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CLINICAL STUDIES

Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin

The lipoprotein and coronary atherosclerosis study

Ali J. Marian, MD, FACC^*, Faye Safavi, BS^*, Laura Ferlic, MS^*, J. Kay Dunn, PhD^*, Antonio M. Gotto, MD, DPhil, FACC and Christie M. Ballantyne, MD, FACC^*

^* Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
Cornell University Medical College, New York, New York, USA

Manuscript received February 28, 1999; revised manuscript received June 24, 1999, accepted October 5, 1999.

Reprint requests and correspondence: Dr. A. J. Marian, Section of Cardiology, One Baylor Plaza, 543E, Houston, Texas 77030
amarian{at}bcm.tmc.edu

	Abstract

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OBJECTIVES

Our objectives were to determine whether angiotensin-1 converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the severity of coronary artery disease (CAD) and its progression/regression in response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population.

BACKGROUND

Genetic factors are involved in susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which accounts for half of the variance of plasma and tissue levels of ACE, has been implicated in susceptibility to CAD and myocardial infarction (MI).

METHODS

Angiotensin-1 converting enzyme genotypes were determined by polymerase chain reaction (PCR). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo.

RESULTS

Ninety-one subjects had DD, 198 ID and 75 II genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of coronary lesions and total occlusions were not significantly different at baseline or follow-up among the genotypes. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In response to fluvastatin therapy, subjects with DD, compared with those with ID and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite progression was less (14%) and regression was more common (24%) in DD as compared with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023). Changes in the mean MLD and lesion-specific MLD also followed the same trend.

CONCLUSIONS

Angiotensin-1 converting enzyme I/D polymorphism is associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of CAD.

Abbreviations and Acronyms   ACE = angiotensin-1 converting enzyme   ANOVA = analysis of variance   apo = apolipoprotein   CAD = coronary artery disease   DMSO = dimethyl sulfoxide   HDL-C = high density lipoprotein-cholesterol   HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A   I/D = insertion/deletion   LCAS = Lipoprotein and Coronary Atherosclerosis Study   LDL-C = low density lipoprotein-cholesterol   MI = myocardial infarction

Despite the well-established role of genes in susceptibility to coronary atherosclerosis, identification of the responsible genes has been problematic. The commonly used technique of case-control polymorphism (allelic) association, whereby the frequency of the variants (alleles) of a candidate gene are compared in cases and controls, is notorious for spurious results (8). This is exemplified by the conflicting data on the possible role of a common insertion/deletion (I/D) polymorphism in the angiotensin-1 converting enzyme (ACE) gene in susceptibility to CAD and MI (4). A better approach is a longitudinal study of a well-characterized cohort, which does not have the inherent weaknesses of case-control allelic association studies (8).

Interest in the role of ACE I/D genotypes in the susceptibility to CAD stems from observations that the I/D genotypes account for half of the variability of the plasma, cellular and tissue levels of ACE (9–11) and from compelling experimental data implicating ACE in vascular homeostasis and atherosclerosis (12). To examine further the role of ACE in atherosclerosis, we analyzed data from a longitudinal study of a well-characterized cohort, the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population (13), for possible associations of the I/D genotypes with baseline demographic, biochemical and coronary angiographic variables and the response of biochemical and angiographic variables to treatment with the cholesterol lowering agent fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.

	Methods

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Study population.   All subjects provided written informed consent and the study was approved by the Institutional Review Board. The study population was comprised of 429 subjects (349 men and 80 women). The design and primary results of LCAS have been published (13–15). In brief, patients between 35 and 75 years who had at least one coronary lesion causing 30% to 75% diameter stenosis and low density lipoprotein-cholesterol (LDL-C) of 115–190 mg/dl despite diet were randomized to 40 mg fluvastatin daily or placebo. Total cholesterol, LDL-C, HDL-C, triglyceride and apolipoprotein (apo) levels were measured in all subjects at baseline and throughout the study. Subjects underwent quantitative coronary angiography upon enrollment (n = 429) and 2.5 years following randomization (n = 340). The primary end point was within-subject per-lesion change in the minimum lumen diameter (MLD) of qualifying lesions, defined by MLD 25% of the reference lumen diameter at baseline and MLD 0.8 mm less than the reference lumen diameter at either baseline or follow-up. Subjects were also categorized as having definite progression, definite regression or mixed angiographic change. Definite progression was defined as 1 qualifying lesion with MLD decrease 0.4-mm, including new total occlusions and no qualifying lesion with MLD increase 4 mm. Definite regression was defined as 1 qualifying lesion with MLD increase 0.4 mm, no qualifying lesion with MLD decrease 0.4 mm and no new total occlusion. Subjects that showed neither definite progression nor definite regression were classified as having mixed change. Clinical events monitored were definite or probable MI, unstable angina requiring hospitalization, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, all-cause mortality and cardiovascular mortality.

