A. F.C. Schut

Heritability of the Function and Structure of the Arterial Wall: Findings of the Erasmus Rucphen Family (ERF) Study

Background and Purpose— Using 930 individuals connected in a single pedigree from an isolated population, participants of the Erasmus Rucphen Family (ERF) study, we investigated the heritability of carotid–femoral pulse wave velocity (PWV), carotid intima media thickness (IMT), and carotid plaque score. Methods— PWV was measured between the carotid and femoral arteries as an indicator of aortic stiffness. Common carotid IMT and plaque score, quantifying alterations in arterial wall structure, were measured by ultrasonography. Results— All 3 traits were significantly associated with classic cardiovascular risk factors. Age- and gender-adjusted heritability estimates were 0.36 for PWV, 0.41 for carotid IMT, and 0.28 for plaque score. After adjustment for appropriate risk factors, the heritabilities were 0.26, 0.35, and 0.21 for PWV, IMT, and plaque score, respectively. All heritability estimates were statistically significant (P<0.001). Taking into account different proportions of variance associated with covariates for each trait, genetic factors explained ≈12% of the total variability for each of the phenotypes. Conclusions— To our knowledge, this is the first report on the heritability of PWV. The heritability estimates of IMT and plaque score were similar to those in previous reports. We conclude that genetic factors significantly contribute to arterial structure and function in this isolated population, presenting the opportunity to locate susceptibility genes related to cardiovascular disorders.

Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes.

Objective To study the heritability of four blood pressure traits and the proportion of variance explained by four blood-pressure-related genes. Methods All participants are members of an extended pedigree from a Dutch genetically isolated population. Heritability and genetic correlations of systolic blood pressure, diastolic blood pressure, mean arterial pressure and pulse pressure were assessed using a variance components approach (SOLAR). Polymorphisms of the α-adducin (ADD1), angiotensinogen (AGT), angiotensin II type 1 receptor (AT1R) and G protein β3 (GNB3) genes were typed. Results Heritability estimates were significant for all four blood pressure traits, ranging between 0.24 and 0.37. Genetic correlations between systolic blood pressure, diastolic blood pressure and mean arterial pressure were high (0.93–0.98), and those between pulse pressure and diastolic blood pressure were low (0.05). The ADD1 polymorphism explained 0.3% of the variance of pulse pressure (P = 0.07), and the polymorphism of GNB3 explained 0.4% of the variance of systolic blood pressure (P = 0.02), 0.2% of mean arterial pressure (P = 0.05) and 0.3% of pulse pressure (P = 0.06). Conclusion Genetic factors contribute to a substantial proportion of blood pressure variance. In this study, the effect of polymorphisms of ADD1, AGT, AT1R and GNB3 explained a very small proportion of the heritability of blood pressure traits. As new genes associated with blood pressure are localized in the future, their effect on blood pressure variance should be calculated.

Genetic polymorphisms and heart failure

Heart failure is a complex clinical syndrome. There is evidence for a genetic contribution to the pathophysiology of heart failure. Considering the fundamental role of neurohormonal factors in the pathophysiology and progression of cardiac dysfunction and hypertrophy, variants of genes involved in this system are logical candidate genes in heart failure. In this report, genetic polymorphisms of the major neurohormonal systems in heart failure will be discussed. Studies on polymorphisms of the renin-angiotensin-aldosterone system (RAAS), adrenergic receptor polymorphisms, endothelin (receptor) polymorphisms, and a group of miscellaneous polymorphisms that may be involved in the development or phenotypic expression of heart failure will be reviewed. Research on left ventricular hypertrophy is also included. The majority of genetic association studies focused on the ACE I/D polymorphism. Initial genetic associations have often been difficult to replicate, mainly due to problems in study design and lack of power. Promising results have been obtained with genetic polymorphisms of the RAAS and sympathetic system. Considering the evidence so far, a modifying role for these polymorphisms seems more likely than a role of these variants as susceptibility genes. Besides the need for larger studies to examine the effects of single nucleotide polymorphisms and haplotypes, future studies also need to focus on the complexity of these systems and study gene-gene interactions and gene-environment interactions.

A study of gene–environment interaction on the gene for angiotensin converting enzyme: a combined functional and population based approach

Introduction: Studies on the role of the insertion/deletion (I/D) polymorphism of the gene coding for angiotensin converting enzyme (ACE) in atherosclerosis have been inconsistent. In a meta-analysis, we recently showed that this relationship is stronger in high risk populations. In this paper, we used a combined functional and population based approach to investigate the gene–environment interaction of the ACE I/D polymorphism in relation to carotid artery wall thickness. Methods: The study was part of the Rotterdam Study, a prospective population based cohort study. In 5321 subjects, IMT was measured in the carotid arteries by ultrasonography and ACE genotype was determined by size analysis of polymerase chain reaction products. Results: In multiple regression analysis, I/D polymorphism and smoking were the main determinants for plasma ACE activity (r2 = 0.28). There was a positive association between the D allele of the I/D polymorphism and carotid artery thickness among current smokers (p = 0.03). Subjects carrying only one of the risk factors (smoking or the D allele) did not show significant differences in IMT compared with the non-/former smokers group carrying two II alleles, while carriers of both risk factors had significant higher IMT. The association was not present in non-/former smokers. Discussion: The results provide further evidence that genetic and environmental factors interact in the formation of the arterial lesions. This study shows that large population based studies can be extremely helpful in unravelling the genetic origin of complex diseases such as atherosclerosis.

