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Am Heart J. 2007 January ; 153(1): 54–58. doi:10.1016/j.ahj.2006.10.019.

Absence of an interaction between the angiotensin converting

enzyme (ACE) insertion-deletion polymorphism and pravastatin
on cardiovascular disease in high-risk hypertensives: The
GenHAT Study

Anke-Hilse Maitland-van der Zee, PharmD, PhD1,2, Eric Boerwinkle, PhD1, Donna K. Arnett,
PhD3, Barry R. Davis, MD, PhD1, Catherine Leiendecker-Foster, MS4, Michael B. Miller,
PhD3, Olaf H. Klungel, PharmD, PhD2, Charles E. Ford, PhD1, and John H. Eckfeldt, MD,
PhD4

1
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University of Texas Health Science Center at Houston, School of Public Health, 1200 Hermann
Pressler, Houston Tx 77030. Phone 713 500 9817, Fax 713 500 0900 Email:
a.h.maitland@pharm.uu.nl 2 Department of Pharmacoepidemiology & Pharmacotherapy, Utrecht
Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands 3
University of Alabama at Birmingham, 1665 University Avenue, Birmingham, AL, 35294 4 University
of Minnesota, Department of Laboratory Medicine and Pathology, 420 Delaware Street SE MMC
609, Minneapolis, MN 55455

Abstract
Background—The aim of this study was to determine whether the ACE insertion-deletion (I/D)
polymorphism interacts with pravastatin to modify the risk of CHD and other cardiovascular
endpoints in a large clinical trial.
Methods—GenHAT is an ancillary study of the Antihypertensive and Lipid Lowering Treatment
to Prevent Heart Attack Trial (ALLHAT). The ACE ID genotyped population in the lipid lowering
arm of ALLHAT included 9,467 participants randomly assigned to pravastatin (n=4741) or to usual
care (n=4726). The efficacy of pravastatin in reducing the risk of primary outcome (all cause
mortality), and secondary outcomes (fatal CHD and non-fatal MI, CVD mortality, CHD, stroke, other
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CVD, non-CVD mortality, stroke and heart failure) was compared between the genotype strata
(dominant model ID+II versus DD, additive model II vs ID vs DD), by examining an interaction
term in a Cox proportional Hazard model.
Results—The relative risk of fatal CHD and nonfatal MI among subjects randomized to pravastatin
compared to subjects randomized to usual care was similar in subjects with the II genotype (HR 0.84
[95% CI 0.59–1.18]), the ID genotype (HR 0.84 [95%CI 0.68–1.03], and the DD genotype (HR 0.99
[95%CI:0.77–1.27]).
Conclusions—We found no evidence that ACE I/D genotype was a major modifier of the efficacy
of pravastatin in reducing the risk of cardiovascular events.

Correspondence to: Anke-Hilse Maitland-van der Zee.

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Introduction
The efficacy of cholesterol-lowering drug therapy in primary and secondary prevention has
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been firmly established. The combined results of 9 large long-term statin trials (including the
ALLHAT-lipid lowering trial (ALLHAT-LLT)) showed a 27% reduction in coronary heart
disease (CHD) events and a 14% reduction in all-cause mortality [1–9]. These reductions,
however, were average effects of statin therapy for all patients included in the trials.
Pharmacogenetic findings suggest that patients may differ in their response to statins because
of their genetic constitution [10].

The angiotensin converting enzyme (ACE) is thought to play an important role in the
development of coronary artery disease. Plasma and cellular levels of ACE are associated with
a large insertion/deletion polymorphism located in intron 16 of the ACE gene. DD carriers
have about twice the plasma levels of ACE compared with II carriers, while heterozygotes
have intermediate levels [11]. In a meta-analysis including 145 reports with an overall sample
size of 49,959, the excess risk in subjects with the DD genotype compared to subjects with the
II genotype was 32% for coronary heart disease (30 studies) and 45% for myocardial infarction
(20 studies) [12].