Genotyping.   Laboratory personnel who had no knowledge of the clinical data performed the genotyping and two individuals read the genotypes. Angiotensin-1 converting enzyme genotypes were determined using polymerase chain reaction (PCR) (16) in 364/429 (85%) subjects. In 54 subjects DNA samples were not available, and in the remaining 11 subjects, the PCR reactions did not work. Each PCR reaction contained 100 g of DNA template, 0.125 µM of each primer, 200 uM of 4dNTPs, 1 U of Taq DNA polymerase and 1.5 mM of MgCl₂ and 5% dimethyl sulfoxide (DMSO). DNA was amplified for 30 cycles, each comprised of denaturation at 94°C for 1 min, annealing at 58°C for 1 min, extension at 72°C for 1 min with a final extension time of 3 min. To avoid possible mistyping of the genotypes, in addition to using DMSO (17), those with the DD genotype were reanalyzed by PCR using a set of insertion-specific primers (18). The PCR products were separated by electrophoresis on 2% agarose gel and identified by ethidium bromide staining.

Statistical analysis.   Continuous variables were expressed as mean ± SD (with the exception of lesion-specific MLD which was expressed as mean ± SE) and their differences among genotypes were compared by analysis of variance (ANOVA). Variables that were unsuited for ANOVA because of inequality of variance were analyzed by the Kruskal-Wallis test. Distribution of categorical variables among genotypes was compared using chi-square or Fisher’s exact tests. To determine the association of ACE genotypes with response to fluvastatin treatment, mean changes in lipid levels and MLD among the genotypes were compared using ANOVA. The ANOVA performed in this study utilizes Yates’ weighted squares of means technique, which has the ability to obtain the proper sums of squares for testing main and interaction effects on data with disproportional unequal subclass sizes. In addition, analyses were repeated using the following assigned weights to the genotypes according to their known biological association with plasma, cellular and tissue levels of ACE (9–11): DD = 2, ID = 1.5, II = 1. The results of weighted analysis are reported when they did not differ substantially from the results of unweighted analysis, otherwise both results are reported. Statistical analysis was performed using STATA, version 5.0, (Stata Corporation, College Station, Texas).

	Results

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ACE genotypes.   The products of D and I alleles were identified by the presence of 190 and 490 base pair bands on agrose gel electrophoresis, respectively. Repeat PCR using insertion-specific primers did not identify genotype mistyping, which may be due to the routine use of DMSO in the PCR reaction (17). The frequencies of D and I alleles were 0.52 and 0.48, respectively. The frequencies of genotypes are shown in Table 1.

Plasma lipid levels.   Table 2 shows the baseline and final values and percent change of lipid levels in the placebo and fluvastatin treatment groups according to genotype. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), LDL-C (0.005), and apo B (p = 0.045). Subjects with the DD genotype, as compared with subjects with the ID and II genotypes, had a greater reduction in plasma levels of total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%), respectively, in response to fluvastatin therapy. The magnitude of the reduction in total cholesterol, LDL-C and apo B followed the genetic gradient and the biological effect of the I/D genotypes on tissue, cellular and plasma levels of ACE (DD>ID>II) (9–11).

Progression or regression of CAD and clinical events.   Angiographic results (n = 308) are shown in Table 3. Concordant with the influence of ACE I/D genotype on the response of plasma LDL-C levels to fluvastatin, subjects with the DD genotype were less likely to have definite progression (14%) and more likely to have definite regression (24%) compared with those with ID (32% progression and 17% regression) or II (33% progression and 3% regression) genotypes (p = 0.023). Mean MLD also increased in those with the DD genotype (increase: 0.05 ± 0.20 mm) indicative of regression, whereas it decreased in those with the ID (decrease: 0.04 ± 0.26 mm) or II (decrease: 0.01 ± 0.26) genotypes, which indicate progression. Lesion-specific MLD also followed the same trend. These differences did not reach statistical significance.

