Strategies for the assessment of genetic coronary artery disease risk.

In atherosclerotic diseases, genetic factors have a substantial influence on the age of onset and the frequency and severity of clinical symptoms, as well as response to therapy. In myocardial infarctions occurring at young age, genetics may be the leading causative factor. Despite such a prominent role of genetics in the pathophysiology of atherosclerosis clinical risk assessment and therapeutic decision making are still based on classical risk factors. In this paper we analyse the reasons for the current lack of predictive power of genetics-based algorithms and we speculate why future developments might open the door to a role for genetics in the clinical management of atherosclerosis.     

Candidate gene polymorphisms and the 9p21 locus in acute coronary syndromes

It is now widely accepted that the classic environmental risk factors for atherosclerosis only partly explain the incidence of coronary artery disease and the development of acute coronary syndromes. Therefore, genetic factors that vary among human populations seem to be involved in the clinical manifestations of such patients. Substantial data suggest that a significant proportion of genetic polymorphisms involved in endothelial function, inflammation, lipid metabolism, thrombosis and fibrinolysis are often present in patients with acute coronary syndromes. In particular, a common variant on chromosome 9p21 was recently identified to affect the risk of myocardial infarction. Here, we review the progress of candidate gene studies and genome-wide association studies in identifying the genetic bases of complex cardiovascular diseases such as acute coronary syndromes.     

Arterial wall-determined risk factors to vascular diseases

Many decades of research have led to considerable in-depth understanding of circulating factors that may lead to coronary atherosclerosis. However, not every individual with serious known risk factors such as hypercholesterolemia or cigarette smoking develops atherosclerosis. Differential susceptibility of the arterial wall to circulating atherogenic risk factors, which may be largely controlled by genetic variants, may provide this missing link. Endothelial cells, the lining of the arterial wall, are responsible for the integrity and responses to the circulating environment. Dysfunctional endothelial cells and the subsequent proliferation of vascular smooth muscle cells are the prelude of atherosclerosis and acute coronary syndrome. Yet, there have been no detailed studies exploring the interaction between circulating environmental and arterial wall endogenous risk factors in living human subjects. This deficiency is largely the result of restricted access. Genetic factors almost certainly play a key role in directing how the arterial wall responds to circulating "environmental" factors. This endogenous-exogenous (i.e. the arterial wall-circulating) blood balance is the reflection of nature-nurture or gene-environment interaction. Understanding the interaction fully will require direct access to the arteries, and nonhuman primates can provide an excellent model for such investigations. In the current review, we discuss the importance of arterial wall factors in vascular diseases and present a baboon model for practical studies of arterial wall factors and their interaction with circulating factors. Direct biopsy access to baboon arteries will provide a unique opportunity to explore arterial wall susceptibilities and to evaluate the direct effects of diet or pharmaceutical agents on vascular diseases. The use of baboons from large pedigreed families in these studies will enable the identification of genes that interact with these environmental factors in determining individual risk of atherosclerosis.     

Scavenger receptor regulation and atherosclerosis

Atherosclerosis and its complications, such as coronary heart disease, heart infarction and stroke, are the leading causes of death in the developed world. High blood pressure, diabetes, smoking and a diet high in cholesterol and lipids clearly increase the likelihood of premature atherosclerosis, albeit other factors, such as the individual genetic makeup, may play an additional role. During atherosclerosis, uncontrolled cholesterol and lipid accumulation in macrophages and smooth muscle cells leads to foam cell formation and to the progression of the atherosclerotic plaque. This review will focus on foam cell formation within the atherosclerotic lesion, the involvement of the scavenger receptor genes in this process, and the possibility to interfere with scavenger receptor function to reduce the progression of atherosclerosis. To date, the regulatory mechanisms for the expression of scavenger receptor genes and their role in atherosclerosis are not well characterized. Knowledge on this subject could lead to a better understanding of the process, prevention and therapy of this disease.     

Endothelial Cell Senescence and Age-Related Vascular Diseases

Advanced age is an independent risk factor for ageing-related complex diseases,such as coronary artery disease,stroke,and hypertension,which are common but life threatening and related to the ageing-associated vascular dysfunction.On the other hand,patients with progeria syndromes suffer from serious atherosclerosis,suggesting that the impaired vascular functions may be critical to organismal ageing,or vice versa.However,it remains largely unknown how vascular cells,particularly endothelial cell,become senescent and how the senescence impairs the vascular functions and contributes to the age-related vascular diseases over time.Here,we review the recent progress on the characteristics of vascular ageing and endothelial cell senescence in vitro and in vivo,evaluate how genetic and environmental factors as well as autophagy and stem cell influence endothelial cell senescence and how the senescence contributes to the agerelated vascular phenotypes.such as atherosclerosis and increased vascular stiffness,and explore the possibility whether we can delay the age-related vascular diseases through the control of vascular ageing.     