Contradictory results have been published on the influence of the ACE I/D polymorphism on
the effectiveness of statins. In the Cholesterol And Recurrent Events (CARE) trial no effect
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was found for the ACE I/D polymorphism alone on the efficacy of pravastatin in reducing the
primary endpoint [13]. In the Lipoprotein and Coronary Atherosclerosis (LCAS) study,
subjects with the ACE DD genotype had the strongest reduction of coronary atherosclerosis
with pravastatin. However, the distribution of clinical events among genotypes was not
significantly different [14]. In an observational cohort study among subjects with
hypercholesterolemia the beneficial effect of statins on coronary heart disease was different
for men with different ACE genotypes. In men with two I alleles, the largest beneficial effects
of statins were demonstrated while in men with two D alleles no beneficial effects were
demonstrated [15]. The objective of this study was to determine whether the ACE I/D
polymorphism interacts with pravastatin to modify the risk of CHD and other cardiovascular
endpoints in a large randomized clinical trial of high-risk individuals.

Methods
Study Population and Design
GenHAT is an ancillary study of the Antihypertensive and Lipid Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT). The lipid lowering trial (LLT) component of ALLHAT
was designed to evaluate the impact of large sustained cholesterol reductions on all-cause
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mortality in a hypertensive cohort with at least 1 other CHD risk factor and to assess CHD
reduction and other benefits in populations that had been excluded or underrepresented in
previous trials, particularly older persons, women, racial and ethnic minority groups, and
persons with diabetes. A priori secondary outcomes included combination of CHD death [fatal
CHD, coronary revascularization related mortality, previous angina or MI and no known
potentially lethal non coronary disease process] and non-fatal MI, CVD mortality [mortality
due to CHD, stroke, other treated angina, heart failure, peripheral disease], CHD [CHD death,
coronary revascularization, hospitalized angina], fatal stroke, other CVD, non-CVD mortality,
stroke [fatal and non-fatal] and heart failure. The design of ALLHAT including the LLT, and
its participant and clinical site recruitment and selection have been reported elsewhere [9,16–
18]. Briefly, ALLHAT-LLT was a randomized, non-blinded, large simple trial conducted from
February 1994 through March 2002 at 513 clinical centers in the United States, Puerto Rico,
US Virgin Islands, and Canada. The intervention was open-label pravastatin (40 mg/d) versus
usual care. Participants were drawn exclusively from the ALLHAT antihypertensive trial. The

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protocol of ALLHAT was approved by each participating center’s Institutional Review Board.
The GenHAT study was approved by the Institutional Review Boards of the University of
Minnesota and The University of Texas Health Science Center at Houston.
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Statistical methods
Participants were stratified according to genotype and baseline characteristics were compared
using chi-square and t-tests. The efficacy of pravastatin in reducing the risk of the primary
outcome (all-cause mortality) and of a-priori secondary outcomes is compared between the
genotype strata (II + ID vs DD), using an interaction term in the Cox proportional Hazard
model. These analyses were adjusted for potential confounding baseline factors: sex (men/
women), race (black/white), current smoking status (yes/no), history of diabetes (yes/no),
history of CHD (yes/no), visit 1 systolic blood pressure (mm Hg), and age (years).. Because
on our previous finding that the interaction between the ACE I/D polymorphism and
effectiveness of statins may be modified by gender [19] a 3-way interaction for gender-ACE
genotype-statin therapy was included in the model to compare the interaction between men
and women. We also included a three-way interaction for race-ACE genotype-statin therapy
in the model to examine whether ethnicity accounted for differences in the pharmacogenetic
effect of the ACE ID genotype on the primary and secondary outcomes.

Results
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The genotyped population in the lipid lowering arm of ALLHAT included 9,467 participants.
Of these 4,741 were in the pravastatin treatment group, and 4,726 were in the usual care group.
In Table 1 baseline characteristics according to ACE ID genotype for subjects randomized to
pravastatin and subjects in the usual care group are shown.

