This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Samani, N. J. Articles by Woods, K. L. Search for Related Content PubMed PubMed Citation Articles by Samani, N. J. Articles by Woods, K. L.

(Circulation. 1996;94:708-712.)
© 1996 American Heart Association, Inc.

Articles

A Meta-analysis of the Association of the Deletion Allele of the Angiotensin-Converting Enzyme Gene With Myocardial Infarction

Nilesh J. Samani, MD, FRCP; John R. Thompson, PhD; Laurence O'Toole, MRCP; Kevin Channer, MD, FRCP; Kent L. Woods, MD, FRCP

the Departments of Cardiology (N.J.S.), Medicine and Therapeutics (N.J.S., K.L.W.), and Ophthalmology (J.R.T.), University of Leicester (United Kingdom); and the Department of Cardiology (L.O., K.C.), Royal Hallamshire Hospital, Sheffield, United Kingdom.

Correspondence to Dr N.J. Samani, Department of Cardiology, Clinical Sciences Wing, Glenfield Hospital, Groby Rd, Leicester LE3 9QP, UK.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background The ACE gene is characterized by a polymorphism based on the presence (insertion [I]) or absence (deletion [D]) within intron 16 of a 287-basepair alu repeat sequence, resulting in three genotypes. Subsequent studies have produced conflicting findings. To further evaluate the association of the ACE I/D genotype with MI risk, we carried out a meta-analysis of all the published studies.

Methods and Results In total, 15 studies containing 3394 MI cases and 5479 control subjects were analyzed. The overall distribution of genotypes in the control subjects was 22.7% II, 49.0% ID, and 28.3% DD. The mean odds ratio for MI for DD versus ID/II genotypes across all studies was 1.26 (95% CI, 1.15, 1.39; P<.0001). Pairwise odds ratios were 1.36 (95% CI, 1.19, 1.55) for DD and II, 1.24 (95% CI, 1.11, 1.38) for DD and ID, and 1.09 (95% CI, 0.96, 1.23) for ID and II. The relative risk appeared to be increased in Japanese populations (2.55; 95% CI, 1.75, 3.70).

Conclusions Within the limitations of the available data, the meta-analysis therefore supports an association of the ACE D allele with MI risk and strengthens the justification for further evaluation in appropriately powered studies.

Key Words: genes • myocardial infarction • enzymes • angiotensin • risk factors • meta-analysis

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Angiotensin-converting enzyme is a ubiquitous carboxypeptidase. Among other actions, it catalyzes the conversion of angiotensin I to angiotensin II and the breakdown of bradykinin to kinin degradation products. Both angiotensin II and bradykinin are powerful vasoactive molecules with multiple acute and chronic effects on the cardiovascular system. Therefore, with its pivotal role in two important cardiovascular hormonal regulatory systems, the renin-angiotensin system and the kallikrein-kinin system, ACE has an important impact on cardiovascular structure and function.¹ Plasma ACE levels are stable with time within individuals but show marked interindividual variability. Approximately 50% of this variability is accounted for by a major gene effect.² After its cloning, the ACE gene was shown to be characterized by an insertion/deletion polymorphism based on the presence (insertion [I]) or absence (deletion [D]) within intron 16 of a 287-basepair alu repeat sequence, resulting in three genotypes (DD and II homozygotes and ID heterozygotes).³ The I/D polymorphism was found to be in strong linkage disequilibrium with the major gene locus controlling plasma ACE with mean plasma ACE level in DD subjects approximately twice that of II subjects, with ID subjects having intermediate values.^{4 5}

In 1992 in a retrospective, multicenter, case-control study, Cambien et al⁶ reported that the frequency of the DD genotype was increased in subjects with MI recruited between 3 and 9 months after the event. Since then, studies both supporting the finding as well as those questioning the veracity of the association have been published,^{7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24} leading to an uncertain picture at present about the importance of the polymorphism. Despite the different conclusions, the 95% CI of the odds ratio for DD versus ID/II genotypes for most of the positive and negative studies are wide and overlap, thus suggesting that the findings may not be as heterogeneous as they appear at first sight and may to some extent reflect the statistical power of the studies to detect or exclude a particular effect. In this situation, if a sufficient number of studies examining the same question have been carried out, a meta-analysis of such studies may provide a more reliable assessment of the significance of the association. In this study we have carried out such an analysis with respect to the association of the ACE I/D polymorphism with myocardial infarction (MI).

