The impact of apolipoprotein E on dementia in persons with Down's syndrome.

Apolipoprotein E (APOE) is consistently associated with dementia in the general population. Findings on the role of this gene in persons with Down's syndrome (DS) are inconclusive. We studied the effects of APOE on mortality and dementia in a longitudinal prospective study of a large population-based sample of persons with DS (n=425), demented and non-demented. There was evidence that APOE epsilon4 is correlated with the rate of decline in the social competence rating scale (SRZ) (p=0.04). In our population, we found overall a modest but not statistical significant effect on the prevalence of dementia (OR=1.57, 95%CI: 0.87-2.82). We did observed a significant long-term effect on the incidence of dementia (HR=4.66, 95%CI: 1.35-16.14), but for those with a follow-up less than 3 years the risk was not significantly increased: HR=0.83 (95%CI 0.35-1.94). When pooling our data in a meta-analysis, the APOE epsilon4 allele shows a 1.59-fold (95%CI: 1.19-2.12) increase in risk of dementia in persons with DS. We conclude that APOE is influencing the risk of dementia in persons with DS.

ACE polymorphisms.

Angiotensin converting enzyme (ACE) plays an essential role in two physiological systems, one leading to the production of angiotensin II and the other to the degradation of bradykinin. The wide distribution and multifunctional properties of these peptides suggest that ACE could be involved in various pathophysiological conditions. The discovery that ACE levels are under genetic control ushered in a new era of investigation; most studies focused on an insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene as a marker for a functional polymorphism. Recently, many single nucleotide polymorphisms were detected in the gene and the search for the locations of functional polymorphisms became a topic of extensive investigation. Nevertheless, association studies on the I/D polymorphism and clinical outcomes continued, mostly with conflicting results. This article reviews the current state of knowledge regarding ACE polymorphisms and suggests that a functional polymorphism is most likely located between intron 18 and the 3' UTR. The potential existence of another functional polymorphism in the 5' UTR, however, cannot be excluded. This review also presents an overview of ACE function in different pathophysiological systems, and summarizes previous reports on ACE and clinical outcomes. Although findings on the I/D polymorphism and disorders like diabetic nephropathy and Alzheimer disease can be considered conclusive, reports on most of the cardiovascular phenotypes are still controversial. Genotypic and phenotypic misclassifications, insufficient power in some studies, and the presence of interaction with other genes or environmental factors are possible explanations for the contradictory findings.

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.

Angiotensin converting enzyme gene, smoking and mortality in a population-based study.

BACKGROUND: The genetic and environmental risk factors, which may influence longevity and mortality, have received much attention during more than one decade. One of the major risks for mortality is cardiovascular disease and the renin angiotensin system (RAS) plays a major role in maintaining blood pressure homeostasis. In this system, the Angiotensin Converting Enzyme (ACE) is one of the key regulators and has been studied in relation to cardiovascular disease and mortality. We aimed to evaluate if the ACE I/D polymorphism is related to total mortality in the elderly. MATERIALS AND METHODS: Some 6968 elderly individuals from the Rotterdam study were genotyped for this polymorphism. Smoking was studied as a possible covariable or effect modifier. To examine the effect of the ACE genotype on mortality, a Cox proportional hazards model was fitted. RESULTS: Our results show an increased risk of total mortality in subjects with age at death below 65 years carriers of the DD genotype (HR 1.8, 95% CI 1.1-2.9, P = 0.016). This association was significant in total and cause specific mortality only in those who smoke (P-value < 0.001 for gene-age interaction). Our findings suggest that the ACE gene is rather associated with early mortality than with late. CONCLUSIONS: Individuals who carry the DD genotype appear to be susceptible to early mortality if they smoke, suggesting a possible interaction between smoking and the ACE gene.

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.

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 (r(2) = 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.

The prevalence of coronary artery disease in an urban population in Isfahan, Iran.