The proportions and characteristics within each of the three genotypes assigned to each
treatment (pravastatin versus usual care) were well balanced. The total number of trial events
and the cumulative 6-year Kaplan-Meier event rates of clinical outcomes by ACE genotype
and treatment are shown in Table 2. The effects of ACE ID on the clinical outcomes (regardless
of pravastatin treatment assignment) can be found in Table 3. Subjects with the ID genotype
had a statistically significant lower risk of fatal and nonfatal stroke compared with subjects
with the II genotype (HRadj =0.76 [95% CI 0.59–0.99]). This finding was marginally significant
for fatal strokes alone (p =0.051).

Hazard ratios of the effect of statin use are shown, by genotype, in Table 4. Three-way analyses
of the ACE I/D genotypes, treatment and primary clinical outcome (all-cause mortality)
identified no differences in efficacy of pravastatin between subjects with the II and DD
genotype (interaction hazard ratio 0.81 [95% CI 0.58–1.14] p=0.31), or between subjects with
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the ID and DD genotype (interaction hazard ratio 0.90 [95% CI 0.69–1.17] p=0.42) (Table 4).
The secondary endpoints were consistent with these negative findings. No significant gene
drug interactions were found. We evaluated gene-drug interactions in relation to the primary
and secondary outcomes in subgroups based on gender and on race. There were no apparent
gene-treatment interactions across gender-gene-drug or race-gene-drug subgroups (data not
shown).

Discussion
The GenHAT-LLT study is a large pharmacogenetic trial of pravastatin versus usual care.
Based on genotype data collected from almost 10,000 individuals, who were followed for
cardiovascular events using standard, well-defined definitions for cardiovascular outcomes,
we found no compelling evidence that ACE I/D genotype is a major determinant of the efficacy
of pravastatin in reducing the risk of cardiovascular events. We did not find any significant

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interactions in the response to therapy, despite the large number of tests performed. We did
observe that participants with the II and ID genotypes tended to fare better on pravastatin than
usual care for most of the outcomes examined, while the opposite was true for the DD
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participants. The IIvs DD and the ID vs DD interaction hazards ratios were below 1.00 for all
outcomes except heart failure, ranging from 0.47 for fatal strokes (II vs DD) to 0.98 for CHD
(ID vs DD). This is in concordance with what would be expected based on a previous study
[15].

The GenHAT study selected individuals based on pre-existing coronary risk factors and
hypertension. Therefore there is some uncertainty about the applicability of the findings of this
study to the association in subjects without these risk factors.

In the ALLHAT study no overall beneficial effect of pravastatin was demonstrated on the
primary outcome. After 6 years of follow-up 26% of subjects in the usual care arm used statins,
and 16% in the pravastatin arm did not use a lipid lowering drug anymore. There was no
significant differential in crossovers among ACE genotypes, and therefore would not affect
the interaction between pravastatin and the ACE polymorphism.

Our finding that the ACE I/D polymorphism did not modify the efficacy of statins were in
concordance with three studies [13,14,19]. Results were different from the results of the
Rotterdam study that found a significant interaction in men [15]. Even though no statistically
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significant interaction was found in GenHAT, there was a trend towards better efficacy in the
subjects with the II and ID genotype compared with the DD genotype. For example, subjects
with the ID genotype tended to fare better on pravastatin than usual care for fatal CHD and
nonfatal MI (HRadj 0.84 [95% CI 0.68–1.03]), while there was no effect of pravastatin in
subjects with the DD genotype (adjusted HR 0.99 [95% CI 0.77–1.27]). This result is similar
to the findings in the Rotterdam study. However, we did not find evidence that there were
differences in efficacy between men and women as was found in the Rotterdam Study. The
physiological role of the renin-angiotensin system varies with sodium intake, age and disease
status [20]. Since this trial included high risk hypertensives, while the Rotterdam cohort study
included a hypercholesterolemic subset of the general population, this might be an explanation
for the different findings in men. A strength of the GenHAT study, however, is that it was
performed in a large clinical trial with reasonable event rates in both subjects randomized to
pravastatin and in subjects randomized to usual care. Furthermore since only the I/D
polymorphism was studied an effect of other polymorphisms in the ACE gene on pravastatin
cannot be ruled out. These pharmacogenetic analyses of the ALLHAT-LLT in combination
with results from earlier studies provide no rationale for using ACE I/D genotype to guide
decisions about treatment with pravastatin. Since there was a trend towards less efficacy in
subjects with the DD genotype, more research in larger settings, possibly combinations of
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different trials/cohort studies, is necessary.