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Identification of Studies
Since the field is relatively new, most of the studies published in the field were already known to the authors. However, in addition, a search was performed on MEDLINE and "Reference Update" CD ROM to identify other articles and abstracts reporting a link between MI and the ACE genotype (yielding three additional studies) and of published abstracts from the major cardiovascular conferences since 1992 (yielding one additional study). Where studies on the same cases or control subjects had been reported more than once, only one study was included, and where studies included more than one geographical population, each population was considered separately. For studies involving investigation of both MI and other cardiovascular phenotypes, the data on MI were extracted and used in the analysis. All studies had to contain sufficient information to at least allow a comparison of the DD versus ID/II genotypes between cases and control subjects.

Statistical Analysis
The studies were pooled by averaging the natural logarithms of the odds ratios weighted by the inverses of their variances. This method gives a very similar result to the Mantel-Haenszel estimate but enables the inclusion of studies when the odds ratio and its variance but not the raw data are available.²⁵ Heterogeneity was tested by ² statistic obtained by summing the weighted squares of the deviations of each estimate from the pooled estimate. Publication bias was examined by plotting a funnel plot of reported effect, as assessed with the natural log of the odds ratio, against trial size.²⁶

	Results

Top Abstract Introduction Methods Results Discussion References

 
Fourteen studies^{6 8 11 12 13 14 15 17 18 20 24} that satisfied the specified criteria were found that had been published before the end of September 1995. In addition, our study²⁷ carried out in Leicester and Sheffield was included. Table 1 shows the details of the individual studies and the methods of case and control recruitment. In total, the studies contain 3394 cases and 5479 control subjects. The overall distribution of genotypes in the control subjects were 22.7% (range, 13.3 to 41.2) II, 49.0% (33.0 to 58.8) ID, and 28.3% (15.7 to 31.7) DD.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Studies Reporting ACE Genotype Distribution in MI Patients and Control Subjects

The genotype distribution and allele frequencies in individual studies are shown in Table 2. In most studies, the genotype frequencies in the control populations are consistent with Hardy-Weinberg equilibrium. Notable exceptions are the study by Nakai et al¹⁴ and the Toulouse subgroup of the study by Cambien et al⁶ (Table 2). The individual odds ratios (with 95% CI) for MI for DD versus ID/II genotypes and the pooled estimate are shown in Fig 1. The mean odds ratio across all studies is 1.26 (95% CI, 1.15, 1.39; P<.0001). There is significant evidence against homogeneity of the odds ratio (²=45.0, P=.0004). Examination of the distribution of genotypes in control subjects shows a significant difference (²=66.2, P<.001) between the three studies in Japanese populations and others carried out in predominantly Caucasian populations (Table 2). The D allele frequency in the two groups is 0.39 and 0.54, respectively (P<.001). The Japanese studies have a higher average odds ratio for MI for DD versus ID/II genotypes (2.55; 95% CI, 1.75, 3.70; P<.0001). Exclusion of these studies from the meta-analysis gave a much reduced heterogeneity (²=29.4, P=.02) and a pooled odds ratio for the Caucasian studies of 1.18 (1.07, 1.30; P=.0008). The remaining heterogeneity between these studies is largely due to a higher than expected (on the basis of the other Caucasian studies) number of cases with the DD genotype (41 versus 25 predicted) in the study by Beohar et al²¹ and a lower than expected number (57 versus 74 predicted) in the study by Bohn et al.⁸

View this table: [in this window] [in a new window]   Table 2. Distribution of Genotypes and Allele Frequency in Individual Studies

View larger version (24K): [in this window] [in a new window]   Figure 1. Odds ratios for myocardial infarction comparing ACE DD genotype with ID and II genotypes combined (D, deletion; I, insertion). Estimates and 95% confidence intervals for each center together with the pooled estimate are shown. See Table 1 for references to studies. Block sizes are inversely proportional to the standard error of the log odds ratio. The solid vertical line shows an odds ratio of 1. The dashed vertical line shows the pooled estimate of 1.26. For all centers, except for Katsuya et al,20 the odds ratio was calculated from the raw data. For Katsuya et al, the odds ratio (age- and sex-adjusted) was taken directly from the study because full information to recalculate the ratio was not provided.

