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. 2001 Apr;85(4):458–462. doi: 10.1136/heart.85.4.458

Increased risk for ischaemic events is related to combined RAS polymorphism

P P van Geel 1, Y Pinto 1, A Zwinderman 1, R Henning 1, A J van Boven 1, J Jukema 1, A Bruschke 1, J Kastelein 1, W H van Gilst 1, G BAXTER 1
PMCID: PMC1729671  PMID: 11250978

Abstract

OBJECTIVE—To determine whether the angiotensin converting enzyme (ACE) and the angiotensin II type 1 receptor (AT1R A1166C) gene polymorphism interact to increase the risk of ischaemic events, and whether this can be explained by the progression of angiographically defined coronary atherosclerosis.
DESIGN—Prospective defined substudy of the lipid lowering regression trial (REGRESS).
SETTING—University hospital.
PATIENTS—885 male patients with stable coronary artery disease.
MAIN OUTCOME MEASURES—Incidence of ischaemic events during a two year follow up; serial quantitative coronary arteriography (mean segment diameter and minimum obstruction diameter) at baseline and after two years.
RESULTS—Patients who carried both the ACE-DD and AT1R-CC genotype had significantly more ischaemic events during the two year follow up than those carrying other genotype combinations (p = 0.035, Mantel-Haenszel test for linear association). There was no association between the two genotypes and mean segment diameter or minimum obstruction diameter at baseline or after two years.
CONCLUSIONS—The suggestion that ACE-DD and AT1R-CC genotypes interact to increase the risk of ischaemic events is confirmed. However, this increased risk was not accompanied by increased progression of angiographically defined coronary atherosclerosis.


Keywords: renin-angiotensin system; polymorphism; coronary atherosclerosis; ischaemic events

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Figure 1  .

