Apolipoprotein E4, lipoprotein lipase C447 and angiotensin-I converting enzyme deletion alleles were not associated with increased wall thickness of carotid and femoral arteries in healthy subjects from the Stanislas cohort
Introduction
Atherosclerosis is a very slow process in humans that begins early in life and develops over decades. Measurement of carotid artery wall intima-media thickness (IMT) using high resolution B-mode ultrasonography can be used to assess directly in vivo early arterial changes and carotid intima-media thickness is becoming increasingly accepted as an early indicator of generalized atherosclerosis [1]. Indeed, increased carotid artery IMT has been associated with coronary atherosclerosis [2], myocardial infarction [3]and stroke [4]. Carotid artery IMT has also been associated with cardiovascular risk factors such as gender, smoking, hypercholesterolemia, hypertriglyceridemia, hypertension, diabetes and left ventricular hypertrophy 5, 6, 7, 8, 9, 10. So, the investigation of candidate genes of IMT variability will facilitate studies and research of putative risk factors for early development of atherosclerosis. Apolipoprotein E (apo E), lipoprotein lipase (LPL) and angiotensin converting enzyme (ACE) genes could be potential candidate genes of IMT variability. Apo E is a key apolipoprotein of cholesterol metabolism and is encoded in humans by three common alleles ε2, ε3 and ε4. This polymorphism has been associated with plasma total and LDL-cholesterol levels in a large number of studies [11]and the apo ε4 allele has been associated with an increased risk for CAD [12]. Lipoprotein lipase is essential for the hydrolysis of triglycerides in circulating lipoproteins. Several polymorphisms have been identified at the LPL locus and have been associated with serum triglycerides levels and/or coronary heart disease [13]. ACE is a key enzyme of the renin-angiotensin system (RAS), located principally in vascular endothelial cells. ACE converts the inactive peptide angiotensin I into the vasoconstrictor angiotensin II (AngII) and also inactives the vasodilator peptide bradikinine. These two peptides have opposite effects on vascular tone, myocardial and vascular smooth muscle cell growth and on the production of extra-cellular matrix [14]. Therefore, chronic exposure to higher levels of ACE might results in vascular wall thickening. The insertion/deletion (I/D) polymorphism in the gene encoding for ACE accounts for nearly half the variation in serum ACE level, with the D allele associated with higher ACE levels than the I allele [15]. This polymorphism has also been associated with an increased risk of myocardial infarction 16, 17and left ventricular hypertrophy [18].
The relations between IMT variability and the gene encoding for apo E and ACE have been assessed in some studies and contrasting results have been produced 19, 20, 21, 22, 23, 24, 25. However, these were studies with different designs (case-controls, random population or healthy subjects), with sample populations of different ethnic origins and with different indexes of IMT measurements (maximum IMT, mean values from different arterial sites as mean of common, internal and bifurcation sites). To our knowledge, only one study evaluated the relation between the LPL gene and IMT variability [26]and this study showed a relation between the LPL/HindIII polymorphism and carotid IMT, in normolipidemic and hypertriglyceridemic men, but not in women. Furthermore, studies have been done generally in subjects aged over 45 years; thus the influence of genetic factors could be masked by environmental factors, as found for the ACE gene, smoking and carotid IMT [22]. So in young adult subjects less exposed to environmental and risk factors, the impact of genetic factors may be more important than in older subjects. The purpose of this study was to evaluate in healthy young to middle aged men and women the relations between the IMT of carotid and femoral arteries and polymorphisms of the apo E, LPL and ACE genes.
Section snippets
Subjects
For this specific study, a subgroup of 76 men and 74 women, aged from 33 to 50 years, was selected from the Stanislas cohort, a longitudinal survey involving 1006 nuclear families and designed to investigate factors related to cardiovascular diseases. The subjects of the Stanislas cohort, recruited between January 1994 and August 1995 at the Centre for Préventive Médicine of Vandoeuvre-lès-Nancy (East of France) had to be of European origin and free of chronic diseases. Informed consent was
Results
The clinical and biological characteristics of the 76 men and 74 women included in the study are summarized in Table 1. Serum apo E and Lp(a) levels were not significantly different between men and women. Mean values for all the other studied parameters were significantly higher in men than in women except for serum apo AI level which was lower in men than in women. In the whole group, alcohol and tobacco consumption were higher in men than in women, the percentage of drinkers and smokers in
Discussion
The first important result we found in our sample of healthy young adults was that carotid or femoral IMT increased with age, tobacco consumption, systolic blood pressure, BMI, serum apo B level and was higher in men than in women, as already reported for older subjects 2, 5, 6, 8, 32, 33. So, even in young normotensive subjects, systolic blood pressure correlated with IMT variability and smoking was also related to wall thickening even in relatively young people.
The second result was that the
Acknowledgements
We thank the management, reception and preclinic staff of the Centre for Préventive Médecine of Vandoeuvre-lès-Nancy, France, for their help during this study. We are also indebted to the families of the Stanislas survey, who made this study possible. This work was supported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés (CNAM), the university Henri Poincaré Nancy I, the Centre Nationale de Recherche Scientifique (CNRS), the Institut National de Santé et de Recherche
References (36)
- et al.
Wall thickening of carotid and femoral arteries in male subjects with isolated hypercholesterolemia
Atherosclerosis
(1995) - et al.
Restricting isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI
J Lipid Res
(1990) - et al.
Minisymposium: ultrasound in clinical trials of atherosclerosis. Carotid artery intima-media thickness as an indicator of generalized atherosclerosis
J Intern Med
(1994) - et al.
Distribution and correlates of sonographically detected carotid artery disease in the cardiovascular health study
Stroke
(1992) - et al.
Ultrasound B-mode imaging in observational studies of atherosclerotic progression
Circulation
(1993) - et al.
Ultrasonographic correlates of carotid atherosclerosis in transient ischemic attack and stoke
Stroke
(1995) - et al.
Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardiovascular risk factors in the ARIC study
Am J Epidemiol
(1991) - et al.
Active and passive smoking are associated with increased wall thickness
Arch Intern Med
(1994) - et al.
Evidence for in vivo carotid and femoral wall thickening in human hypertension
Hypertension
(1993) - et al.
Left ventricular concentric remodeling and carotid structural changes in essential hypertension
J Hypertens
(1996)