Pairwise comparisons (excluding only data in Reference 19, in which individual genotypes for cases were not given) show significant differences in mean odds ratios between DD and II (1.36; 95% CI, 1.19, 1.55; P<.0001) and DD and ID (1.24; 95% CI, 1.11, 1.38; P=.0001) and borderline difference between ID and II genotypes (1.09; 95% CI, 0.96, 1.23; P=.06).

The funnel plot of the estimate of the log odds ratio for DD versus ID/II genotypes against trial size is shown in Fig 2. In the absence of publication bias, one would expect studies of all sizes to be scattered equally above and below the pooled estimate, with smaller studies having larger standard errors, thus creating a horizontal funnel effect. However, examination of the plot shows the smaller studies to be almost all above the line showing the pooled estimate. This suggests publication bias with the smaller studies being published only if they show a significant effect. However, since three of these studies are the Japanese studies (Fig 2), this interpretation is to some extent dependent on whether the relative risk in Japanese subjects is the same as the overall risk (see "Discussion").

View larger version (13K): [in this window] [in a new window]   Figure 2. Funnel plot to look for publication bias in studies looking at the association of the ACE I/D (insertion/deletion) genotype with myocardial infarction risk. Estimate of the log odds ratio for DD versus ID/II genotypes against trial size (log scale) for each study is shown. The horizontal dashed line shows the pooled estimate of the log odds ratio across all studies. The three Japanese studies are shown as diamonds. The study by Samani et al27 (see "Results") is shown as an open circle.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this study, using data on >8500 subjects from all currently available studies, we provide a pooled estimate of the association between genetic variation at the ACE gene locus defined by the I/D polymorphism and risk of MI. The analysis supports the proposition that the D allele confers an increased risk of MI. However, at the level of increased risk found, it seems unlikely that ACE I/D genotyping will make a useful contribution to risk stratification of the individual; its main value will be in elucidating the mechanism of the association.

These conclusions must be viewed in the context of important limitations of the available data. First, as can be seen from Table 1, several of the studies have been carried out in either highly selected groups of cases and/or used control subjects who may not be ideal. This raises the questions of whether confounding factors influence results (and contribute to the apparent heterogeneity between studies) and whether the findings are generalizable to the whole population. A major limitation of all studies, apart from that by Lindpaintner et al,¹⁷ is that cases were recruited some (and variable) time after the incident MI, raising the possibility of selection by mortality influencing the result and again contributing to heterogeneity of findings. Finally, a degree of publication bias seems likely. As can be seen from Fig 2, most of the larger studies lie at or below the pooled estimate of the odds ratio, whereas the smaller studies are inevitably positive. The likely impact of this will be to cause an overestimation of the true effect of the D allele on MI risk, and thus the pooled odds ratio should be viewed with this borne in mind.

An important confounding factor recognized in association studies is ethnicity. We found both a different genotype distribution in control subjects and a higher odds ratio in Japanese populations. However, these studies are small, and, interestingly, the genotype distribution in Japanese cases is much more similar to that of Caucasian cases (Table 2). Therefore, whether these findings imply selection bias or a different relationship between DD genotype and MI risk in Japanese compared with Caucasian populations requires further investigation.

The findings in the meta-analysis are consistent with data linking the D allele to coronary artery disease risk using other criteria,^{10 16 18 21} particularly the finding in several studies of an increased familial risk of MI in those carrying the D allele.^{7 9 19}

An important unresolved issue concerning the effect of the D allele on MI risk concerns the genetic mechanism, ie, whether the effect is recessive, codominant, or dominant. This is relevant because the effect of the ACE genotype on the favored intermediary phenotype-tissue/plasma ACE level-is codominant.^{5 28} The meta-analysis shows clear differences in risk between DD and II or ID genotypes. The difference between II and ID genotypes failed to reach conventional significance, although the trend seen suggests that a single D allele probably also confers increased risk. However, given the limitations in the data, it would seem imprudent to overinterpret this finding and its relationship to ACE levels or the mechanism involved. One also needs to bear in mind that the I/D polymorphism is probably only a marker for the functional polymorphism that influences ACE levels^{4 5 29} and presumably MI risk and that the degree of linkage disequilibrium between the two may vary from population to population. This, as well as the other limitations of the data discussed previously, precludes a meaningful estimate of the attributable risk for MI for the ACE locus to be calculated until results from prospective studies, preferably with direct analysis of the susceptibility polymorphism, are available.

