Angiotensin converting enzyme genotypes and diseaseBMJ 1995; 311 doi: https://doi.org/10.1136/bmj.311.7008.763 (Published 23 September 1995) Cite this as: BMJ 1995;311:763
- Koon K Teo
- Associate professor of medicine 2C2 Walter Mackenzie Centre, University of Alberta Hospital, Edmonton, Alberta, Canada T6G 2R7
Conflicting results from research leave the picture unclear
Ischaemic heart disease has both environmental and genetic influences, but research has concentrated on the environmental angle. The main modifiable risk factors have been identified and preventive measures introduced with substantial success. Our knowledge of genetic factors has yet to be established in the same ways. The idea of routine tests evaluating genetic risk factors seems appealing but it has not been feasible. Test results could not at present provide a clinician with more than confirmation of a positive family history as an indicator of increased susceptibility to the disease.
The picture has changed with recent reports that a genotype of the angiotensin converting enzyme (ACE) gene may be a risk factor for ischaemic heart disease.1 2 These studies show the potential of modern molecular biology as a research tool for establishing genetic risk factors for cardiovascular diseases. Moreover, in this case a treatment--angiotensin converting enzyme inhibition--is available and may prove useful for those at risk. As yet, however, the predictive utility of the data from genetic and epidemiological studies remains uncertain.
A report in Nature by Cambien et al first raised the possibility of an association between ACE gene polymorphism and increased risk for myocardial infarction in relatively homogeneous groups of French and Irish men. This was a retrospective case control comparison of men studied three to nine months after acute myocardial infarction.1 The gene polymorphism is due to the presence (insertion or I) or absence (deletion or D) of a 287 base pair sequence in a non-coding section of the ACE gene. The DD genotype was found in 32.3% of patients and 27.3% of controls and was associated with a 34% (adjusted odds ratio 1.34) excess risk for acute myocardial infarction when compared with that for patients with the other two genotypes ID and II. The association seemed particularly strong in a subgroup with an overall low risk from conventional factors (adjusted odds ratio 3.2). The DD genotype was also associated with higher mean plasma concentrations of angiotensin converting enzyme--suggesting that the increased risk from this genotype may result from raised concentrations of angiotensin converting enzyme and associated higher concentrations of angiotensin II.
The hypothesis that this genetic variation of the ACE locus could be associated with an increased risk for acute myocardial infarction was further strengthened by the observation made by the same authors of an apparent excess of both DD and ID genotypes among those having a parental history of acute myocardial infarction.2 The higher prevalence of the DD genotype or D allele in patients with diabetes and coronary heart disease,3 patients with hypertrophic cardiomyopathy experiencing sudden death from cardiac causes,4 and patients with left ventricular hypertrophy5 and ischaemic and idiopathic dilated cardiomyopathy6 suggests that the D allele may play a part in the pathogenesis.
Unfortunately, some other studies have not confirmed the association between the DD genotype and ischaemic heart disease.7 8 9 Bohn et al studied 185 men and 49 women, survivors of acute myocardial infarction, 2.7 years after the event. They compared the frequency of the DD genotype in this group with that of 366 controls7 and found that it was present less often among men patients (23%) than controls (35%), but they found no difference between women patients (31%) and controls (29%).7 Miettinen et al found no association between ACE gene polymorphism and the risk of premature coronary heart disease.8 The frequency of DD genotype in their study was 27% in patients and 18% in controls.
The conflict between Cambien's initial report and these later studies may be explained by chance because of small sample sizes; biases in selection of subjects or controls, or both; preferential loss of DD individuals in those who have died; or differences in genetic environmental interactions, but the inconsistencies raise doubts about the predictive utility of this genotype as a risk factor for ischaemic heart disease.
These doubts have been reinforced by a recent prospective study on 1250 men with ischaemic heart disease matched with 2340 controls from the physicians' health study of 22071 men, mostly white American physicians.9 The researchers analysed blood samples of men taken when they entered the study--so that these included both the survivors and non-survivors of myocardial infarction. This is an important and essential feature not included in the other studies. The results showed no association between the D allele and the risk of ischaemic heart disease or myocardial infarction. The odds ratio for risk of ischaemic heart disease in the overall group of patients with the DD genotype compared to the other two genotypes (ID and II) was 1.09 (95% confidence interval 0.92 to 1.27), and for myocardial infarction was 1.08 (95% confidence interval 0.85 to 1.38). These negative results could be due to the heterogeneous genetic background of this North American population, which may have been too diverse to show an association between ACE gene polymorphism and ischaemic heart disease. Other reasons could be suggested, such as that the men in this study may have been at too low overall risk. Possibly, however, there may simply be no association.
Nevertheless, the renin-angiotensin system has a crucial role in the pathogenesis of ischaemic heart disease. This is shown by the undoubted benefits of angiotensin converting enzyme inhibition in reducing ischaemic events10 11 and the evidence from many laboratory and clinical studies. This clinical benefit is thought to be due either to reduced formation of angiotensin II as a result of angiotensin converting enzyme inhibition or to variations in types or responses in angiotensin II receptors. Further work from Cambien's group has suggested other reasons for the increased risk of coronary artery disease--such as a synergistic effect of the increased levels of angiotensin converting enzyme associated with the D allele and a polymorphism of the gene for the AT1 receptor (a subtype of angiotensin II receptors)12; or another polymorphism in the ACE gene which influences the plasma concentrations of angiotensin converting enzyme--which in turn may be an independent risk factor for myocardial infarction.13 Yet other studies have suggested that a variant of the angiotensinogen gene (T235) may play a part.14 This last genetic variant is also associated with essential hypertension in both white15 and Japanese populations16 and may potentially be concerned in several pathways leading to the pathogenesis of ischaemic heart disease.
Where do we stand? The early promise that the ACE I/D gene polymorphism would prove to be an independent risk factor for ischaemic heart disease has not been substantiated by other studies. The interaction of angiotensin converting enzyme and the renin-angiotensin system has, however, important actions on blood vessels, including modulation of the formation of the atherosclerotic plaque. At present the responsible genetic factor has not been identified, but one or more genetic risk factors or markers from the angiotensin converting enzyme renin-angiotensin systems may well be found. The genetic basisfor ischaemic heart disease has always been assumed to be multifactorial.