	Discussion

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Findings.   The main finding of this study is that ACE I/D genotypes influence the response of plasma lipids to treatment with fluvastatin. Subjects with the DD genotype had a greater reduction in plasma levels of LDL-C than those with ID or II genotypes. Similarly, the reductions in plasma levels of total cholesterol and apo B were also greater in subjects with the DD genotype. The interaction between the ACE I/D genotypes with the response of plasma lipids to fluvastatin therapy exhibited a gene-dose effect and was in accord with the known biological association of the I/D genotypes with plasma, cellular and tissue levels of ACE (DD>ID>II) (9–11). Consistent with a greater reduction in LDL-C in response to fluvastatin therapy, subjects with the DD genotype also exhibited a higher rate of regression and a lower rate of progression of coronary atherosclerosis as determined by quantitative coronary angiography. Another main finding of this study is that the ACE genotypes were not associated with baseline severity of CAD, progression or regression of coronary atherosclerosis in the placebo group or clinical events.

In the entire LCAS population, treatment with fluvastatin reduced the mean LDL-C and increased the mean HDL-C by 27% and 6%, respectively (13). The mean MLD of qualifying lesions showed significantly less progression in the fluvastatin group. There were also fewer subjects with the progression and more subjects with the regression of coronary atherosclerosis in the fluvastatin treatment group as compared with the placebo group (13). A similar trend, which was not statistically significant, was also observed in clinical event rates (13). The greatest angiographic and clinical benefit was observed in subjects with low HDL-C (15).

Evidence favoring a true association.   The observed association between ACE I/D genotypes and the response of plasma lipids to treatment with fluvastatin was unexpected and requires further validation in additional data sets. Nonetheless, it is likely a true association for the following reasons. The strength of the observed association (p = 0.005) is considered strong (8,19). The concordant associations with several variables, namely, three related plasma lipid components and angiographic indexes of progression/regression also favor a true association (8). In addition, the presence of a gene-dose effect (genetic gradient), which is consistent with the association of the ACE I/D genotypes with plasma, cellular and tissue levels of ACE (biological gradient) (9–11) further supports a true association. Furthermore, the prospective nature of this longitudinal study and the detailed characterization of the subjects reduce the chance of a spurious association (8).

A total of 108 (including 79 subjects in whom angiographic data are available) in the LCAS were also treated with cholestyramine. To exclude the possible confounding effect of cholestyramine therapy on the results of this study, the distribution of ACE genotypes among subjects treated with or without cholestyramine was compared and did not differ significantly (data not shown). In addition, possible genotype-by-treatment (with cholestyramine) interactions were analyzed and no significant interactions were detected (data not shown). Regarding the possible confounding effect of patient compliance, we note that the compliance rate with fluvastatin treatment, defined as medication compliance of at least 80%, in the entire LCAS population was 95%. Therefore, it is unlikely that the overall results would be significantly affected by the presence of possible unexpected differences in the compliance rates among the subjects with different ACE genotypes.

Potential limitations.   The design of LCAS (and hence, the choice of end points) had been determined prior to the decision to perform genetic analyses and therefore, this study is a secondary data analysis. In addition, no adjustment was made for multiple testing as the examination of each variable for the possible existence of a significant genotype-by-treatment interaction is considered a form of multiple unrelated hypotheses (20). According to J.W. Tukey (20), it is only mandatory to adjust the significance level for multiple hypotheses when the hypotheses being tested are not fully independent of one another (20). In view of multiple testing, significant p values (p < 0.05) should be regarded as potential associations.

As it is true for all association studies, the results of this study require confirmation in additional data sets. In this regard, the preliminary analysis of a similar study showed no association between the plasma lipid levels and response to treatment with pravastatin (21). However, patients with the DD genotype showed a blunted effect of pravastatin therapy on coronary atherosclerosis despite identical plasma lipid response (21).

We could not determine the ACE genotypes in 65 of the 429 subjects due to reasons of either unavailability of DNA samples or PCR reactions not working. This might have created unequal treatment sample sizes among the placebo and treatment groups. The loss of genotyping data is essentially random and is unlikely to account for the observed genotype-treatment interactions. In addition, the statistical methods used in this study takes into account disproportional unequal subclasses sizes.

