Can Genetic Pleiotropy Replicate Common Clinical Constellations of Cardiovascular Disease and Risk?

The relationship between obesity, diabetes, hyperlipidemia, hypertension, kidney disease and cardiovascular disease (CVD) is established when looked at from a clinical, epidemiological or pathophysiological perspective. Yet, when viewed from a genetic perspective, there is comparatively little data synthesis that these conditions have an underlying relationship. We sought to investigate the overlap of genetic variants independently associated with each of these commonly co-existing conditions from the NHGRI genome-wide association study (GWAS) catalog, in an attempt to replicate the established notion of shared pathophysiology and risk. We used pathway-based analyses to detect subsets of pleiotropic genes involved in similar biological processes. We identified 107 eligible GWAS studies related to CVD and its established comorbidities and risk factors and assigned genes that correspond to the associated signals based on their position. We found 44 positional genes shared across at least two CVD-related phenotypes that independently recreated the established relationship between the six phenotypes, but only if studies representing non-European populations were included. Seven genes revealed pleiotropy across three or more phenotypes, mostly related to lipid transport and metabolism. Yet, many genes had no relationship to each other or to genes with established functional connection. Whilst we successfully reproduced established relationships between CVD risk factors using GWAS findings, interpretation of biological pathways involved in the observed pleiotropy was limited. Further studies linking genetic variation to gene expression, as well as describing novel biological pathways will be needed to take full advantage of GWAS results.     

Genetic variants predisposing to cardiovascular disease

PURPOSE OF REVIEW: The goal of this review is to provide an update on the most recent and relevant findings in the area of genotype-phenotype associations as well as the relationships between genetic factors and cardiovascular disease risk markers and events. In addition, emphasis will be placed on the methodological problems associated with studying the genetics of complex disorders, specifically cardiovascular diseases. RECENT FINDINGS: Genes associated with cardiovascular disease predisposition have been examined, including traditional cardiovascular disease candidate genes, such as ACE, AGT, eNOS, PON and MTHFR, new loci that have recently been added to the growing list of cardiovascular disease candidate genes (i.e. MEF2A, ALOX5, LTA, APOM, PDE4D), and genes that have been shown to be at the intersection of several age-related disorders through interaction with one another or with environmental factors (i.e. APOA5, APOE, PPARgamma, LPL and LIPC). SUMMARY: During the last year, tremendous effort has been made in elucidating new genes associated with cardiovascular disease predisposition. For the most part, however, major breakthroughs have not been made, primarily due to the poor replication of results among studies, as a consequence of poor experimental design. Nevertheless, we have increased our understanding of the complexity of cardiovascular disease and the relevance of gene-environment interactions as the ultimate drivers of the individual predisposition to the disease. It is essential, therefore, that present and future genetic studies in this area take into consideration the inclusion of high-quality environmental data in the analytical process to test the clinical usefulness of a genetic marker as a risk predictor.     

Genetic factors affecting HDL levels, structure, metabolism and function

PURPOSE OF REVIEW: HDL is a recognized negative risk factor for the cardiovascular diseases. Establishing the genetic determinants of HDL concentration and functions would add to the prediction of cardiovascular risk and point to the biochemical mechanisms underlying this risk. The present review focuses on various approaches to establish genetic determinants of the HDL concentration, structure and function. RECENT FINDINGS: While many genes contribute to the HDL concentration and collectively account for half of the variability, polymorphism of individual candidate genes contributes little. There are strong interactions between environmental and genetic influences. Recent findings have confirmed that APOA1 and ABCA1 exert the strongest influence on HDL concentrations and risk of atherosclerosis. CETP and lipases also affect the HDL concentration and functionality, but their connection to the atherosclerosis risk is conditional on the interaction between environmental and genetic factors. SUMMARY: Analysis of genetic determinants of HDL-cholesterol in patients with specific disease states or in response to the environmental condition may be a more accurate way to assess variations in HDL concentration. This may result in defining the rules of interaction between genetic and environmental factors and lead to understanding the mechanisms responsible for the variations in HDL concentration and functionality.     