An important purpose of a meta-analysis is to help direct future research. Our findings certainly suggest that further research into the association of genetic variability at the ACE locus and MI risk is warranted. The analysis provides an indication of the size of study likely to provide useful information regarding the overall association. If one assumes that the increase in risk of MI with the DD genotype is 26% (odds ratio, 1.26), then a study of 1400 cases and a similar number of control subjects is required to have 80% power to detect a difference at a probability of .05 between DD and II/ID genotypes. So far, none of the studies have been anywhere near this size. If, as discussed above, the impact of the genotype is even smaller, the numbers required rise further, and to show a difference between the II and ID genotypes will require >5000 individuals in each group. Alternately, the meta-analysis finding also strengthens the case for testing specific hypotheses related to possible mechanisms underlying the association in smaller numbers of subjects by constructing ad hoc protocols.

Some studies have reported that the risk of MI associated with the DD genotype is particularly increased in subjects who would otherwise be considered at "low" risk on the basis of conventional risk factors.^{6 13 18 23} This has not been confirmed in other studies.¹⁷ Enough studies have not reported in sufficient detail on other risk factors to conduct a meaningful meta-analysis and the question of whether certain subgroups carrying the DD genotype are at much higher risk remains open but should be answerable by the types of studies described above. Likewise, whether the D allele influences the risk of MI through an effect on coronary atheroma formation or through other mechanisms such as the risk of acute thrombosis remains contentious^{16 18} and requires further evaluation, as do potential interactions with other genetic loci.³⁰

Summary
A meta-analysis of the currently available studies supports an association of the ACE DD genotype with risk of MI. This finding must be interpreted in the context of the limitations of the data but provides a basis for planning further studies on the relationship between genetic variation at the ACE gene locus and manifestations of coronary heart disease.

Received December 4, 1995; revision received February 15, 1996; accepted February 17, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Erdos EG. Angiotensin I-converting enzyme and the changes in our concepts through the years. Hypertension. 1990;16:363-370.[Abstract/Free Full Text]
   
2. Cambien F, Alhenc-Gelas F, Herbeth B, Andre JL, Rakatovao R, Gonzales MF, Allegrini J, Bloch C. Familial resemblance of plasma angiotensin-converting enzyme level: the Nancy study. Am J Hum Genet. 1988;43:774-780.[Medline] [Order article via Infotrieve]
   
3. Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin I converting enzyme gene (DCPI). Nucleic Acids Res. 1992;20:1433.[Free Full Text]
   
4. Tiret L, Rigat B, Visvikis S, Breda C, Corvol P, Cambien F, Soubrier F. Evidence from combined segregation and linkage analysis that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE. Am J Hum Genet. 1992;51:197-205.[Medline] [Order article via Infotrieve]
   
5. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I converting gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86:1343-1346.
   
6. Cambien F, Poirier O, Lecerf L, Evans A, Cambou J-P, Arveiler D, Luc G, Bard J-M, Bara L, Ricard S, Tiret L, Amouyel P, Alhenc-Gelas F, Soubrier F. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992;359:641-643.[Medline] [Order article via Infotrieve]
   
7. Tiret L, Kee F, Poirier O, Nicaud V, Lecerf L, Evans A, Cambou J-P, Arveiler D, Luc G, Amouyel P, Cambien F. Deletion polymorphism in the angiotensin-converting enzyme gene associated with parental history of myocardial infarction. Lancet. 1993;341:991-992.[Medline] [Order article via Infotrieve]
   