Possible mechanisms.   This study shows a gene-treatment interaction without exploring the responsible mechanism(s). It is also not known whether treatment-genotype interaction is specific for fluvastatin and whether it is common to other HMG-CoA reductase inhibitors remains to be explored. Existing data do not provide a clear biologically plausible mechanism to explain the observed association. However, they indicate complex interactions between angiotensin II and bradykinin, the products of ACE enzymatic activity and LDL-C peroxidation as well as the activity of the HMG-CoA reductase inhibitors (22,23). It is well-established that angiotensin II increases not only the macrophage-mediated oxidation of LDL (24), but also the cellular uptake of oxidized LDL by the scavenger receptors (25,26). In contrast, fluvastatin inhibits LDL oxidation and stimulates the removal of LDL from the circulation (27). It is intriguing to speculate that the differences in the plasma, cellular and tissue concentrations of ACE (9–11), angiotensin II and bradykinin in subjects with different genotypes affect LDL peroxidation, removal of the oxidized LDL by the macrophages, the rate of receptor-mediated uptake of the LDL or the pharmacokinetics of fluvastatin itself.

Gene-treatment interactions.   Although this study is the first to show an interaction between ACE I/D genotypes and the response of plasma lipids to therapy, interactions between genetic polymorphisms and drug efficacy have been recognized for many years (28). The classic example is that of cytochrome P450 isozymes, which determine interindividual variations in the metabolism of many drugs in the liver, including the HMG-CoA reductase inhibitors (28). With regard to lipids metabolism, polymorphisms in genes coding for apo B, apo A1/CIII and apo E have been shown to influence the response of plasma lipids to treatment with gemfibrozil (29) and probucol (30), respectively. Similarly, polymorphisms in the genes coding for cholesteryl ester transfer protein, apo E, apo A-1, apo A-IV have been associated with response of plasma lipids to dietary interventions (5,6,31). Other examples of gene-treatment interaction include polymorphisms in the neurotransmitter sertonin type IIA receptor and alpha-adducin genes which are associated with the clinical response to antipsychotic drugs in schizophrenic patients (32) and to diuretics in hypertensive patients (33), respectively. Thus, genetic polymorphisms, in part, form the basis for interindividual variations in the response to drug therapy.

In summary, the results of this prospective study show that the I/D variants of the ACE gene are associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects the DD genotype exhibited a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of coronary atherosclerosis.

	Acknowledgments

 
We would like to express our sincere gratitude to Ms. Kerrie Jara for critical review of the manuscript and helpful suggestions.

	Footnotes

 
This study was supported, in part, by Novartis Pharmaceuticals Corporation, grant no. B351 and National Institutes of Health GCRC, grant no. 5M01RR00350. This work was also supported, in part, by a grant from Abercrombie Foundation. C.M. Ballantyne and A.J. Marian are recipients of Established Investigator Awards from American Heart Association National Center, Dallas, Texas.

	References

Top Abstract Methods Results Discussion References

 