Genetic Variants and Their Interactions in the Prediction of Increased Pre-Clinical Carotid Atherosclerosis: The Cardiovascular Risk in Young Finns Study

The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control designs and the statistical significance testing procedures being used in most association studies. Our objective here was to investigate whether an alternative approach—in which common disorders are treated as quantitative phenotypes that are continuously distributed over a population—can reveal predictive insights into the early atherosclerosis, as assessed using ultrasound imaging-based quantitative measurement of carotid artery intima-media thickness (IMT). Using our population-based follow-up study of atherosclerosis precursors as a basis for sampling subjects with gradually increasing IMT levels, we searched for such subsets of genetic variants and their interactions that are the most predictive of the various risk classes, rather than using exclusively those variants meeting a stringent level of statistical significance. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the variants, and cross-validation was used to assess how well the predictive models will generalize to other subsets of subjects. By means of our predictive modeling framework with machine learning-based SNP selection, we could improve the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period (average AUC 0.844 and 0.761), compared to that of using conventional cardiovascular risk factors alone (average AUC 0.741 and 0.629), or when combined with the statistically significant variants (average AUC 0.762 and 0.651). The predictive accuracy remained relatively high in an independent validation set of subjects (average decrease of 0.043). These results demonstrate that the modeling framework can utilize the “gray zone” of genetic variation in the classification of subjects with different degrees of risk of developing atherosclerosis.     

Epigenetic histone acetylation modifiers in vascular remodelling – new targets for therapy in cardiovascular disease

In the past decade, research into cardiovascular diseases, such as atherosclerosis and restenosis, has been focused on the identification of genetic factors that determine disease risk besides clinical risk factors. Many genes in lipid metabolism, vascular homeostasis, haemostasis and inflammation have been found to be related to coronary artery disease1 and the multifactorial nature of the disease suggests a role for many other, yet uninvestigated genes. Previous research from our department has demonstrated the importance of genetics in restenosis after a percutaneous coronary intervention (PCI). Polymorphisms in several inflammatory genes, such as TNFα, eotaxin, CD14, GM-CSF, IL-10, caspase-1, but also noninflammatory genes, such as LPL, stromelysin-1 and the β adrenergic receptor have been found to be associated with the risk of restenosis.2-5 It has become clear, however, that part of the gene-environmental interactions relevant for complex diseases is regulated by epigenetic mechanisms such as histone acetylation and DNA methylation.     

Regulation of apolipoprotein expression]

Recent data and concepts on the structure and functioning of apolipoprotein genes as well as on the role of hereditary factors in pathogenesis of atherosclerosis are reviewed. The most important variants of inherited disorders in the system of apolipoproteins promoting the development of atherosclerosis are considered. Special attention is paid to the RFLP of apolipoprotein genes which serves as a peculiar genetic background, increasing probability of the atherosclerosis development in certain individuals.     

Thematic review series: systems biology approaches to metabolic and cardiovascular disorders. Reverse engineering gene networks to identify key drivers of complex disease phenotypes

Diseases such as obesity, diabetes, and atherosclerosis result from multiple genetic and environmental factors, and importantly, interactions between genetic and environmental factors. Identifying susceptibility genes for these diseases using genetic and genomic technologies is accelerating, and the expectation over the next several years is that a number of genes will be identified for common diseases. However, the identification of single genes for disease has limited utility, given that diseases do not originate in complex systems from single gene changes. Further, the identification of single genes for disease may not lead directly to genes that can be targeted for therapeutic intervention. Therefore, uncovering single genes for disease in isolation of the broader network of molecular interactions in which they operate will generally limit the overall utility of such discoveries. Several integrative approaches have been developed and applied to reconstructing networks. Here we review several of these approaches that involve integrating genetic, expression, and clinical data to elucidate networks underlying disease. Networks reconstructed from these data provide a richer context in which to interpret associations between genes and disease. Therefore, these networks can lead to defining pathways underlying disease more objectively and to identifying biomarkers and more-robust points for therapeutic intervention.     