8. Bohn M, Berge KE, Bakken A, Erikssen J, Berg K. Insertion/deletion polymorphism at the locus for angiotensin I-converting enzyme and myocardial infarction. Clin Genet. 1993;44:292-297.[Medline] [Order article via Infotrieve]
   
9. Bohn M, Berge KE, Bakken A, Erikssen J, Berg K. Insertion/deletion (I/D) polymorphism at the locus for angiotensin I-converting enzyme and parental history of myocardial infarction. Clin Genet. 1993;44:298-301.[Medline] [Order article via Infotrieve]
   
10. Evans AE, Poirier O, Kee F, Lecerf L, McCrum E, Falconer T, Crane J, O'Rourke DF, Cambien F. Polymorphisms of the angiotensin-converting-enzyme gene in subjects who die from coronary heart disease. QJM. 1994;87:211-214.[Abstract/Free Full Text]
    
11. Ruiz J, Blanche H, Cohen N, Velho G, Cambien F, Cohen D, Passa P, Froguel P. Insertion/deletion polymorphism of the angiotensin-converting enzyme gene is strongly associated with coronary heart disease in non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A. 1994;91:3662-3665.[Abstract/Free Full Text]
    
12. Leatham E, Barley J, Redwood S, Hussein W, Carter N, Jeffery S, Bath PMW, Camm A. Angiotensin-1 converting enzyme (ACE) polymorphism in patients presenting with myocardial infarction or unstable angina. J Hum Hypertens. 1994;8:635-638.[Medline] [Order article via Infotrieve]
    
13. Zhao Y, Higashimori K, Higaki J, Kamitani A, Ohishi M, Katsuya T, Miki T, Mikami H, Minamino T, Ogihara T. Significance of deletion polymorphism of the angiotensin converting enzyme gene as a risk factor for myocardial infarction in Japanese. Hypertens Res. 1994;17:55-57.
    
14. Nakai K, Itoh C, Miura Y, Hotta K, Musha T, Itoh T, Miyakawa T, Iwasaki R, Hiramori K. Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with serum ACE concentrations and increased risk for coronary artery disease in the Japanese. Circulation. 1994;90:2199-2202.[Abstract/Free Full Text]
    
15. Friedl W, Krempler F, Paulweber B, Pichler M, Sandhofer F. A deletion polymorphism in the angiotensin converting enzyme gene is not associated with coronary heart disease in an Austrian population. Atherosclerosis. 1995;112:137-143.[Medline] [Order article via Infotrieve]
    
16. Mattu RK, Needham EWA, Galton DJ, Frangos E, Clark AJL, Caulfield M. A DNA variant at the angiotensin-converting enzyme gene locus associates with coronary artery disease in the Caerphilly Heart study. Circulation. 1995;91:270-274.[Abstract/Free Full Text]
    
17. Lindpaintner K, Pfeffer MA, Kreutz R, Stampfer MJ, Grodstein F, LaMotte F, Buring J, Hennekens CH. 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]
    
18. Ludwig E, Corneli PS, Anderson JL, Marshall HW, Lalouel J-M, Ward RH. Angiotensin-converting enzyme gene polymorphism is associated with myocardial infarction but not with development of coronary stenosis. Circulation. 1995;91:2120-2124.[Abstract/Free Full Text]
    
19. Badenhop RF, Wang XL, Wilcken DEL. Angiotensin-converting enzyme genotype in children and coronary events in their grandparents. Circulation. 1995;91:1655-1658.[Abstract/Free Full Text]
    
20. Katsuya T, Koike G, Yee TW, Sharpe N, Jackson R, Norton R, Horiuchi M, Pratt RE, Dzau VJ, MacMahon S. Association of angiotensinogen gene T235 variant with increased risk of coronary heart disease. Lancet. 1995;345:1600-1603.[Medline] [Order article via Infotrieve]
    
21. Beohar N, Damaraju S, Prather A, Yu Q-T, Raizner A, Kleiman NS, Roberts R, Marion AJ. Angiotensin-1 converting enzyme genotype DD is a risk factor for coronary artery disease. J Invest Med. 1995;43:275-280.[Medline] [Order article via Infotrieve]
    