Ethnic differences in atherosclerosis, cardiovascular disease and lipid metabolism

PURPOSE OF REVIEW: Comparison of risk factors and cardiovascular disease among racial and ethnic groups is a powerful approach to study genetics and lifestyle, or environmental interactions. RECENT FINDINGS: Most, mean or median, cardiovascular risk factor levels are similar among black and white people. There are much greater differences in the distribution of risk factor level within a specific race and ethnic group than between US populations. There are also very large differences in levels of risk factors for coronary heart disease between specific ethnic migrant populations such as comparing black people in Africa with those in the US, or Japanese people in Japan with those in Hawaii and California. Differences in distribution of risk factors and disease between race and ethnic group are a function of the frequency of specific genotypes and interaction with environmental factors. Several of the most important differences between racial groups are higher blood pressure, lower triglycerides and higher HDL cholesterol among blacks, higher prevalence of diabetes and insulin resistance among Mexican Americans and American Indians, and higher triglyceride levels among the Japanese. SUMMARY: Further studies of racial and ethnic differences should focus on unique phenotypes and genotypic differences, international and migrant studies and large enough sample sizes to provide robust results. The sprinkling of a percentage of minority participants in each study is worthless. The study of racial and ethnic differences in disease and detection of risk factor levels must be based on solid hypotheses that can evaluate the interaction of lifestyle and possible genetic attributes. Many of the reported ethnic differences in risk factors and disease in US populations are primarily a function of differences in education, socioeconomic variations, and utilization of preventive and clinical treatments.     

Maintaining or Abandoning African Rice: Lessons for Understanding Processes of Seed Innovation

Rice breeding and crop research predominantly emphasize adaptation to ecological conditions. Based on qualitative and quantitative research conducted between 2000 and 2012 we show how ecological factors, combined with socioeconomic variables, cultural norms and values, shape the use and development of local technologies related to the cultivation of African rice (Oryza glaberrima Steud.) in seven West African countries (Ghana, Guinea, Guinea-Bissau, Senegal, Sierra Leone, The Gambia and Togo). In this region the role of African rice is diverse across ethnic groups. Findings suggest that farmers, through various pathways, are active in the development of promising new varieties based on genetic resources of Asian rice, African rice, or both, as well as in the adoption of modern varieties. These findings require further research into interactions among ecological, genetic, socioeconomic and cultural factors within farmers?? innovation systems and recognition of emergent knowledge and technologies resulting from such interactions.     

Genetic,epigenetic, and gene-by-diet interaction effects underlie variation in serum lipids in a LG/J×SM/J murine model

Variation in serum cholesterol, free-fatty acids, and triglycerides is associated with cardiovascular disease (CVD) risk factors. There is great interest in characterizing the underlying genetic architecture of these risk factors, because they vary greatly within and among human populations and between the sexes. We present results of a genome-wide scan for quantitative trait loci (QTL) affecting serum cholesterol, free-fatty acids, and triglycerides in an F₁₆ advanced intercross line of LG/J and SM/J (Wustl:LG,SM-G16). Half of the population was fed a high-fat diet and half was fed a relatively low-fat diet. Context-dependent genetic (additive and dominance) and epigenetic (imprinting) effects were characterized by partitioning animals into sex, diet, and sex-by-diet cohorts. Here we examine genetic, environmental, and genetic-by-environmental interactions of QTL overlapping previously identified loci associated with CVD risk factors, and we add to the serum lipid QTL landscape by identifying new loci.     

Genetic and environmental influences on body fat distribution, fasting insulin levels and CVD: are the influences shared?

Central body fat distribution has been shown to be related to hyperinsulinemia, insulin resistance, hypertriglyceridemia, and atherosclerosis to a greater degree than general obesity. There are known to be both genetic and environmental effects on all components of this clustering. Whether these genetic effects are due to one set of genes in common to the components or whether genetic influences on insulin resistance and/or general/abdominal fatness 'turn on' other genes that affect other components of the syndrome is not clear. We analyzed data from the Swedish Adoption/Twin Study of Aging (60% female; monozygotic = 116, dizygotic = 202; average age 65 years) to determine whether there were genetic and/or environmental factors shared among general body fat distribution, abdominal body fat distribution, fasting insulin levels and cardiovascular disease. We found additive genetic effects in males to be significantly different from those in females with genetic effects accounting for variance in waist-hip ratio (males = 28%; females = 49%), body mass index (males = 58%; females = 73%), fasting insulin levels (FI) (males = 27%; females = 49%), and cardiovascular disease (CVD) (males = 18%; females = 37%). There were also shared genetic and environmental effects among all the variables except CVD, but a majority of the genetic variance for these measures was trait specific.     