2型糖尿病合并下肢动脉粥样硬化的危险因素

下肢动脉粥样硬化是2型糖尿病(T2DM)患者最常见的大血管并发症之一。作为T2DM患者严重的慢并发症之一,下肢动脉粥样硬化可引起糖尿病足的发生,严重情况下可导致足坏疽。因此,阐明T2DM合并下肢动脉粥样硬化的危险因素,早期预防和治疗糖尿病合并下肢动脉粥样硬化症,不仅提高了患者的生活质量,而且减轻了家庭和社会的经济负担,具有较大的现实意义。影响T2DM患者下肢动脉粥样硬化的因素错综复杂,分为不可调控的和可调控的因素,不可调控的危险因素包括年龄、种族、遗传等,可调控的危险因素包括吸烟、高血糖、高血脂、高血压,以及近年提出的肥胖、胰岛素抵抗、高纤维蛋白血症、炎症等。本文就T2DM合并下肢动脉粥样硬化的危险因素做一综述。     

Genetic determinants of atherosclerosis,obesity, and energy balance in consomic mice

Metabolic diseases such as obesity and atherosclerosis result from complex interactions between environmental factors and genetic variants. A panel of chromosome substitution strains (CSSs) was developed to characterize genetic and dietary factors contributing to metabolic diseases and other biological traits and biomedical conditions. Our goal here was to identify quantitative trait loci (QTLs) contributing to obesity, energy expenditure, and atherosclerosis. Parental strains C57BL/6 and A/J together with a panel of 21 CSSs derived from these progenitors were subjected to chronic feeding of rodent chow and atherosclerotic (females) or diabetogenic (males) test diets, and evaluated for a variety of metabolic phenotypes including several traits unique to this report, namely fat pad weights, energy balance, and atherosclerosis. A total of 297 QTLs across 35 traits were discovered, two of which provided significant protection from atherosclerosis, and several dozen QTLs modulated body weight, body composition, and circulating lipid levels in females and males. While several QTLs confirmed previous reports, most QTLs were novel. Finally, we applied the CSS quantitative genetic approach to energy balance, and identified three novel QTLs controlling energy expenditure and one QTL modulating food intake. Overall, we identified many new QTLs and phenotyped several novel traits in this mouse model of diet-induced metabolic diseases.     

Genetic impact of TNF-beta on risk factors for coronary atherosclerosis

BACKGROUND: Inflammatory processes are considered to play an important role in the development of coronary atherosclerosis. The proinflammatory cytokine, tumor necrosis factor beta (TNF-beta), is thought to contribute to the pathogenesis of atherosclerosis. STUDY DESIGN: In this clinical study, the influence of genetic variants of TNF-beta (c.7G>A, IVS1+90G>A, C13R, T60N) on major coronary risk factors, including gender, smoking, history of cardiovascular diseases, biochemical data (inflammatory markers, factors of lipid metabolism, coagulation/fibrinolysis balance), and angiographically-proven coronary state, was investigated in 176 European Caucasian probands (130 males, mean age: 51.9 +/- 8.9 y). RESULTS: The most frequent combinations of the polymorphisms investigated were significantly associated with four of the coronary risk factors evaluated: hypertension, body mass index, the common inflammatory marker TNF-alpha (mRNA expression), and fibrinogen (p < 0.05). However, on testing the impact of the genetic background on the incidence of coronary stenosis in this sample of European Caucasians, no significant influence of these polymorphisms (stepwise binary logistic regression analysis) could be proven. These findings emphasise a distinct influence of TNF-beta polymorphisms on important modulators of the development of coronary atherosclerosis, but exclude its genetic background, investigated in this study as an independent coronary risk factor.     

Association of a common TLR-6 polymorphism with coronary artery disease – implications for healthy ageing?

Background

The pro-inflammatory status of the elderly triggers most of the age-related diseases such as cancer and atherosclerosis. Atherosclerosis, the leading cause world wide of morbidity and death, is an inflammatory disease influenced by life-style and genetic host factors. Stimuli such as oxLDL or microbial ligands have been proposed to trigger inflammation leading to atherosclerosis. It has recently been shown that oxLDL activates immune cells via the Toll-like receptor (TLR) 4/6 complex. Several common single nucleotide polymorphisms (SNPs) of the TLR system have been associated with atherosclerosis. To investigate the role of TLR-6 we analyzed the association of the TLR-6 SNP Pro249Ser with atherogenesis.