22. Fujisawa T, Ikegami H, Shen G-Q, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Ueda H, Rakugi H, Higaki J, Ohishi M, Fujii K, Fukuda M, Ogihara T. Angiotensin-1 converting enzyme gene polymorphism is associated with myocardial infarction, but not with retinopathy or nephropathy, in NIDDM. Diabetes Care. 1995;18:983-985.[Abstract]
    
23. Keavney BD, Dudley CRK, Stratton IM, Holman RR, Matthews DR, Ratcliffe PJ, Turner RC. UK Prospective Diabetes Study (UKPDS) 14: association of angiotensin-converting enzyme insertion/deletion polymorphism with myocardial infarction in NIDDM. Diabetologia. 1995;38:948-952.[Medline] [Order article via Infotrieve]
    
24. Ahnve S, Flodin T, Berglund L, Eggertsen G, Sylven C. Angiotensin converting enzyme gene polymorphism in acute myocardial infarction patients. J Am Coll Cardiol. 1995;276A-277A. Abstract.
    
25. Greenlander S. Quantitative methods in the review of the epidemiological literature. Epidemiol Rev. 1987;9:1-30.[Free Full Text]
    
26. Dickersin K, Berlin JA. Meta-analysis: state-of-the-science. Epidemiol Rev. 1992;14:154-176.[Free Full Text]
    
27. Samani NJ, O'Toole L, Martin D, Rai H, Fletcher S, Lodwick D, Thompson JR, Morice AH, Channer K, Woods KL. The insertion/deletion polymorphism in the angiotensin-converting enzyme gene and the risk of and prognosis following myocardial infarction. J Am Coll Cardiol. In press.
    
28. 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.
    
29. Cambien F, Costerousse O, Tiret L, Poirier O, Lecerf L, Gonzales MF, Evand A, Arveiler D, Cambou JP, Luc G, Rakotavao R, Ducimetiere P, Soubrier F, Alhenc-Gelas F. Plasma level and gene polymorphism of angiotensin-converting enzyme in relation to myocardial infarction. Circulation. 1994;90:669-676.[Abstract/Free Full Text]
    
30. Tiret L, Bonnardeaux A, Poirier O, Ricard S, Marques-Vidal P, Evans A, Arveiler D, Luc G, Kee F, Ducimetiere P, Soubrier F, Cambien F. Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction. Lancet. 1994;344:910-914.[Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				E. Zintzaras, G. Raman, G. Kitsios, and J. Lau Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphic Variant as a Marker of Coronary Artery Disease: A Meta-analysis Arch Intern Med, May 26, 2008; 168(10): 1077 - 1089. [Abstract] [Full Text] [PDF]

				O. A. Iakoubova, C. H. Tong, C. M. Rowland, T. G. Kirchgessner, B. A. Young, A. R. Arellano, D. Shiffman, M. S. Sabatine, H. Campos, C. J. Packard, et al. Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials. J. Am. Coll. Cardiol., January 29, 2008; 51(4): 435 - 443. [Abstract] [Full Text] [PDF]

				T.-H. Lin, H.-C. Chiu, Y.-T. Lee, H.-M. Su, W.-C. Voon, H.-W. Liu, W.-T. Lai, and S.-H. Sheu Association Between Functional Polymorphisms of Renin-Angiotensin System, Left Ventricular Mass, and Geometry Over 4 Years in a Healthy Chinese Population Aged 60 Years and Older J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2007; 62(10): 1157 - 1163. [Abstract] [Full Text] [PDF]

				K. Tiroch, W. Koch, N. von Beckerath, A. Kastrati, and A. Schomig Heme oxygenase-1 gene promoter polymorphism and restenosis following coronary stenting Eur. Heart J., April 2, 2007; 28(8): 968 - 973. [Abstract] [Full Text] [PDF]

				A. Bilici, M. S. Ulgen, H. Nazaroglu, O. Ozturk, F. Ekici, C. Akgul, and B. Alan The Effect of ACE Gene Polymorphisms on Doppler Blood Flow Parameters of Carotid and Brachial Arteries in Patients With Myocardial Infarction Angiology, January 1, 2007; 57(6): 681 - 685. [Abstract] [PDF]

