Population Genomics of Cardiometabolic Traits: Design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium

Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.     

Metabolic syndrome: from epidemiology to systems biology

Metabolic syndrome (MetSyn) is a group of metabolic conditions that occur together and promote the development of cardiovascular disease (CVD) and diabetes. Recent genome-wide association studies have identified several novel susceptibility genes for MetSyn traits, and studies in rodent models have provided important molecular insights. However, as yet, only a small fraction of the genetic component is known. Systems-based approaches that integrate genomic, molecular and physiological data are complementing traditional genetic and biochemical approaches to more fully address the complexity of MetSyn.     

Do genetic variations alter the effects of exercise training on cardiovascular disease and can we identify the candidate variants now or in the future?

Cardiovascular disease (CVD) and CVD risk factors are highly heritable, and numerous lines of evidence indicate they have a strong genetic basis. While there is nothing known about the interactive effects of genetics and exercise training on CVD itself, there is at least some literature addressing their interactive effect on CVD risk factors. There is some evidence indicating that CVD risk factor responses to exercise training are also heritable and, thus, may have a genetic basis. While roughly 100 studies have reported significant effects of genetic variants on CVD risk factor responses to exercise training, no definitive conclusions can be generated at the present time, because of the lack of consistent and replicated results and the small sample sizes evident in most studies. There is some evidence supporting "possible" candidate genes that may affect these responses to exercise training: APO E and CETP for plasma lipoprotein-lipid profiles; eNOS, ACE, EDN1, and GNB3 for blood pressure; PPARG for type 2 diabetes phenotypes; and FTO and BAR genes for obesity-related phenotypes. However, while genotyping technologies and statistical methods are advancing rapidly, the primary limitation in this field is the need to generate what in terms of exercise intervention studies would be almost incomprehensible sample sizes. Most recent diabetes, obesity, and blood pressure genetic studies have utilized populations of 10,000-250,000 subjects, which result in the necessary statistical power to detect the magnitude of effects that would probably be expected for the impact of an individual gene on CVD risk factor responses to exercise training. Thus at this time it is difficult to see how this field will advance in the future to the point where robust, consistent, and replicated data are available to address these issues. However, the results of recent large-scale genomewide association studies for baseline CVD risk factors may drive future hypothesis-driven exercise training intervention studies in smaller populations addressing the impact of specific genetic variants on well-defined physiological phenotypes.     

Association between osteoprotegerin gene polymorphisms and cardiovascular disease in type 2 diabetic patients

Osteoprotegerin (OPG) gene polymorphisms (T245G, T950C and G1181C) have been associated with osteoporosis and early predictors of cardiovascular disease. The aim of this study was to evaluate whether these polymorphisms contribute to cardiovascular disease (CVD) in type 2 diabetic patients. We performed a case-control study with 178 CVD subjects with diabetes and 312 diabetic patients without CVD to assess the impact of variants of the OPG gene on the risk of CVD. The OPG gene polymorphisms were analyzed by using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). There was no significant association between the T245G and G1181C polymorphisms and CVD in the additive genetic model (OR = 0.96, 95% CI 0.64–1.45, p = 0.79; OR = 1.06, 95% CI 0.81–1.39, p = 0.65, respectively). However, the C allele of the T950C polymorphism was independently associated with a risk of CVD in type 2 diabetic patients in this genetic model (OR = 1.38, 95% CI 1.07–1.80, p = 0.01). This study provides evidence that the C allele of the T950C polymorphism is associated with increased risk of CVD in diabetic patients. However, well-designed prospective studies with a larger sample size are needed to validate these results.     

Lipotoxicity and cardiac dysfunction in mammals and Drosophila

The lipotoxic effects of obesity are important contributing factors in cancer, diabetes, and cardiovascular disease (CVD), but the genetic mechanisms, by which lipotoxicity influences the initiation and progression of CVD are poorly understood. Hearts, of obese and diabetic individuals, exhibit several phenotypes in common, including ventricular remodeling, prolonged QT intervals, enhanced frequency of diastolic and/or systolic dysfunction, and decreased fractional shortening. High systemic lipid concentrations are thought to be the leading cause of lipid-related CVD in obese or diabetic individuals. However, an alternative possibility is that obesity leads to cardiac-specific steatosis, in which lipids and their metabolites accumulate within the myocardial cells themselves and thereby disrupt normal cardiovascular function. Drosophila has recently emerged as an excellent model to study the fundamental genetic mechanisms of metabolic control, as well as their relationship to heart function. Two recent studies of genetic and diet-induced cardiac lipotoxicity illustrate this. One study found that alterations in genes associated with membrane phospholipid metabolism may play a role in the abnormal lipid accumulation associated with cardiomyopathies. The second study showed that Drosophila fed a diet high in saturated fats, developed obesity, dysregulated insulin and glucose homeostasis, and severe cardiac dysfunction. Here, we review the current understanding of the mechanisms that contribute to the detrimental effects of dysregulated lipid metabolism on cardiovascular function. We also discuss how the Drosophila model could help elucidate the basic genetic mechanisms of lipotoxicity- and metabolic syndrome-related cardiomyopathies in mammals.     