Results

Genotyping of two independent groups with CAD, as well as of healthy controls revealed a significant association of the homozygous genotype with a reduced risk for atherosclerosis (odds ratio: 0.69, 95% CI 0.51-0.95, P?=?0.02). In addition, we found a trend towards an association with the risk of restenosis after transluminal coronary angioplasty (odds ratio: 0.53, 95% CI 0.24-1.16, P?=?0.12). In addition, first evidence is presented that the frequency of this protective genotype increases in a healthy population with age. Taken together, our results define a role for TLR-6 and its genetic variations in modulating the inflammatory response leading to atherosclerosis.

Conclusions

These results may lead to a better risk stratification, and potentially to an improved prophylactic treatment of high-risk populations. Furthermore, the protective effect of this polymorphism may lead to an increase of this genotype in the healthy elderly and may therefore be a novel genetic marker for the well-being during aging.

     

Allele frequencies for candidate genes in atherosclerosis and diabetes among Trinidadian neonates

Trinidadians of South Asian origin have a high prevalence of cardiovascular disease and diabetes compared to Trinidadians of African origin. The degree to which these differences are related to genetic and/or environmental factors is unclear. To determine whether there might be a genetic basis for this difference in prevalence of deleterious phenotypes we examined allele frequencies for candidate genes in atherosclerosis and diabetes. We genotyped 81 consecutive neonates of African origin and 103 consecutive neonates of South Asian origin. We evaluated common polymorphisms in 11 candidate genes for atherosclerosis and diabetes. We found differences between the two subpopulations in the allele frequencies of several candidate genes, including APOE, LIPC, APOC3, PON1, PON2, and PPP1R3. However, the differences in the allele frequencies were not all consistent with the pattern of CHD expression between these two ethnic groups in adulthood. Thus, differences in genetic architecture alone may not explain the wide disparities in disease prevalence between these two subpopulations. It is very likely that environmental factors, or unmeasured genetic factors, influence the genetic susceptibility to disease in these subpopulations.     

Intrauterine undernutrition and programming as a new risk of cardiovascular disease in later life

It is believed that atherogenesis is a multifactorial process, which could already start in utero. Development of atherosclerosis progresses over decades and leads to the cardiovascular morbidity and mortality in adulthood. At present, we have no exact explanation for all the risk factors acting in the pathogenesis of atherosclerosis. This review should provide an overview about the possible role of intrauterine undernutrition in the development of risk factors for cardiovascular disease. Intrauterine undernutrition leads to changes in fetal growth and metabolism and programs later development of some of these risk factors. A number of experimental and human studies indicates that hypertension as well as impaired cholesterol and glucose metabolism are affected by intrauterine growth. Intrauterine undernutrition plays an important role and acts synergistically with numerous genetic and environmental factors in the development of atherosclerosis. There is evidence that undernutrition of the fetus has permanent effects on the health status of human individuals.     

Gene-environment interactions in atherosclerosis

The importance of environment and genetics working together to shape an individual's risk for atherosclerosis seems intuitively obvious. However, it is only recently that research strategies have begun to evolve that attempt to answer questions related to apportionment of risk that is due to specific environmental and genetic factors. These factors may impact upon risk either singly or, more likely, through a complex interaction that affects the metabolic history of the whole organism. Because the genetic bases of lipid and lipoprotein metabolism have been well-studied, and because of the epidemiologic and pathobiochemical associations between genetic disorders of lipid metabolism and atherosclerosis, researchers have searched for gene-environment interactions within animal and human systems in which the phenotype is defined by some index of lipoprotein metabolism. From work done in the lipoprotein area to this point a clear case can be made for: 1) the genetic influence over the phenotypic response to an environmental stimulus; 2) the environmental modulation of the phenotypic expression of severe genetic defects. In the realm of gene-environment interactions that affect lipoprotein phenotype, diet is the best-studied environmental factor.     