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Table 1
Baseline characteristics of the pravastatin and usual care subgroups, according to ACE insertion/deletion genotype.

ACE Genotype

II ID DD
Characteristic Pravastatin Usual care Pravastatin Usual care Pravastatin Usual care

Sample size 951 (20.1) 922 (19.5) 2376 (50.1) 2336 (49.4) 1414 (29.8) 1468 (31.1)
Age 65.95 (7.5) 66.13 (7.8) 66.64 (7.7) 66.17 (7.4) 66.32 (7.8) 66.34 (7.6)
Race
 White 551 (57.9) 567 (61.5) 1358 (57.2) 1367 (58.5) 778 (55.1) 806 (54.9)
 Black 304 (32.0) 274 (29.7) 897 (37.8) 824 (35.3) 572 (40.4) 587 (40.0)
 Other 96 (10.1) 81 (8.8) 121 (5.0) 145 (6.2) 64 (4.5) 75 (5.1)
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Gender (Male) 481 (50.6) 471 (51.1) 1218 (51.3) 1185 (50.7) 735 (52.0) 747 (50.9)
Lipid Meds in last year 14 (1.5) 19 (2.1) 38 (1.6) 33 (1.4) 27 (1.9) 20 (1.4)
SBP, mm Hg 145 (13.9) 146 (14.2) 145 (14.1) 145 (13.9) 145 (13.7) 145 (14.1)
DBP, mm Hg 84 (9.7) 84 (9.9) 84 (10.0) 84 (9.7) 84 (9.6) 84 (10.0)
Smoker 211 (22.2) 245 (26.6) 548 (23.1) 525 (22.5) 353 (25.0) 339 (23.1)
History of diabetes 359 (37.8) 286 (31.0) 843 (35.5) 834 (35.7) 477 (33.7) 501 (34.1)
History of MI or Stroke 164 (17.3) 145 (15.7) 397 (16.7) 408 (17.5) 248 (17.5) 268 (18.3)
History of CHD 131 (13.8) 146 (15.8) 333 (14.0) 344 (14.7) 178 (12.6) 227 (15.5)
BMI 30.1 (6.0) 29.7 (6.2) 29.8 (5.9) 29.9 (6.1) 29.8 (5.9) 30.2 (6.2)
Total cholesterol 224.7 (26.2) 223.1 (26.3) 223.2 (27.3) 223.5 (26.3) 223.5 (26.9) 223.9 (26.6)
HDL cholesterol 47.0 (13.6) 46.9 (13.5) 47.6 (13.4) 47.2 (13.2) 47.9 (13.3) 47.7 (13.9)
LDL cholesterol 145.5 (20.5) 144.9 (20.9) 145.2 (21.9) 145.3 (21.4) 145.8 (21.1) 145.5 (21.3)
Antihypertensive treatment group
Doxazosin 180 (18.9) 194 (21.0) 497 (20.9) 508 (21.8) 316 (22.3) 309 (21.1)
Chlorthalidone 367 (38.9) 348 (37.7) 838 (35.3) 850 (36.4) 513 (36.3) 516 (35.2)
Amlodipine 196 (20.6) 197 (21.4) 536 (22.6) 501 (21.5) 292 (20.7) 315 (21.5)
Lisinopril 208 (21.9) 183 (19.9) 505 (21.3) 477 (20.4) 293 (20.7 328 (22.3)

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Table 2
Total number of trial events and cumulative 6-year Kaplan-Meier risk estimates of clinical outcomes by ACE genotype and lipid treatment
group.