				W. Koch, P. Hoppmann, A. Pfeufer, A. Schomig, and A. Kastrati Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population Eur. Heart J., November 1, 2006; 27(21): 2524 - 2529. [Abstract] [Full Text] [PDF]

				Prepared by: British Cardiac Society, British Hype JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice Heart, December 1, 2005; 91(suppl_5): v1 - v52. [Full Text] [PDF]

				D. J. Lehmann, M. Cortina-Borja, D. R. Warden, A. D. Smith, K. Sleegers, J. A. Prince, C. M. van Duijn, and P. G. Kehoe Large Meta-Analysis Establishes the ACE Insertion-Deletion Polymorphism as a Marker of Alzheimer's Disease Am. J. Epidemiol., August 15, 2005; 162(4): 305 - 317. [Abstract] [Full Text] [PDF]

				M. BEDNARSKA-MAKARUK, M. RODO, C. MARKUSZEWSKI, A. ROZENFELD, M. SWIDERSKA, B. HABRAT, and H. WEHR POLYMORPHISMS OF APOLIPOPROTEIN E AND ANGIOTENSIN-CONVERTING ENZYME GENES AND CAROTID ATHEROSCLEROSIS IN HEAVY DRINKERS Alcohol Alcohol., July 1, 2005; 40(4): 274 - 282. [Abstract] [Full Text] [PDF]

				F A Sayed-Tabatabaei, A F C Schut, A Arias Vasquez, A M Bertoli-Avella, A Hofman, J C M Witteman, and C M van Duijn Angiotensin converting enzyme gene polymorphism and cardiovascular morbidity and mortality: the Rotterdam Study J. Med. Genet., January 1, 2005; 42(1): 26 - 30. [Abstract] [Full Text] [PDF]

				I. Cascorbi, M. Paul, and H. K. Kroemer Pharmacogenomics of heart failure - focus on drug disposition and action Cardiovasc Res, October 1, 2004; 64(1): 32 - 39. [Abstract] [Full Text] [PDF]

				A. Slowik, W. Turaj, T. Dziedzic, A. Haefele, J. Pera, M. T. Malecki, L. Glodzik-Sobanska, P. Szermer, D. A. Figlewicz, and A. Szczudlik DD genotype of ACE gene is a risk factor for intracerebral hemorrhage Neurology, July 27, 2004; 63(2): 359 - 361. [Abstract] [Full Text] [PDF]

				S. E. Humphries, P. M. Ridker, and P. J. Talmud Genetic Testing for Cardiovascular Disease Susceptibility: A Useful Clinical Management Tool or Possible Misinformation? Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 628 - 636. [Abstract] [Full Text] [PDF]

				D. Petrovic, D. Bregar, B. Guzic-Salobir, E. Skof, M. Span, R. Terzic, M. G. Petrovic, I. Keber, M. Letonja, M. Zorc, et al. Sex Difference in the Effect of ACE-DD Genotype on the Risk of Premature Myocardial Infarction Angiology, March 1, 2004; 55(2): 155 - 158. [Abstract] [PDF]

				J. S. Elkins, V. C. Douglas, and S. C. Johnston Alzheimer disease risk and genetic variation in ACE: A meta-analysis Neurology, February 10, 2004; 62(3): 363 - 368. [Abstract] [Full Text] [PDF]

				M. M. Fernandez, J. J. Rodriguez Reguero, and P. Gonzalez Angiotensin-converting enzyme polymorphism (I/D) and coronary heart disease in young adults J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1864 - 1864. [Full Text] [PDF]

				V. A. Cameron and B. R. Palmer Angiotensin-converting enzyme polymorphism (I/D) and coronary heart disease in young adults: Reply J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1864 - 1864. [Full Text] [PDF]

				S Ye, S Dhillon, R Seear, L Dunleavey, L B Day, W Bannister, I N M Day, and I Simpson Epistatic interaction between variations in the angiotensin I converting enzyme and angiotensin II type 1 receptor genes in relation to extent of coronary atherosclerosis Heart, October 1, 2003; 89(10): 1195 - 1199. [Abstract] [Full Text] [PDF]