Polymorphism in the promoter region of the insulin-like growth factor I gene is related to carotid intima-media thickness and aortic pulse wave velocity in subjects with hypertension

Background and Purpose— Low circulating levels of insulin-like growth factor I (IGF-I) have been associated with an increased risk for atherosclerosis. Absence of the 192-bp (wild-type) allele in the promoter region of the IGF-I gene has been associated with low circulating IGF-I levels. We examined the role of this polymorphism in relation to blood pressure and 2 early markers of atherosclerosis: carotid intima-media thickness (IMT) and aortic pulse wave velocity (PWV). Methods— A total of 5132 subjects of the Rotterdam Study, aged 55 to 75 years, were included in this study. In 3769 subjects who did not use blood pressure–lowering medication, the association between the IGF-I polymorphism and blood pressure was examined. In the total population, and in 3484 normotensive subjects, 1648 hypertensive and 462 untreated hypertensive subjects, the association between this polymorphism and IMT and PWV was examined. Results— Mean systolic and diastolic blood pressure did not differ between genotypes. In hypertensive subjects IMT was significantly increased in noncarriers of the 192-bp allele (0.83 mm) compared with heterozygous or homozygous carriers (0.80 mm) (P =0.04). PWV was also significantly higher in hypertensive subjects who were noncarriers of the 192-bp allele (14.3 m/s) compared with heterozygous (14.1 m/s) or homozygous carriers (13.7 m/s) (P =0.02). Findings were more pronounced in hypertensive subjects without medication use. In normotensive subjects, no association between this polymorphism, IMT, and PWV was observed. Conclusions— Our study suggests that hypertensive subjects who have low IGF-I levels because of a genetic polymorphism in the IGF-I gene are at increased risk of developing atherosclerosis.

Familial aggregation, the PDE4D gene, and ischemic stroke in a genetically isolated population

Objective: The purpose of this investigation was to study the familial aggregation of ischemic stroke and the association between the PDE4D gene and ischemic stroke. Methods: The study was performed in an isolated population in The Netherlands, where the authors identified 91 patients with ischemic stroke. Ischemic stroke was subclassified in large- and small-vessel infarction. The authors calculated kinship and inbreeding coefficients and genotyped all patients for three single-nucleotide polymorphisms (SNPs) in the PDE4D gene. Results: The proportion of related pairs was higher in patients with ischemic stroke (68.8%) compared with controls (30.7%; p < 0.001). For large-vessel infarction, the proportion of related pairs was higher (71%) compared with small-vessel infarction (62.8%; p < 0.001). Familial aggregation was strongest for patients with early onset (age at onset <45 years). All stroke groups were significantly more inbred compared with controls. In inbred individuals, the C allele of SNP45 increased the risk of small-vessel infarction 4.8 times (95% CI 1.1 to 22.3) compared with controls (p = 0.04). The T allele of SNP39 increased the risk of small-vessel infarction 6.3 times (95% CI 1.4 to 28.7) compared with controls (p = 0.02). No associations were found for large-vessel stroke. Conclusions: There was familial aggregation of ischemic stroke and a difference in degree of familial clustering between stroke subtypes. The authors also found that the PDE4D gene is significantly associated with small-vessel infarction in inbred individuals.

Angiotensin converting enzyme gene polymorphism and cardiovascular morbidity and mortality: the Rotterdam Study

Background: Findings on the association between the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene and cardiovascular morbidity and mortality have been inconsistent. Considering the possible interaction between this polymorphism and smoking, we evaluated the association between ACE I/D polymorphism and myocardial infarction (MI), mortality due to coronary heart disease (CHD), and cardiovascular disease (CVD). Methods: The study was performed within the Rotterdam Study, a population based cohort study. The ACE I/D polymorphism was determined for 6714 participants and smoking status recorded at baseline. Fatal and non-fatal MIs and mortality events were regularly recorded. Cox proportional hazard analysis was performed separately for current smokers and non-smokers. We used age as the follow up time, presenting age specific survivals. Results: During follow up, 248 MIs and 301 and 482 deaths, respectively, due to CHD and CVD occurred. There were no significant differences between the genotypes as regards MI incidence. Among smokers, there was an increased risk of CHD and CVD mortality in carriers of the DD genotype compared to the II genotype, which diminished at later ages (p<0.01 for gene-age interaction). Subgroup analysis in a younger and older group (based on the median age of 68.2 years) showed a significantly increased risk of CVD mortality in the younger group (hazard ratio = 5.19; 95% confidence interval: 1.15 to 23.42). Conclusions: This study showed that the ACE I/D polymorphism is not a strong risk factor for MI but its interaction with smoking might play a role in cardiovascular mortality especially at younger ages.