ACE Insertion/Deletion Genotype

ALL II ID DD

Trial Outcome Prav UC Prav UC Prav UC Prav UC

Sample Size 4,741 4,726 951 922 2,376 2,336 1,414 1,468
All-cause mortality 584 566 101 108 302 286 181 172
0.1441 0.1402 0.1328 0.1409 0.1482 0.1460 0.1462 0.1363
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CVD deaths 273 272 45 55 145 139 83 78

0.0685 0.0670 0.0570 0.0666 0.0732 0.0704 0.0686 0.0617
 CHD 149 150 24 27 82 78 43 45
0.0371 0.0372 0.0309 0.0314 0.0397 0.0399 0.0377 0.0356
 Stroke 48 49 9 15 19 17 20 17
0.0120 0.0127 0.0125 0.0219 0.0088 0.0088 0.0173 0.0139
 Other CVD 76 73 12 13 44 44 20 16
0.0208 0.0184 0.0145 0.0149 0.0263 0.0232 0.0151 0.0134
Non-CVD mortality 277 259 50 46 141 131 86 82
0.0711 0.0694 0.0684 0.0693 0.0719 0.0709 0.0720 0.0719
Fatal CHD and nonfatal MI 349 392 61 70 172 198 116 124
0.0904 0.1031 0.0830 0.0921 0.0864 0.1063 0.1032 0.1032
Fatal and nonfatal stroke 192 212 38 50 84 90 70 72
0.0552 0.0510 0.0537 0.0727 0.0469 0.0449 0.0593 0.0615
Heart failure (hospitalized or 229 232 40 50 128 107 61 75
fatal)
0.0604 0.0616 0.0541 0.0650 0.0677 0.0555 0.0505 0.0678

ACE = Angiotensin converting enzyme; Prav = pravastatin; UC = usual care; CVD = cardiovascular disease; CHD= coronary heart disease; MI = myocardial infarction.

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Table 3
Unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CI) of the ID and DD genotypes relative to the II genotype
for combined randomized groups.

II ID DD
reference HR (unadjusted) 95% CI HR (adjusted)1 95% CI HR (unadjusted) 95% CI HR (adjusted) 1 95% CI

All Cause Mortality 1 1.12 (0.96, 1.31) 1.11 (0.94, 1.29) 1.09 (0.91, 1.29) 1.08 (0.91, 1.29)
CVD mortality 1 1.13 (0.90, 1.42) 1.12 (0.89, 1.41) 1.04 (0.81, 1.33) 1.03 (0.80, 1.33)
 CHD 1 1.25 (0.91, 1.71) 1.25 (0.91, 1.71) 1.11 (0.79, 1.57) 1.10 (0.78, 1.56)
 Stroke 1 0.59 (0.35, 1.00) 0.59 † (0.35, 0.99) 1.00 (0.60, 1.67) 0.96 (0.57, 1.61)
 Other CVD 1 1.40 (0.90, 2.19) 1.36 (0.87, 2.13) 0.93 (0.56, 1.56) 0.95 (0.57, 1.58)
Non-CVD mortality 1 1.13 (0.89, 1.42) 1.11 (0.88, 1.40) 1.13 (0.88, 1.45) 1.14 (0.88, 1.46)
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Fatal CHD and nonfatal MI 1 1.13 (0.92, 1.38) 1.14 (0.93, 1.39) 1.19 (0.96, 1.48) 1.20 (0.97, 1.49)
Stroke (fatal and nonfatal) 1 0.78 (0.61, 1.01) 0.76 ‡ (0.59, 0.98) 1.04 (0.80, 1.36) 1.00 (0.76, 1.31)
Heart Failure (hospitalized or fatal) 1 1.04 (0.81, 1.32) 1.03 (0.81, 1.31) 0.98 (0.75, 1.27) 0.98 (0.75, 1.28)