1. Hennekens CH. Increasing burden of cardiovascular disease: current knowledge and future directions for research on risk factors. Circulation. 1998;97:1095–1102[Free Full Text]
2. Slack J, Evans KA. The increased risk of death from ischemic heart disease in first degree relatives of 121 men and 96 women with ischemic heart disease. J Med Genetics. 1966;3:239–257[Medline]
3. Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med. 1994;330:1041–1046[Abstract/Free Full Text]
4. Marian AJ. Genetic risk factors for myocardial infarction. Curr Opin Cardiol. 1998;13:171–178[Medline]
5. Dullaart RP, Hoogenberg K, Riemens SC, et al. Cholesteryl ester transfer protein gene polymorphism is a determinant of HDL cholesterol and of the lipoprotein response to a lipid-lowering diet in type 1 diabetes. Diabetes. 1997;46:2082–2087[Abstract]
6. Ordovas JM, Lopez-Miranda J, Mata P, Perez-Jimenez F, Lichtenstein AH, Schaefer EJ. Gene-diet interaction in determining plasma lipid response to dietary intervention. Atherosclerosis. 1995;118(Suppl):S11–S27
7. Brenn T. Genetic and environmental effects on coronary heart disease risk factors in northern Norway. The cardiovascular disease study in Finnmark. Ann Hum Genet. 1994;58:369–379[Medline]
8. Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994;265:2037–2048[Abstract/Free Full Text]
9. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86:1343–1346[Medline]
10. Danser AH, Schalekamp MA, Bax WA, et al. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation. 1995;92:1387–1388[Abstract/Free Full Text]
11. Costerousse O, Allegrini J, Lopez M, Alhenc-Gelas F. Angiotensin I-converting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in T-lymphocytes. Biochem J. 1993;290:33–40
12. Dzau VJ. Mechanism of protective effects of ACE inhibition on coronary artery disease. Eur Heart J. 1998;19(Suppl J):J2–J6
13. Herd JA, Ballantyne CM, Farmer JA, et al, for LCAS investigators. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoportein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol 1997;80:278–86.
14. West MS, Herd JA, Ballantyne CM, et al, for LCAS investigators. The Lipoprotein and Coronary Atherosclerosis Study (LCAS): design, methods and baseline data of a trial of fluvastatin in patients without severe hypercholesterolemia. Control Clin Trials 1996;17:550–83.
15. Ballantyne CM, Herd JA, Ferlic LL, et al. Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation. 1999;99:736–743[Abstract/Free Full Text]
16. Dakik HA, Mahmarian JJ, Verani MS, Farmer JA, Zhao G, Marian AJ. Association of angiotensin I-converting enzyme gene polymorphism with myocardial ischemia and patency of infarct-related artery in patients with acute myocardial infarction. J Am Coll Cardiol. 1997;29:1468–1473[Abstract]
17. Shanmugam V, Sell KW, Saha BK. Mistyping ACE heterozygotes. PCR Methods Appl. 1993;3:120–121[Medline]
18. Lindpaintner K, Pfeffer MA, Kreutz R, et al. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med. 1995;332:706–711[Abstract/Free Full Text]
19. Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995;11:241–247[CrossRef][Medline]
20. Tukey JW. The philosophy of multiple comparisons. Statistical Science. 1991;6:100–116
21. van Geel PP, Pinto YM, Zwinderman AH, et al. The angiotensin-converting enzyme deletion-type gene is associated with ischemic events and a blunted effect on lipid-lowering treatment on angiographically defined coronary atherosclerosis. Eur Heart J. 1997;18(Suppl):486
22. Aviram M, Hussein O, Rosenblat M, Schlezinger S, Hayek T, Keidar S. Interactions of platelets, macrophages and lipoproteins in hypercholesterolemia: antiatherogenic effects of HMG-CoA reductase inhibitor therapy. J Cardiovasc Pharmacol. 1998;31:39–45[CrossRef][Medline]
23. Mombouli JV. ACE inhibition, endothelial function and coronary artery lesions. Role of kinins and nitric oxide. Drugs. 1997;54(Suppl 5):12–22
24. Scheidegger KJ, Butler S, Witztum JL. Angiotensin II increases macrophage-mediated modification of low density lipoprotein via a lipoxygenase-dependent pathway. J Biol Chem. 1997;272:21609–21615[Abstract/Free Full Text]
25. Keidar S, Kaplan M, Aviram M. Angiotensin II-modified LDL is taken up by macrophages via the scavenger receptor, leading to cellular cholesterol accumulation. Arterioscler Thromb Vasc Biol. 1996;16:97–105[Abstract/Free Full Text]
26. Leitersdorf E, Stein O, Stein Y. Angiotensin II stimulates receptor-mediated uptake of LDL by bovine adrenal cortical cells in primary culture. Biochim Biophys Acta. 1985;835:183–190[Medline]
27. Hussein O, Schlezinger S, Rosenblat M, et al. Reduced susceptibility of low density lipoprotein to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL. Atherosclerosis. 1997;128:11–18[CrossRef][Medline]
28. Cholerton S, Daly AK, Idle JR. The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends Pharmacol Sci. 1992;13:434–439[CrossRef][Medline]
29. Aalto-Setala K, Kontula K, Manttari M, et al. DNA polymorphisms of apolipoprotein B and AI/CIII genes and response to gemfibrozil treatment. Clin Pharmacol Ther. 1991;50:208–214[Medline]
30. Nestruck AC, Bouthillier D, Sing CF, Davignon J. Apolipoprotein E polymorphism and plasma cholesterol response to probucol. Metabolism. 1987;36:743–747[CrossRef][Medline]
31. McCombs RJ, Marcadis DE, Ellis J, Weinberg RB. Attenuated hypercholesterolemic response to a high-cholesterol diet in subjects heterozygous for the apolipoprotein A-IV-2 allele. N Engl J Med. 1994;331:706–710[Abstract/Free Full Text]
32. Arranz M, Collier D, Sodhi M, et al. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet. 1995;346:281–282[CrossRef][Medline]
33. Cusi D, Barlassina C, Azzani T, et al. Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet. 1997;349:1353–1357[CrossRef][Medline]

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