Role of CYP2C9 and CYP2C19 polymorphisms in patients with atherosclerosis

The arachidonic acid metabolizing CYP enzymes with prominent roles in vascular regulation are epoxygenases of the two gene family which generate epoxyeicosatrienoic acids. Carriers of CYP2C9 mutant alleles exhibit a diminished CYP2C9 metabolic capacity leading to decreased endothelium-derived hyperpolarizing factors (EDHF) synthesis and an increased risk for atherosclerosis. We investigated whether the polymorphisms of CYP2C9/19 are related with atherosclerosis. We examined 108 patients having angioraphically > or =70 coronary artery narrowing and 90 healthy controls. CYPC2C9/19*2 and CYP2C9/19*3 alleles were investigated in both patients and controls by a real time PCR instrument. There was no significant difference in the distribution of the CYP2C9*2/*3 alleles between cases and the controls. We found that smoker patients having CYP2C9*2 heterozygote genotype have 3.7-fold risk of developing atherosclerosis. CYP2C19*3 heterozygote alleles are more frequent in patients than in controls (10.2%, 5.6% respectively) and it is related with a three-fold risk of atherosclerosis (odds ratio (OR) = 3.75, confidence interval (CI) = 0.75-18.65). It becomes clear that cigarette smoking can cause almost all major diseases prevalent today, such as cancer or heart disease. This inter-subject variability in cigarette-induced pathologies is partly mediated by genetic variants of genes that may participate in detoxification processes, e.g., cytochrome P450 (CYP), cellular susceptibility to toxins, such as p53, or disease development such as atherosclerosis.     

Anti‐atherosclerotic effects of vitamin E – myth or reality?

Atherosclerosis and its complications such as coronary heart disease, myocardial infarction and stroke are the leading causes of death in the developed world. High blood pressure, diabetes, smoking and a diet high in cholesterol and lipids clearly increase the likelihood of premature atherosclerosis, albeit other factors, such as the individual genetic makeup, may play an additional role. Several epidemiological studies and intervention trials have been performed with vitamin E, and some of them showed that it prevents atherosclerosis. For a long time, vitamin E was assumed to act by decreasing the oxidation of LDL, a key step in atherosclerosis initiation. However, at the cellular level, vitamin E acts by inhibition of smooth muscle cell proliferation, platelet aggregation, monocyte adhesion, oxLDL uptake and cytokine production, all reactions implied in the progression of atherosclerosis. Recent research revealed that these effects are not the result of the antioxidant activity of vitamin E, but rather of precise molecular actions of this compound. It is assumed that specific interactions of vitamin E with enzymes and proteins are at the basis of its non-antioxidant effects. Vitamin E influences the activity of several enzymes (e.g. PKC, PP2A, COX-2, 5-lipooxygenase, nitric oxide synthase, NADPH-oxidase, superoxide dismutase, phopholipase A2) and modulates the expression of genes that are involved in atherosclerosis (e.g. scavenger receptors, integrins, selectins, cytokines, cyclins). These interactions promise to reveal the biological properties of vitamin E and allow designing better strategies for the protection against atherosclerosis progression.     

Identifying novel genes for atherosclerosis through mouse-human comparative genetics

Susceptibility to atherosclerosis is determined by both environmental and genetic factors. Its genetic determinants have been studied by use of quantitative-trait-locus (QTL) analysis. So far, 21 atherosclerosis QTLs have been identified in the mouse: 7 in a high-fat-diet model only, 9 in a sensitized model (apolipoprotein E- or LDL [low-density lipoprotein] receptor-deficient mice) only, and 5 in both models, suggesting that different gene sets operate in each model and that a subset operates in both. Among the 27 human atherosclerosis QTLs reported, 17 (63%) are located in regions homologous (concordant) to mouse QTLs, suggesting that these mouse and human atherosclerosis QTLs have the same underlying genes. Therefore, genes regulating human atherosclerosis will be found most efficiently by first finding their orthologs in concordant mouse QTLs. Novel mouse QTL genes will be found most efficiently by using a combination of the following strategies: identifying QTLs in new crosses performed with previously unused parental strains; inducing mutations in large-scale, high-throughput mutagenesis screens; and using new genomic and bioinformatics tools. Once QTL genes are identified in mice, they can be tested in human association studies for their relevance in human atherosclerotic disease.     

慢性应激动脉粥样硬化动物模型和应激与AS的发生研究进展

动脉粥样硬化(Atherosclerosis,AS)是缺血性心脑血管病的主要病理基础,环境、遗传等多因素共同影响下都能促进AS的形成与发展,越来越多研究表明慢性应激对于AS形成起到关键的作用,慢性应激可通过过度激活交感神经系统、肾素-血管紧张素系统与下丘脑-垂体-肾上腺皮质轴促进AS的形成,并且与Toll样受体、肿瘤坏死因子α、白细胞介素-6、脂联素等因素有密切联系。在研究慢性应激与AS发生的模型中,目前Apo E-/-小鼠、SD大鼠、Wistar大鼠等啮齿类动物仍然是主要模型,灵长类动物模型研究虽然更具有临床意义,但由于其成本、数量等因素限制了广泛使用。本文主要就慢性应激与AS的动物模型研究、慢性应激促进AS发生发展的相关机制进行综述。