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.     

Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics

Sex differences occur in most non-communicable diseases, including metabolic diseases, hypertension, cardiovascular disease, psychiatric and neurological disorders and cancer. In many cases, the susceptibility to these diseases begins early in development. The observed differences between the sexes may result from genetic and hormonal differences and from differences in responses to and interactions with environmental factors, including infection, diet, drugs and stress. The placenta plays a key role in fetal growth and development and, as such, affects the fetal programming underlying subsequent adult health and accounts, in part for the developmental origin of health and disease (DOHaD). There is accumulating evidence to demonstrate the sex-specific relationships between diverse environmental influences on placental functions and the risk of disease later in life. As one of the few tissues easily collectable in humans, this organ may therefore be seen as an ideal system for studying how male and female placenta sense nutritional and other stresses, such as endocrine disruptors. Sex-specific regulatory pathways controlling sexually dimorphic characteristics in the various organs and the consequences of lifelong differences in sex hormone expression largely account for such responses. However, sex-specific changes in epigenetic marks are generated early after fertilization, thus before adrenal and gonad differentiation in the absence of sex hormones and in response to environmental conditions. Given the abundance of X-linked genes involved in placentogenesis, and the early unequal gene expression by the sex chromosomes between males and females, the role of X- and Y-chromosome-linked genes, and especially those involved in the peculiar placenta-specific epigenetics processes, giving rise to the unusual placenta epigenetic landscapes deserve particular attention. However, even with recent developments in this field, we still know little about the mechanisms underlying the early sex-specific epigenetic marks resulting in sex-biased gene expression of pathways and networks. As a critical messenger between the maternal environment and the fetus, the placenta may play a key role not only in buffering environmental effects transmitted by the mother but also in expressing and modulating effects due to preconceptional exposure of both the mother and the father to stressful conditions.     

Effects of particulate air pollution on cardiovascular health: a population health risk assessment

Particulate matter (PM) air pollution is increasingly recognized as an important and modifiable risk factor for adverse health outcomes including cardiovascular disease (CVD). However, there are still gaps regarding large population risk assessment. Results from the nationwide Behavioral Risk Factor Surveillance System (BRFSS) were used along with air quality monitoring measurements to implement a systematic evaluation of PM-related CVD risks at the national and regional scales. CVD status and individual-level risk factors were collected from more than 500,000 BRFSS respondents across 2,231 contiguous U.S. counties for 2007 and 2009. Chronic exposures to PM pollutants were estimated with spatial modeling from measurement data. CVD outcomes attributable to PM pollutants were assessed by mixed-effects logistic regression and latent class regression (LCR), with adjustment for multicausality. There were positive associations between CVD and PM after accounting for competing risk factors: the multivariable-adjusted odds for the multiplicity of CVD outcomes increased by 1.32 (95% confidence interval: 1.23-1.43) and 1.15 (1.07-1.22) times per 10 μg/m(3) increase in PM(2.5) and PM(10) respectively in the LCR analyses. After controlling for spatial confounding, there were moderate estimated effects of PM exposure on multiple cardiovascular manifestations. These results suggest that chronic exposures to ambient particulates are important environmental risk factors for cardiovascular morbidity.     

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.     

Why study gene-environment interactions?

