjects respond better to antihypertensive drug treatment and this might have resulted in greater differences in atherosclerosis levels. Therefore, the results can not be generalized to the general population. Another limitation is that it is unknown how long a patient should be treated with antihypertensive drugs before a change in peripheral, carotid or aortic atherosclerosis can be achieved. In our analysis, we used 4 years as a cut-off value for cumulative duration of antihypertensive drug use. The data were also analysed with other cut-off values, i.e. 2 and 3 years. The results changed slightly, but there was no consistent drug–gene interaction with any of the three candidate gene polymorphisms. Due to the limited number of subjects treated for ≥5 years, we could not extend our drug treatment window. In addition, the effect of the polymorphisms on the progression of atherosclerosis is unknown. Since pharmacy dispensing data were collected from 1991, we were unable to determine whether those who were unresponsive to therapy switched to other antihypertensives prior to recruitment into the cohort. To deal with this potential confounding by indication, we also performed an analysis restricted to incident users during follow-up. Although the risk estimates were more or less similar, results were no longer significant due to low numbers. We were also unable to determine whether the risk of atherosclerosis varies between angiotensin II receptor antagonist due to limited power. Another limitation is that only one single nucleotide polymorphism per gene was examined, which may not explain the full variation in plasma or tissue levels. Therefore, we are able to exclude only a candidate gene polymorphism and not a complete gene as candidate for a drug–gene interaction. Despite the caveats, the results did not indicate the presence of a strong drug–gene interaction between the use of ACE-inhibitors or β-blockers and the ACE I/D, AGT M235T or AGTR1 573C/T polymorphism on the overall risk of atherosclerosis.

Acknowledgments

The Netherlands Heart Foundation financially supported this study, grant number 2001.064. The Rotterdam Study is funded by the Netherlands Organization for Scientific Research (NWO) and the Municipality of Rotterdam.

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