New approaches to disease mapping in admixed populations

Admixed populations such as African Americans and Hispanic Americans are often medically underserved and bear a disproportionately high burden of disease. Owing to the diversity of their genomes, these populations have both advantages and disadvantages for genetic studies of complex phenotypes. Advances in statistical methodologies that can infer genetic contributions from ancestral populations may yield new insights into the aetiology of disease and may contribute to the applicability of genomic medicine to these admixed population groups.     

The value of studying gene-environment interactions in culturally diverse populations

Cardiovascular disease (CVD) is the leading cause of death and disability in the world. It is anticipated that CVD will reach pandemic proportions by the year 2020. Although the major causes of CVD are well documented and explain the majority of cardiovascular deaths, the prevalence of conventional cardiovascular risk factors vary substantially across diverse cultural groups. These differences are attributed to cultural or genetic differences or to interactions between genes and environmental factors. Substantial efforts have been invested in determining the genetic influences on CVD development, and it is unlikely that a single gene is responsible for the development of atherosclerotic CVD or its classical risk factors such as blood pressure or plasma lipids. It is more plausible that multiple genes, acting either alone or in concert with one another, which display effect modification in the presence of certain environmental factors, are modestly associated with CVD or its main risk factors. Following this hypothesis, studying populations with diversity in environmental factors may increase the discovery potential of gene-environmental interactions. In this brief review, the advantage of studying gene-environment interactions across heterogeneous groups with diverse lifestyles is discussed.     

Lipotoxicity and cardiac dysfunction in mammals and Drosophila

The lipotoxic effects of obesity are important contributing factors in cancer, diabetes, and cardiovascular disease (CVD), but the genetic mechanisms, by which lipotoxicity influences the initiation and progression of CVD are poorly understood. Hearts, of obese and diabetic individuals, exhibit several phenotypes in common, including ventricular remodeling, prolonged QT intervals, enhanced frequency of diastolic and/or systolic dysfunction, and decreased fractional shortening. High systemic lipid concentrations are thought to be the leading cause of lipid-related CVD in obese or diabetic individuals. However, an alternative possibility is that obesity leads to cardiac-specific steatosis, in which lipids and their metabolites accumulate within the myocardial cells themselves and thereby disrupt normal cardiovascular function. Drosophila has recently emerged as an excellent model to study the fundamental genetic mechanisms of metabolic control, as well as their relationship to heart function. Two recent studies of genetic and diet-induced cardiac lipotoxicity illustrate this. One study found that alterations in genes associated with membrane phospholipid metabolism may play a role in the abnormal lipid accumulation associated with cardiomyopathies. The second study showed that Drosophila fed a diet high in saturated fats, developed obesity, dysregulated insulin and glucose homeostasis, and severe cardiac dysfunction. Here, we review the current understanding of the mechanisms that contribute to the detrimental effects of dysregulated lipid metabolism on cardiovascular function. We also discuss how the Drosophila model could help elucidate the basic genetic mechanisms of lipotoxicity- and metabolic syndrome-related cardiomyopathies in mammals.     

Linkage mapping of CVD risk traits in the isolated Norfolk Island population

To understand the underlying genetic architecture of cardiovascular disease (CVD) risk traits, we undertook a genome-wide linkage scan to identify CVD quantitative trait loci (QTLs) in 377 individuals from the Norfolk Island population. The central aim of this research focused on the utilization of a genetically and geographically isolated population of individuals from Norfolk Island for the purposes of variance component linkage analysis to identify QTLs involved in CVD risk traits. Substantial evidence supports the involvement of traits such as systolic and diastolic blood pressures, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, body mass index and triglycerides as important risk factors for CVD pathogenesis. In addition to the environmental influences of poor diet, reduced physical activity, increasing age, cigarette smoking and alcohol consumption, many studies have illustrated a strong involvement of genetic components in the CVD phenotype through family and twin studies. We undertook a genome scan using 400 markers spaced approximately 10 cM in 600 individuals from Norfolk Island. Genotype data was analyzed using the variance components methods of SOLAR. Our results gave a peak LOD score of 2.01 localizing to chromosome 1p36 for systolic blood pressure and replicated previously implicated loci for other CVD relevant QTLs.     