Figure 1  

Kaplan-Meier curves for the event-free survival of patients according to ACE-DD and AT1R-CC genotypes. The p value indicates the overall significance of the Mantel-Haenszel test for linear association between the curves.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amant C., Hamon M., Bauters C., Richard F., Helbecque N., McFadden E. P., Escudero X., Lablanche J. M., Amouyel P., Bertrand M. E. The angiotensin II type 1 receptor gene polymorphism is associated with coronary artery vasoconstriction. J Am Coll Cardiol. 1997 Mar 1;29(3):486–490. doi: 10.1016/s0735-1097(96)00535-9. [DOI] [PubMed] [Google Scholar]
  2. Arbustini E., Grasso M., Fasani R., Klersy C., Diegoli M., Porcu E., Banchieri N., Fortina P., Danesino C., Specchia G. Angiotensin converting enzyme gene deletion allele is independently and strongly associated with coronary atherosclerosis and myocardial infarction. Br Heart J. 1995 Dec;74(6):584–591. doi: 10.1136/hrt.74.6.584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berkenboom G. Unstable atherosclerotic plaque. Pathophysiology and therapeutic guidelines. Acta Cardiol. 1998;53(4):235–241. [PubMed] [Google Scholar]
  4. Bonnardeaux A., Davies E., Jeunemaitre X., Féry I., Charru A., Clauser E., Tiret L., Cambien F., Corvol P., Soubrier F. Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension. 1994 Jul;24(1):63–69. doi: 10.1161/01.hyp.24.1.63. [DOI] [PubMed] [Google Scholar]
  5. Cambien F., Poirier O., Lecerf L., Evans A., Cambou J. P., Arveiler D., Luc G., Bard J. M., Bara L., Ricard S. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992 Oct 15;359(6396):641–644. doi: 10.1038/359641a0. [DOI] [PubMed] [Google Scholar]
  6. Diet F., Pratt R. E., Berry G. J., Momose N., Gibbons G. H., Dzau V. J. Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation. 1996 Dec 1;94(11):2756–2767. doi: 10.1161/01.cir.94.11.2756. [DOI] [PubMed] [Google Scholar]
  7. Fatini C., Abbate R., Pepe G., Battaglini B., Gensini F., Ruggiano G., Gensini G. F., Guazzelli R. Searching for a better assessment of the individual coronary risk profile. The role of angiotensin-converting enzyme, angiotensin II type 1 receptor and angiotensinogen gene polymorphisms. Eur Heart J. 2000 Apr;21(8):633–638. doi: 10.1053/euhj.1999.1738. [DOI] [PubMed] [Google Scholar]
  8. Gardemann A., Nguyen Q. D., Humme J., Stricker J., Katz N., Tillmanns H., Hehrlein F. W., Rau M., Haberbosch W. Angiotensin II type 1 receptor A1166C gene polymorphism. Absence of an association with the risk of coronary artery disease and myocardial infarction and of a synergistic effect with angiotensin-converting enzyme gene polymorphism on the risk of these diseases. Eur Heart J. 1998 Nov;19(11):1657–1665. doi: 10.1053/euhj.1998.1097. [DOI] [PubMed] [Google Scholar]
  9. Henrion D., Amant C., Benessiano J., Philip I., Plantefève G., Chatel D., Hwas U., Desmont J. M., Durand G., Amouyel P. Angiotensin II type 1 receptor gene polymorphism is associated with an increased vascular reactivity in the human mammary artery in vitro. J Vasc Res. 1998 Sep-Oct;35(5):356–362. doi: 10.1159/000025605. [DOI] [PubMed] [Google Scholar]
  10. Hingorani A. D., Brown M. J. A simple molecular assay for the C1166 variant of the angiotensin II type 1 receptor gene. Biochem Biophys Res Commun. 1995 Aug 15;213(2):725–729. doi: 10.1006/bbrc.1995.2190. [DOI] [PubMed] [Google Scholar]
  11. Jukema J. W., Bruschke A. V., van Boven A. J., Reiber J. H., Bal E. T., Zwinderman A. H., Jansen H., Boerma G. J., van Rappard F. M., Lie K. I. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation. 1995 May 15;91(10):2528–2540. doi: 10.1161/01.cir.91.10.2528. [DOI] [PubMed] [Google Scholar]
  12. Lindpaintner K., Pfeffer M. A., Kreutz R., Stampfer M. J., Grodstein F., LaMotte F., Buring J., Hennekens C. H. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med. 1995 Mar 16;332(11):706–711. doi: 10.1056/NEJM199503163321103. [DOI] [PubMed] [Google Scholar]
  13. Ludwig E., Corneli P. S., Anderson J. L., Marshall H. W., Lalouel J. M., Ward R. H. Angiotensin-converting enzyme gene polymorphism is associated with myocardial infarction but not with development of coronary stenosis. Circulation. 1995 Apr 15;91(8):2120–2124. doi: 10.1161/01.cir.91.8.2120. [DOI] [PubMed] [Google Scholar]