PURPOSE OF REVIEW: We examine the reasons for investigating gene-environment interactions and address recent reports evaluating interactions between genes and environmental modulators in relation to cardiovascular disease and its common risk factors. RECENT FINDINGS: Studies focusing on smoking, physical activity, and alcohol and coffee consumption are observational and include relatively large sample sizes. They tend to examine single genes, however, and fail to address interactions with other genes and other correlated environmental factors. Studies examining gene-diet interactions include both observational and interventional designs. These studies are smaller, especially those including dietary interventions. Among the reported gene-diet interactions, it is important to highlight the strengthened position of APOA5 as a major gene that is involved in triglyceride metabolism and modulated by dietary factors, and the identification of APOA2 as a modulator of food intake and obesity risk. SUMMARY: The study of gene-environment interactions is an active and much needed area of research. Although technical barriers of genetic studies are rapidly being overcome, inclusion of comprehensive and reliable environmental information represents a significant shortcoming of genetics studies. Progress in this area requires inclusion of larger populations but also more comprehensive, standardized, and precise approaches to capturing environmental information.     

The genetics of complex diseases

Genetic factors influence virtually every human disorder, determining disease susceptibility or resistance and interactions with environmental factors. Our recent successes in the genetic mapping and identification of the molecular basis of mendelian traits have been remarkable. Now, attention is rapidly shifting to more-complex, and more-prevalent, genetic disorders and traits that involve multiple genes and environmental effects, such as cardiovascular disease, diabetes, rheumatoid arthritis and schizophrenia. Rather than being due to specific and relatively rare mutations, complex diseases and traits result principally from genetic variation that is relatively common in the general population. Unfortunately, despite extensive efforts by many groups, only a few genetic regions and genes involved in complex diseases have been identified. Completion of the human genome sequence will be a seminal accomplishment, but it will not provide an immediate solution to the genetics of complex traits.     

Effect of Gender on Awareness of Cardiovascular Risk Factors,Preventive Action Taken,and Barriers to Cardiovascular Health in a Group of Austrian Subjects

BackgroundThe incidence of cardiovascular disease (CVD) is increasing in industrialized countries. Preventive action is an important factor in minimizing CVD-associated morbidity and mortality. However, it is not known whether gender differences affect CVD or risk factor awareness influencing self-assessment of personal risk and preventive action.ObjectiveThis study was performed to assess individual CVD and risk factor awareness, preventive action taken, and barriers to cardiovascular health.MethodsThe study included 573 women and 336 men, randomly chosen to complete an anonymous questionnaire to assess individual CVD and risk factor awareness, preventive action taken, and barriers to cardiovascular health. The data were analyzed using SAS software.ResultsCardiovascular disease was identified in 75% of patients, in both sexes, as the leading cause of death; however, both groups showed significant lack of knowledge about CVD risk factors. Type 2 diabetes was identified correctly in only 27.5%. Preventive action was linked more often to family members in 66.5% of women and 62.8% of men. The primary barrier to cardiovascular health in adults was incorrect assessment of personal CVD risk. More than half of female respondents (56.4%) and male respondents (52.7%) underestimated their risk of CVD.ConclusionKnowledge about risk factors for CVD needs to be improved in members of both sexes. Because women, in particular, have difficulty in correctly assessing their personal CVD risk, future education programs are warranted to inform both women and men about CVD and its risk factors, thereby helping them to correctly assess their individual risk. However, greater effort is needed to inform men, compared with women, about the various ways in which to prevent CVD and to motivate them to take preventive action.     

Genes, diet and serum lipid concentrations: lessons from ethnically diverse populations and their relevance to coronary heart disease in Asia

PURPOSE OF REVIEW: The burden of coronary heart disease (CHD) in Asia has risen in tandem with socio-economic development and urbanization. Although all ethnic groups have been affected, some appear to be at particularly high risk. The basis of these ethnic differences remains poorly understood. RECENT FINDINGS: Differing levels of risk factors for CHD have been observed between ethnic groups. Previous studies, however, may be confounded by a large ethnic variation in socio-economic status and place of residence. Few studies have taken dietary factors into account. Recent studies involving Chinese, Malays and Asian Indians living in Singapore suggest that neither dietary nor genetic factors, taken in isolation, sufficiently explain ethnic differences in serum lipid profiles. Several genetic variants in key candidate genes (apolipoprotein E, APOE, cholesteryl ester transfer protein, CETP and hepatic lipase, LIPC) have recently been found to modulate the association between dietary factors and serum lipid concentrations in these ethnic groups and in other populations. SUMMARY: To fully evaluate the differences in CHD risk between ethnic groups, environmental exposures, including dietary factors need to be carefully evaluated, and gene-environment interactions that may give rise to these differences need to be taken into account. These are critical steps in the development of targeted strategies to contain the epidemic of coronary heart disease in Asia. An understanding of the basis of these differences may also provide insights into the pathogenesis of disease that one cannot get through the examination of more homogenous populations.     