				I. B. M. Da Cruz, G. Oliveira, M. Taufer, N. F. Leal, C. H. Schwanke, L. Glock, Y. Moriguchi, and E. H. Moriguchi Angiotensin I-Converting Enzyme Gene Polymorphism in Two Ethnic Groups Living in Brazil's Southern Region: Association With Age J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2003; 58(9): M851 - 856. [Abstract] [Full Text] [PDF]

				F. Aucella, M. Margaglione, M. Vigilante, G. Gatta, E. Grandone, M. Forcella, M. Ktena, A. De Min, G. Salatino, D. A. Procaccini, et al. PAI-1 4G/5G and ACE I/D gene polymorphisms and the occurrence of myocardial infarction in patients on intermittent dialysis Nephrol. Dial. Transplant., June 1, 2003; 18(6): 1142 - 1146. [Abstract] [Full Text] [PDF]

				D. S. Jacoby and D. J. Rader Renin-Angiotensin System and Atherothrombotic Disease: From Genes to Treatment Arch Intern Med, May 26, 2003; 163(10): 1155 - 1164. [Abstract] [Full Text] [PDF]

				B. R. Palmer, A. P. Pilbrow, T. G. Yandle, C. M. Frampton, A. M. Richards, M. G. Nicholls, and V. A. Cameron Angiotensin-converting enzyme gene polymorphism interacts with left ventricular ejection fraction and brain natriuretic peptide levels to predict mortality after myocardial infarction J. Am. Coll. Cardiol., March 5, 2003; 41(5): 729 - 736. [Abstract] [Full Text] [PDF]

				M Hamon, S Fradin, A Denizet, E Filippi-Codaccioni, G Grollier, and R Morello Prospective evaluation of the effect of an angiotensin I converting enzyme gene polymorphism on the long term risk of major adverse cardiac events after percutaneous coronary intervention Heart, March 1, 2003; 89(3): 321 - 325. [Abstract] [Full Text] [PDF]

				F. L Ruberg and J. Loscalzo Prothrombotic determinants of coronary atherothrombosis Vascular Medicine, November 1, 2002; 7(4): 289 - 299. [Abstract] [PDF]

				D. R. Dengel, M. D. Brown, R. E. Ferrell, T. H. Reynolds IV, and M. A. Supiano Exercise-induced changes in insulin action are associated with ACE gene polymorphisms in older adults Physiol Genomics, October 29, 2002; 11(2): 73 - 80. [Abstract] [Full Text] [PDF]

				H. Montgomery, S. Humphries, and S. Danilov Is genotype or phenotype the better tool for investigating the role of ACE in human cardiovascular disease? Eur. Heart J., July 2, 2002; 23(14): 1083 - 1086. [Full Text] [PDF]

				B.-M. Taute, C. Glaser, R. Taute, and H. Podhaisky Progression of Atherosclerosis in Patients with Peripheral Arterial Disease as a Function of Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism Angiology, July 1, 2002; 53(4): 375 - 382. [Abstract] [PDF]

				R. A. Hegele SNP Judgments and Freedom of Association Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1058 - 1061. [Full Text] [PDF]

				F. G. H. van der Kleij, P. E. de Jong, R. H. Henning, D. de Zeeuw, and G. Navis Enhanced Responses of Blood Pressure, Renal Function, and Aldosterone to Angiotensin I in the DD Genotype Are Blunted by Low Sodium Intake J. Am. Soc. Nephrol., April 1, 2002; 13(4): 1025 - 1033. [Abstract] [Full Text]

				J. M. Hagberg, S. D. McCole, M. D. Brown, R. E. Ferrell, K. R. Wilund, A. Huberty, L. W. Douglass, and G. E. Moore ACE insertion/deletion polymorphism and submaximal exercise hemodynamics in postmenopausal women J Appl Physiol, March 1, 2002; 92(3): 1083 - 1088. [Abstract] [Full Text] [PDF]

				B. Swynghedauw Susceptibility-conferring polymorphic genotypes in cardiovascular multifactorial syndromes Eur. Heart J., February 2, 2002; 23(4): 271 - 273. [Full Text] [PDF]

				M. Egger, S. Ebrahim, and G. D. Smith Where now for meta-analysis? Int. J. Epidemiol., February 1, 2002; 31(1): 1 - 5. [Full Text] [PDF]