1
Adjusted for treatment group (pravastatin/usual care), sex (male/female), race (black/white), and eight baseline variables: current smoking status (yes/no), history of diabetes (yes/no), history of CHD
(yes/no), systolic blood pressure level (mm Hg), and age (years).
†
p = 0.047
‡
p = 0.038

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Table 4
Adjusted hazard ratios (HRadj) and 95% confidence limits of the effect of pravastatin versus usual care on study outcomes, according to
II, ID, and DD genotype strata. In addition, the adjusted interaction hazard ratios 1 (IHRadj) of the II versus the DD genotype and the ID
versus DD genotype are given. The interaction hazard ratio estimates for a given outcome were obtained from respective Cox proportional
hazards models incorporating treatment, genotype (II/DD and ID/DD), treatment by genotype interactions, and seven baseline covariates.

HRadj (95% CI) HRadj (95% CI) HRadj(95% CI) IHRadj (95% CI) IHRadj (95% CI)
Trial Outcome II ID DD II vs DD, p-value2 ID vs DD, p-value2

All-Cause Mortality 0.90 (0.68, 1.18) 0.99 (0.84, 1.16) 1.09 (0.89, 1.35) 0.81 (0.58, 1.14), 0.23 0.90 (0.69, 1.17), 0.42
CVD Mortality 0.79 (0.53, 1.18) 0.98 (0.78, 1.24) 1.10 (0.81, 1.50) 0.70 (0.42, 1.15), 0.16 0.87 (0.59, 1.29), 0.49
Maitland-van der Zee et al.

 CHD 0.84 (0.48, 1.46) 1.00 (0.73, 1.37) 1.01 (0.66, 1.53) 0.82 (0.41, 1.64), 0.58 0.98 (0.58, 1.65), 0.94
 Fatal Stroke 0.60 (0.26, 1.39) 1.02 (0.53, 1.97) 1.22 (0.64, 2.33) 0.47 (0.16, 1.34), 0.16 0.83 (0.33, 2.10), 0.70
 Other CVD 0.93 (0.42, 2.05) 0.91 (0.60, 1.39) 1.22 (0.63, 2.36) 0.71 (0.26, 1.99), 0.52 0.71 (0.33, 1.55), 0.39
Non-CVD Mortality 1.04 (0.69, 1.55) 1.00 (0.79, 1.27) 1.09 (0.81, 1.48) 0.95 (0.58, 1.57), 0.85 0.92 (0.63, 1.35), 0.67
Fatal CHD and nonfatal MI 0.84 (0.59, 1.18) 0.84 (0.68, 1.03) 0.99 (0.77, 1.27) 0.84 (0.55, 1.29), 0.43 0.85 (0.61, 1.17), 0.31
Stroke (fatal and nonfatal) 0.73 (0.48, 1.11) 0.88 (0.66, 1.19) 1.03 (0.74, 1.43) 0.69 (0.41, 1.19), 0.18 0.86 (0.55, 1.35), 0.52
Heart Failure (hospitalized or fatal) 0.75 (0.50, 1.14) 1.15 (0.89, 1.48) 0.85 (0.61, 1.20) 0.87 (0.51, 1.49), 0.61 1.32 (0.86, 2.02), 0.20

Adjusted for differences in sex (male/female), race (black/white), and five baseline variables: current smoking status (yes/no), history of diabetes (yes/no), history of CHD (yes/no), systolic blood pressure
level (mm Hg), age (years).
1
The interaction hazard ratio is a ratio of ratios: Prav/UC for II stratum over Prav/UC for DD stratum, and similarly for ID versus DD.
2
Test of null hypothesis: IHRadj = 1.0.

Am Heart J. Author manuscript; available in PMC 2009 October 24.

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