Molecular genetics and genomics of heart failure

Heart failure is a major disease burden worldwide, and its incidence continues to increase as premature deaths from other cardiovascular conditions decline. Although the overall molecular portrait of this multifactorial disease remains incomplete, molecular and genetic studies have implicated, in recent decades, various pathways and genes that participate in the pathophysiology of heart failure. Here, we highlight the current understanding of the molecular and genetic basis of heart failure and show how recently developed genomic tools are providing a new perspective on this complex disease.     

Type 2 diabetes as an inflammatory cardiovascular disorder

Type 2 diabetes carries a 2-6-fold increased risk of cardiovascular disease (CVD) and death. Indeed, the risk of major cardiovascular events in Type 2 diabetic patients without history of coronary heart disease (CHD) is equivalent to that observed in non-diabetic subjects with CHD. However, atherosclerosis may also precede the development of diabetes, suggesting that both disorders share common genetic and environmental antecedent factors ("common soil" hypothesis). One such a possible ancestor is insulin resistance which constitutes both a major feature of Type 2 diabetes and an independent risk factor for CHD. It is well documented that inflammatory processes play an important role in the causation of atherosclerotic CVD. Inflammatory mediators play a paramount role in the initiation, progression, and rupture of atherosclerotic plaques. Thus, markers of inflammation and endothelial dysfunction may provide additional information about a patient's risk of developing CVD and may become new targets for treatment. On the other hand, evidence has emerged suggesting that inflammation is also involved in the development of Type 2 diabetes. Prospective studies have demonstrated that increased levels of pro-inflammatory markers such as CRP or reduced levels of anti-inflammatory markers such as adiponectin predict the development of Type 2 diabetes. Thus, there is accumulating evidence suggesting that inflammation is the bridging link between atherosclerosis and the metabolic syndrome. Interventions by lifestyle modification or agents with anti-inflammatory properties may reduce the risk of both conditions. Drugs exerting anti-inflammatory and vascular effects have future potential to be used within an array of interventions aimed at reducing the enormous cardiovascular burden associated with Type 2 diabetes.     

The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy

Epidemiologic studies have previously suggested that premenopausal females have reduced incidence of cardiovascular disease (CVD) when compared to age-matched males, and the incidence and severity of CVD increases postmenopause. The lower incidence of cardiovascular disease in women during reproductive age is attributed at least in part to estrogen (E2). E2 binds to the traditional E2 receptors (ERs), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ), as well as the more recently identified G-protein-coupled ER (GPR30), and can exert both genomic and non-genomic actions. This review summarizes the protective role of E2 and its receptors in the cardiovascular system and discusses its underlying mechanisms with an emphasis on oxidative stress, fibrosis, angiogenesis, and vascular function. This review also presents the sexual dimorphic role of ERs in modulating E2 action in cardiovascular disease. The controversies surrounding the clinical use of exogenous E2 as a therapeutic agent for cardiovascular disease in women due to the possible risks of thrombotic events, cancers, and arrhythmia are also discussed. Endogenous local E2 biosynthesis from the conversion of testosterone to E2 via aromatase enzyme offers a novel therapeutic paradigm. Targeting specific ERs in the cardiovascular system may result in novel and possibly safer therapeutic options for cardiovascular protection.     

Intervention of integrative medicine treatment has impact on serum levels of ET-1, TNF-α, MLT in RA-CVD

Rheumatoid arthritis (RA) is a systemic autoimmune disease that can destroy peripheral joints. However, very little is known regarding specific biological marker for RA in Chinese patients. In this study, we determined the serum biomarkers and clinical features of RA-CVD. We also evaluated the short-term efficacy of routine RA treatment combined with integrative medicine treatment on RA-CVD. We found that anti-cyclic citrullinated peptide (CCP) and disease activity score in 28 joints (DAS28) are associated with risks of cardiovascular disease (CVD) in RA. And, melatonin (MLT) may play a negative regulatory role in cardiovascular damage in patients with RA. Furthermore, endothelin (ET-1) and inflammatory markers may be subclinical cardiovascular damages in RA. Moreover, of the 17 patients with RA-CVD, test results of ET-1, TNF-α and OSCAR after integrative medicine treatment were significantly decreased than before treatment. Collectively, our results provide a therapeutic potential of integrative medicine to the treatment of RA-CVD.     