The genetics of complex diseases

Genetic factors influence virtually every human disorder, determining disease susceptibility or resistance and interactions with environmental factors. Our recent successes in the genetic mapping and identification of the molecular basis of mendelian traits have been remarkable. Now, attention is rapidly shifting to more-complex, and more-prevalent, genetic disorders and traits that involve multiple genes and environmental effects, such as cardiovascular disease, diabetes, rheumatoid arthritis and schizophrenia. Rather than being due to specific and relatively rare mutations, complex diseases and traits result principally from genetic variation that is relatively common in the general population. Unfortunately, despite extensive efforts by many groups, only a few genetic regions and genes involved in complex diseases have been identified. Completion of the human genome sequence will be a seminal accomplishment, but it will not provide an immediate solution to the genetics of complex traits.     

The genetics of complex diseases

Genetic factors influence virtually every human disorder, determining disease susceptibility or resistance and interactions with environmental factors. Our recent successes in the genetic mapping and identification of the molecular basis of mendelian traits have been remarkable. Now, attention is rapidly shifting to more-complex, and more-prevalent, genetic disorders and traits that involve multiple genes and environmental effects, such as cardiovascular disease, diabetes, rheumatoid arthritis and schizophrenia. Rather than being due to specific and relatively rare mutations, complex diseases and traits result principally from genetic variation that is relatively common in the general population. Unfortunately, despite extensive efforts by many groups, only a few genetic regions and genes involved in complex diseases have been identified. Completion of the human genome sequence will be a seminal accomplishment, but it will not provide an immediate solution to the genetics of complex traits.     

The Georgia Cardiovascular Twin Study.

The Georgia Cardiovascular Twin Study is a longitudinal study of biobehavioral antecedents of cardiovascular disease in youth. It includes roughly equal numbers of African Americans and European Americans, with a total of > 500 twin pairs. Focus of the study is the change in relative influence of genetic and environmental factors on development of risk factors for cardiovascular disease. Future work will explore the influence of polymorphic variation in candidate genes and their potential interaction with the environment on these risk factors.     

Cardiovascular Disease in Women Update: Ischemia,Diagnostic Testing,and Menopause Hormone Therapy

ObjectiveThis update will address 3 areas specifically that are essential to improving cardiovascular outcomes for women.MethodsThe current literature has been reviewed and three important areas of cardiovascular care in women are highlighted. First is that even though women and men share many traditional risk factors for ischemic heart disease, several of these risk factors affect women disproportionately when it comes to CVD risk and events. There are also unique sex-specific risk factors for women and risk factors that are more common in women than in men. Adverse outcomes of pregnancy and hypertensive disorders of pregnancy are associated with an increased long-term risk of CVD and events. At menopause, cardiovascular risks increase, and lipids become unfavorable. Second is that diagnostic testing for ischemic heart disease presents different specificities and sensitivities between men and women and testing should be determined according to what is best and safest for women. Third is that currently, menopause hormone therapy is approved by the U.S. Food and Drug Administration for the treatment of vasomotor and genitourinary symptoms, prevention of osteoporosis, and estrogen replacement in the setting of surgical menopause, hypogonadism, or premature ovarian insufficiency. It is not recommended for the primary or secondary prevention of CVD and not recommended for women with high atherosclerotic CVD risk.ResultsCardiovascular disease (CVD) remains the most common cause of death in women in the United States despite tremendous improvements in cardiovascular care for men and women. The prevention of CVD in women with early detection and implementation of preventive therapies before atherosclerotic CVD develops is critical to improving outcomes for women.