OBJECTIVE: Cardiovascular diseases, especially coronary artery disease (CAD), are responsible for the highest mortality rate in Iran. This study was conducted to determine the prevalence of CAD in an urban sample in Isfahan by the Minnesota code of a 12-lead resting electrocardiogram (ECG), the Rose questionnaire on chest pain and a self-reported previous medical history. METHODS AND RESULTS: Among the target sample of 6,470 men and women aged 35-79 years who were randomly selected from 80 random clusters in Isfahan, 5,773 subjects (about 90%) have participated. The WHO (Rose) questionnaires (Q) on chest pain were completed for all participants and 12-lead ECGs were taken. The overall prevalence of CAD based on the Rose Q and/or ECG was 19.4% (95% CI 18.4% to 20.4%) which was significantly higher among women 21.9% (95% CI 20.5% to 23.3%) than men 16.0% (95% CI 14.5% to 17.5%) (p < 0.05). The prevalence of CAD increased with age in both sexes. The prevalence of definite and possible angina based on the questionnaire was higher among women compared to men (p < 0.05), also a greater prevalence of ECG-based possible ischaemia was observed among woman than men (12.3% vs. 7.5%) (p < 0.05). However, definite and possible MI and definite ischaemia based on ECG abnormalities were higher among men than women (p < 0.05). The total prevalence of symptomatic CAD was 9.3% and about 22% of those with symptoms of CAD on Q have some evidence on ECG. The findings also showed that CAD is more common among people with less education, lower income and the unemployed (p < 0.05). CONCLUSION: These findings indicate that there is a high prevalence of CAD among the Iranian population which need more programmes of health promotion and lifestyle changes and further studies to assess the used epidemiological methods for estimating CAD prevalence, especially among women.

Secular trends in cardiovascular mortality in Iran, with special reference to Isfahan.

OBJECTIVE: There has been a general decline in mortality from cardiovascular diseases (CVDs) in most of the developed countries since the beginning of the 1970s. Still, in recent years developing countries have seen an increasing frequency in CVD mortality. However, mortality rate studies in these populations are scarce. Here we report all-cause and CVD mortality rates for men and women aged 25-74 years over a 16-year period in 24 cities in Iran with special reference to the city of Isfahan. METHODS AND RESULTS: The study was based on national death records using the ninth international classification of diseases and age standardization was performed using the total population of Iran in 1985 as a standard. Due to limitations in available data, mortality rates for the specific categories of CVD for the whole country could not be provided. The in-hospital death rates following myocardial infarction in coronary care units (CCUs) and cardiology departments in Isfahan hospitals were also assessed. The completed medical records from hospitals or the relatives of decedents were reviewed by physicians certified in internal medicine, cardiology and neurology to assess the reliability of death certificate data regarding CVD by determining the sensitivity and specificity of the death certificates against the standard of the reviewers. The official circulatory diseases proportional mortality ratio continues to rise since 1981 with a steep increase since 1987, constituting 26.6% and 47.3% of all deaths in 1981 and 1995, respectively. Age-adjusted all-cause and CVD mortality data were decreasing since 1981 and increasing since 1990. During those years age-adjusted CVD, stroke and other CVD mortality rates were decreasing in Isfahan with a slight increase in ischaemic heart disease (IHD) death rates in both sexes. Mortality rates based on sex showed a 38% and 24.8% decline in all-cause and CVD mortality in men between 1981 to 1995, and a 35% and 34.9% decline for female mortality rates for the same period, respectively. The in-hospital death rate following myocardial infarction in Isfahan was increasing between 1993 and 1995 with a slight decrease thereafter. The results of death certification assessment showed a specificity of 0.89 and a sensitivity of 0.43 with the positive and negative predictive values of 0.82 and 0.57, respectively. CONCLUSION: These data indicate that circulatory diseases remain a serious public health threat in Iran. It suggests the ongoing need for more regular, systematic and innovative surveillance data to improve the capability of measuring, explaining and predicting the disease trend on which the national public health policy depends.