  14. O'Malley J. P., Maslen C. L., Illingworth D. R. Angiotensin-converting enzyme DD genotype and cardiovascular disease in heterozygous familial hypercholesterolemia. Circulation. 1998 May 12;97(18):1780–1783. doi: 10.1161/01.cir.97.18.1780. [DOI] [PubMed] [Google Scholar]
  15. Ohishi M., Ueda M., Rakugi H., Naruko T., Kojima A., Okamura A., Higaki J., Ogihara T. Enhanced expression of angiotensin-converting enzyme is associated with progression of coronary atherosclerosis in humans. J Hypertens. 1997 Nov;15(11):1295–1302. doi: 10.1097/00004872-199715110-00014. [DOI] [PubMed] [Google Scholar]
  16. Osterop A. P., Kofflard M. J., Sandkuijl L. A., ten Cate F. J., Krams R., Schalekamp M. A., Danser A. H. AT1 receptor A/C1166 polymorphism contributes to cardiac hypertrophy in subjects with hypertrophic cardiomyopathy. Hypertension. 1998 Nov;32(5):825–830. doi: 10.1161/01.hyp.32.5.825. [DOI] [PubMed] [Google Scholar]
  17. Pastore L., Tessitore A., Martinotti S., Toniato E., Alesse E., Bravi M. C., Ferri C., Desideri G., Gulino A., Santucci A. Angiotensin II stimulates intercellular adhesion molecule-1 (ICAM-1) expression by human vascular endothelial cells and increases soluble ICAM-1 release in vivo. Circulation. 1999 Oct 12;100(15):1646–1652. doi: 10.1161/01.cir.100.15.1646. [DOI] [PubMed] [Google Scholar]
  18. Pinto Y. M., van Gilst W. H., Kingma J. H., Schunkert H. Deletion-type allele of the angiotensin-converting enzyme gene is associated with progressive ventricular dilation after anterior myocardial infarction. Captopril and Thrombolysis Study Investigators. J Am Coll Cardiol. 1995 Jun;25(7):1622–1626. doi: 10.1016/0735-1097(95)00090-q. [DOI] [PubMed] [Google Scholar]
  19. 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 Oct;86(4):1343–1346. doi: 10.1172/JCI114844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rigat B., Hubert C., Corvol P., Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res. 1992 Mar 25;20(6):1433–1433. doi: 10.1093/nar/20.6.1433-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Samani N. J., Martin D. S., Brack M., Cullen J., Chauhan A., Lodwick D., Harley A., Swales J. D., de Bono D. P., Gershlick A. H. Insertion/deletion polymorphism in the angiotensin-converting enzyme gene and risk of restenosis after coronary angioplasty. Lancet. 1995 Apr 22;345(8956):1013–1016. doi: 10.1016/s0140-6736(95)90756-4. [DOI] [PubMed] [Google Scholar]
  22. Schieffer B., Schieffer E., Hilfiker-Kleiner D., Hilfiker A., Kovanen P. T., Kaartinen M., Nussberger J., Harringer W., Drexler H. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation. 2000 Mar 28;101(12):1372–1378. doi: 10.1161/01.cir.101.12.1372. [DOI] [PubMed] [Google Scholar]
  23. Shanmugam V., Sell K. W., Saha B. K. Mistyping ACE heterozygotes. PCR Methods Appl. 1993 Oct;3(2):120–121. doi: 10.1101/gr.3.2.120. [DOI] [PubMed] [Google Scholar]
  24. Talmud P. J., Watts G. F., McBride S., Mandalia S., Brunt J. N., Coltart D. J., Lewis B., Humphries S. E. Angiotensin converting enzyme gene polymorphism and the course of angiographically defined coronary artery disease. Atherosclerosis. 1995 Apr 7;114(1):133–135. doi: 10.1016/0021-9150(94)05467-w. [DOI] [PubMed] [Google Scholar]
  25. Tiret L., Bonnardeaux A., Poirier O., Ricard S., Marques-Vidal P., Evans A., Arveiler D., Luc G., Kee F., Ducimetière P. Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction. Lancet. 1994 Oct 1;344(8927):910–913. doi: 10.1016/s0140-6736(94)92268-3. [DOI] [PubMed] [Google Scholar]
  26. Tiret L., Kee F., Poirier O., Nicaud V., Lecerf L., Evans A., Cambou J. P., Arveiler D., Luc G., Amouyel P. Deletion polymorphism in angiotensin-converting enzyme gene associated with parental history of myocardial infarction. Lancet. 1993 Apr 17;341(8851):991–992. doi: 10.1016/0140-6736(93)91075-w. [DOI] [PubMed] [Google Scholar]
  27. 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 levels. Am J Hum Genet. 1992 Jul;51(1):197–205. [PMC free article] [PubMed] [Google Scholar]
  28. van Geel P. P., Pinto Y. M., Voors A. A., Buikema H., Oosterga M., Crijns H. J., van Gilst W. H. Angiotensin II type 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II in human arteries. Hypertension. 2000 Mar;35(3):717–721. doi: 10.1161/01.hyp.35.3.717. [DOI] [PubMed] [Google Scholar]

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