Mortality in patients with hypertension on angiotensin-I converting enzyme (ACE)-inhibitor treatment is influenced by the ACE insertion/deletion polymorphism.

Background The response to angiotensin-I converting enzyme (ACE)-inhibitor therapy is highly variable. Residual ACE activity during treatment, potentially modified by the ACE insertion/deletion (I/D) polymorphism, may explain part of this variability. We studied the possible interaction between ACE-inhibitor therapy in patients with hypertension and the ACE I/D polymorphism in incident heart failure and death. Methods We studied 3365 hypertensive participants of the population-based Rotterdam Study, without heart failure at baseline for whom ACE-genotyping was successful. Incident heart failure was defined according to established criteria. In addition, total and cardiovascular mortality were studied as endpoints. A Cox regression model with use of ACE-inhibitors defined as time-dependent covariates was used for data-analysis. Interaction was tested in this model assuming an allele-effect relationship. Results Although we could not demonstrate a beneficial effect of ACE-inhibitors, there was significant interaction between the ACE I/D polymorphism (II-ID-DD) and ACE-inhibitor use in the prediction of total and cardiovascular mortality. Mortality risk associated with treatment increased with the number of D alleles present; e.g. for total mortality in the II genotype group: RR=0.95 (95% CI 0.63–1.45), in the ID genotype group: RR=1.08 (95% CI 0.84–1.38) and in the DD genotype group: RR=1.61 (95% CI 1.18–2.18). No statistically significant interaction was found for incident heart failure. Conclusion The results of our study suggest a relative resistance to ACE-inhibitor therapy in subjects with hypertension and the DD genotype compared to the II genotype, with the ID genotype in an intermediate position.

Smoking-dependent effects of the angiotensin-converting enzyme gene insertion/deletion polymorphism on blood pressure.

Background Studies on the role of the angiotensin-converting enzyme (ACE) gene in the development of hypertension have yielded conflicting results. Recent studies suggested that this gene might have smoking-dependent effects on the development of cardiovascular disease. Objective To study the relationship between the ACE insertion/deletion (I/D) polymorphism, blood pressure and risk of hypertension in current, former and non-smokers in a population-based cohort. Methods We included 2412 non-smokers, 2794 former smokers and 1508 current smokers, all participants in the Rotterdam Study. In each group, we assessed the relationship between the ACE I/D polymorphism, systolic (SBP) and diastolic (DBP) blood pressures and risk of hypertension. Mean blood pressures and prevalence of hypertension were compared between carriers and non-carriers of the D allele. All analyses were adjusted for age, sex, body mass index, diabetes mellitus, high-density lipoprotein cholesterol, total cholesterol and use of antihypertensive medication. Results In non-smokers and former smokers, blood pressure and the risk of hypertension did not differ significantly between genotypes. In smokers, we found a significant increase in SBP in DD carriers (139.6 ± 22.8 mmHg) compared with II carriers (136.0 ± 22.7 mmHg) (P = 0.04). No effect of ACE genotype was observed for DBP. The risk of hypertension was significantly increased in smokers who carried one [odds ratio (OR) 1.4, 95% confidence interval (CI) 1.0 to 1.9; P = 0.05] or two (OR 1.5, 95% CI 1.1 to 2.2; P = 0.02) copies of the D allele. Conclusions The D allele of the ACE polymorphism is associated with a significantly increased SBP and risk of hypertension in smokers. Our study underlines the importance of gene–environment interactions in the study of candidate genes for hypertension.

A promoter polymorphism of the insulin-like growth factor-I gene is associated with left ventricular hypertrophy

Left ventricular hypertrophy (LVH) is a strong predictor of cardiovascular morbidity and mortality. Insulin-like growth factor-I (IGF-I) has an important role in the hypertrophic response of the myocardium.1 A polymorphism in the IGF-I gene promoter region has been identified which influences IGF-I production.2–4 Studying this polymorphism in relation to pathology may better reflect the effects of long term IGF-I exposure than studies on serum IGF-I concentrations, which may fluctuate considerably and are profoundly influenced by various factors. We investigated the association between this IGF-I promoter polymorphism and the occurrence of LVH on echocardiogram. The Rotterdam study is a population based cohort study in 7983 elderly people aged 55 years or over. The baseline examination was conducted in 1990–93, during which time information was obtained on age, sex, history of myocardial infarction, smoking, hypertension, diabetes mellitus, and body mass index (BMI). Cardiac ultrasound was performed in a random subpopulation of 2823 subjects. The present study was performed in subjects aged 55–75 years, without a history of myocardial infarction. The analyses were restricted to persons with an adequate echocardiogram and for whom blood specimens were available for IGF-I typing, a total of 1678 subjects. This is the first genetic case association study that uses the Rotterdam study database to investigate the phenotype of LVH on the echocardiogram. M mode echocardiography was performed …