Integration of genetic and genomic methods for identification of genes and gene variants encoding QTLs in the nonhuman primate

We have developed an integrated approach, using genetic and genomic methods, in conjunction with resources from the Southwest National Primate Research Center (SNPRC) baboon colony, for the identification of genes and their functional variants that encode quantitative trait loci (QTL). In addition, we use comparative genomic methods to overcome the paucity of baboon specific reagents and to augment translation of our findings in a nonhuman primate (NHP) to the human population. We are using the baboon as a model to study the genetics of cardiovascular disease (CVD). A key step for understanding gene–environment interactions in cardiovascular disease is the identification of genes and gene variants that influence CVD phenotypes. We have developed a sequential methodology that takes advantage of the SNPRC pedigreed baboon colony, the annotated human genome, and current genomic and bioinformatic tools. The process of functional polymorphism identification for genes encoding QTLs involves comparison of expression profiles for genes and predicted genes in the genomic region of the QTL for individuals discordant for the phenotypic trait mapping to the QTL. After comparison, genes of interest are prioritized, and functional polymorphisms are identified in candidate genes by genotyping and quantitative trait nucleotide analysis. This approach reduces the time and labor necessary to prioritize and identify genes and their polymorphisms influencing variation in a quantitative trait compared with traditional positional cloning methods.     

Fibroblast growth factor-23 helps explain the biphasic cardiovascular effects of vitamin D in chronic kidney disease

Hypovitaminosis D is highly prevalent in chronic kidney disease (CKD). Recently, vitamin D has sparked widespread interest because of its potential favorable benefits on cardiovascular disease (CVD). Evidence from clinical studies and animal models supports the existence of biphasic cardiovascular effects of vitamin D, in which lower doses suppress CVD and higher doses stimulate CVD. However, the mechanism for the different effects remains unclear. Fibroblast growth factor-23 (FGF-23) is a recently identified member of the FGF family, and thought to be actively involved in renal phosphate and vitamin D homeostasis. More specifically, Vitamin D stimulates FGF-23 secretion and is inhibited by increased FGF-23. Given this background, we hypothesize that FGF-23 may provide a unique tool to explain the biphasic cardiovascular effects of vitamin D in CKD. The data presented in this review support the hypothesis that FGF-23 may be linked with the high cardiovascular risk in CKD through accelerating the onset of vascular calcification, secondary hyperparathyroidism, left ventricular hypertrophy and endothelial dysfunction. Therefore, modulation of FGF-23 may become a potential therapeutic target to lowing cardiovascular risk in CKD. Several clinical interventions, including decreased phosphate intake, phosphate binders, cinacalcet plus concurrent low-dose vitamin D, C-terminal tail of FGF-23 and renal transplantation, have been employed to manipulate FGF-23.     

Fatty acid–genotype interactions and cardiovascular risk

Cardiovascular disease (CVD) risk and rate of progression is determined by genetic, environmental and behavioural factors. Majority of genotype–diet–CVD phenotype research till date has focussed on the interactive impact of single nucleotide polymorphisms (SNP) and dietary fat composition, on blood lipids levels, with strong evidence of the existence of hypo- and hyper-responders. However, a recognised concern in the field of nutrigenetics is a lack of consistency between findings of different studies. This apparent lack of consistency is likely to be attributable to the impact of factors such as ethnicity and gender on the ‘size’ of nutrigenetic interactions, a clear understanding of which needs to be gained. Although not yet ready for widespread use, in the future a greater use of genetic profiling is likely to enhance current strategies of CVD prediction, and improve the design of more personalised approaches to minimise risk in the individual.     

Serum C‐reactive protein in the prediction of cardiovascular diseases: Overview of the latest clinical studies and public health practice

Cardiovascular disease is the most common cause of morbidity and mortality globally. Epidemiological studies using high‐sensitivity assays for serum C‐reactive protein have shown a consistent association between cardiovascular disease risk and serum C‐reactive protein concentrations. C‐reactive protein is a biomarker for inflammation, and has been established in clinical practice as an independent risk factor for cardiovascular disease events. There is evidence that serum C‐reactive protein is an excellent biomarker of cardiovascular disease and is also an independent and strong predictor of adverse cardiovascular events. Further characterization of the impact and influence of lifestyle exposures and genetic variation on the C‐reactive protein response to cardiovascular disease events may have implications for the therapeutic approaches to reduce cardiovascular disease events. This review summarizes the studies that have examined the association between serum C‐reactive protein and the risk of cardiovascular disease. We also discuss the impact of independent factors and C‐reactive protein genetic polymorphisms on baseline plasma C‐reactive protein levels.     

Interpretation of mushroom as a common therapeutic agent for Alzheimer’s disease and cardiovascular diseases

Alzheimer’s disease (AD) and cardiovascular diseases (CVD) share common etiology and preventive strategies. As the population of old-aged people is increasing worldwide, AD complications tend to afflict global healthcare budget and economy heavily. CVD is the prime cause of global mortality and remains a grave threat to both the developed and the developing nations. Mushroom bio-components may be promising in controlling both diseases. Based mainly on in vitro, ex vivo, cell line and animal studies, this review interprets the polypharmaceutic role of mushrooms treating AD and CVD.