Abstract
Background: The genetic factors that contribute to ischemic heart disease (IHD) are poorly understood, and it is likely that multiple genes acting independently or synergistically contribute to the risk of IHD and outcome. The genes for angiotensin‐converting enzyme (ACE) and apolipoprotein E (ApoE) have been implicated independently in the risk of IHD.
Hypothesis: This study examined whether genetic polymorphisms in the ACE and ApoE genes are associated with early onset IHD. Polymorphisms in a third gene, transforming growth factor β2 (TGF β2), with a known role in wound repair and cardiac development, are also examined with respect to early onset IHD.
Methods: In all, 101 patients with IHD and onset of disease before 55 years for men and 60 years for women, and 100 controls with angiographically confirmed normal coronary arteries were recruited for this study. The ACE, ApoE, and TGF β2 genotypes were determined by polymerase chain reaction amplification or Southern blotting and were compared with the patient's clinical and family histories.
Results and Conclusion: The frequency of the ACE D allele was significantly lower in the patient group (0.475) than in the control group (0.59, p = 0.03), which was attributed to a reduction in the number of patients with the DD genotype (patients: 24% DD, controls: 33% DD). Sudden cardiac death was also associated with the DD genotype. These data are consistent with the ACE D allele contributing to a fatal outcome. No association between the DD genotype and risk of myocardial infarction, presenting age, extent of vessel disease, family history, hypertension, or hypercholesterolemia was seen. Analysis of the ApoE genotype showed no association with early onset IHD. There was no evidence for a synergistic effect between the ACE and ApoE genotypes on the risk of early onset IHD. A polymorphism in the TGF (32 gene was rare and not associated with early onset IHD.
Keywords: angiotensin‐converting enzyme; apolipoprotein E; transforming growth factor β2, DNA polymorphisms; ischemic heart disease
Full Text
The Full Text of this article is available as a PDF (612.9 KB).
References
- 1. Cambien F, Poirier O. Lecerf L. Evans A, Cambous J‐P, Arveiler D, Luc G, Bard J‐M, Bara L, Ricard S, Tiret L, Amouyel P, AlhencGelas F, Soubrier F: Deletion polymorphism in the gene for angiotensin‐converting enzyme is a potent risk factor for myocardial infarction, Nature 1992; 359: 641–644 [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: Angiolensin‐converting enzyme gene deletion allele is independently and strongly associated with coronary atherosclerosis and myocardial infarction. Br Heart J 1995; 74: 584–591 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Bohn M, Berge KE, Bakken A, Erikssen J, Berg K: Insertion/delelion (I/D) polymorphism at the locus for angiotensin I‐converting enzyme and myocaixlial infarction. Clin Genet 1993; 44: 292–297 [DOI] [PubMed] [Google Scholar]
- 4. Gardemann A, Weiss T, Schwartz O, Eberbach A, Katz N, Hehrlein FW, Tillmanns H, Waas W, Haberhosch W: Gene polymorphism but not catalytic activity of angiotensin I‐converting enzyme is associated with coronary artery disease and myocardial infarction in low‐risk patients. Circulation 1995; 92: 2796–2799 [DOI] [PubMed] [Google Scholar]
- 5. Ludwig E, Corneli PS, Anderson JL, Marshall HW, Lalouel J‐M. Ward RH: Angiolensin‐converting enzyme gene polymorphism is associated with myocardial infarction but not wilh development of coronory stenosis. Circulation 1995; 91: 2120–2124 [DOI] [PubMed] [Google Scholar]
- 6. 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. Quart J Med 1994; 87: 211–214 [PubMed] [Google Scholar]
- 7. Friedl W, Krempler F, Paulweber B, Pichler M, Sandhofer F: A deletion polymorphism in the angiotensin‐convertingenzyme gene is not associated with coronary heart disease in an Austrian population. Atherosclerosis 1995; 112: 137–143 [DOI] [PubMed] [Google Scholar]
- 8. 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 I receptor gene polymorphisms on risk of myocardial infarcation. Lancet 1994; 344: 910–913 [DOI] [PubMed] [Google Scholar]
- 9. Jeunemaitre X. Ledru F, Battaglia S. Guillanneuf MT, Courbon D, Dumont C, Darmon O, Guize L. Guermonprez JL, Diebold B, Ducimetiere P: Genetic polymorphisms of the renin‐angiotensin system and angiographic extent and severity of coronary artery disease: The Corgene Study. Hum Genet 1997; 99: 66–73 [DOI] [PubMed] [Google Scholar]
- 10. Menzel H‐J, Kladetzky R‐G, Assmann G: Apolipoprotein E polymorphism and coronary artery disease. Arteriosclerosis 1983; 3: 310–315 [DOI] [PubMed] [Google Scholar]
- 11. Davignon J, Gregg RE, Sing CF: Apolipoprolein E polymorphism and atherosclerosis. Arteriosclerosis 1988; 8: 1–21 [DOI] [PubMed] [Google Scholar]
- 12. Humphries SE: DNA polymorphisms of the apolipoprotein genes—their use in the investigation of the genetic component of hyperlipidaemia and atherosclerosis. Atherosclerosis 1988; 72: 89–108 [DOI] [PubMed] [Google Scholar]
- 13. Dickson MC, Slager HG, Duffie E, Mummery CL, Akhurst RJ: RNA and protein localisations of TGF beta 2 in the early mouse embryo suggest an involvement in cardiac development. Development 1993; 117: 625–639 [DOI] [PubMed] [Google Scholar]
- 14. WHO MONICA Project: MONICA Manual. Geneva: Cardiovascular Diseases Unit. World Health Organisation, 1990. [Google Scholar]
- 15. WHO/ISH 1993 Guidelines for the Management of Mild Hypertension. Bulletin of the World Health Organization; (1993) 71 (5): 503–517 [PMC free article] [PubMed] [Google Scholar]
- 16. WHO Guidelines for Diabetes Mellitus, p. 727 Geneva: WHO, 1985. [Google Scholar]
- 17. Sambrook J, Fritsch EF, Maniatis T: Molecular Cloning, a Laboratory Manual. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 1989. [Google Scholar]
- 18. Rigat B, Hubert C, Corvol P, Soubrier F: PCR detection of the insertion/deletion polymorphism of the human angiotensin‐converting enzyme gene (DCP1). Nucl Acids Res 1992; 20: 1433 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Lindpaintner K, Pfeffer MA, Kreutz R, Stampfer MJ, Grodstein PHF. LaMotte F, Birring 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 [DOI] [PubMed] [Google Scholar]
- 20. Thun MJ, Daylally CA, Calle EE. Flanders WD, Heath CW: Excess mortality among cigarette smokers‐changes in a 20‐year interval. Am J Pub/ Health 1995; 85: 1223–1230 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Mattu RK, Needham EWA, Gallon 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 [DOI] [PubMed] [Google Scholar]
- 22. Barley J, Black wood A, Carter ND, Crews DE, Cruickshank JK, Jeffery S, Ogunlesi AO, Sagnella GA: Angiotensin‐converting enzyme insertion/deletion polymorphism: Association with. J Hypeitens 1994; 12: 955–957 [PubMed] [Google Scholar]