2004 Annual Report 1.What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? What does it matter? The goals of this research are: (a) To identify genetic markers for the assessment of cardiovascular health related to plasma lipoprotein levels, diabetes and obesity and to evaluate the effects of specific gene-gene interactions in common metabolic pathways. (b) To investigate the interactions between genetics and nutrients in the development of cardiovascular disease (CVD), the major age-related disorder affecting life expectancy and quality of life in the United States (US). Emphasis is placed on elucidating mechanisms by which genetic variation interacts with dietary and behavioral factors to regulate the homeostasis of the cardiovascular system. (c) To identify genes newly associated with cardiovascular health and overall longevity and determine their expression response to dietary intervention using rodent models of aging. Because the response of the individual to nutrients contains a strong genetic component, our approach aims to uncover sets of genes involved in the dietary response and to describe specific gene-diet interactions. This will be tested, using high throughput genotyping techniques, both in ongoing studies of free-living populations and in intervention studies conducted in a metabolic ward. Our primary focus is to describe gene-diet interactions affecting/influencing progression of the metabolic syndrome, in particular obesity, often a precursor to cardiovascular disease and diabetes. Cardiovascular candidate genes, both those previously described in the literature, as well as those we identify through bioinformatics analysis, will be used to examine associations and interactions on various scales. These include genetic variations, disease-related phenotypes and specific nutrients [fatty acids, cholesterol, plant sterols) and behavioral habits (alcohol consumption, smoking, physical (in)activity]. Rigorous statistical analysis will uncover the associations between phenotypes indicative of increased risk of metabolic syndrome and the genes responsible for such. Because cardiovascular disease and diabetes are traditionally considered diseases of the aged, we will also continue with our investigations to identify genes responsible for healthy aging. The principal approach taken for these studies involves gene expression microarray analysis of fruit fly D. melanogaster populations with a propensity for increased longevity. Candidate aging genes will then be studied in mammalian models as well in human populations. The seriousness of the problem in hand is evident. Cardiovascular diseases (mainly coronary heart disease and stroke) are the leading causes of death in the US, accounting for more than 40 percent of all deaths. About 1 million Americans die of cardiovascular disease each year, which amounts to approximately two deaths every minute. More than half of all these deaths occur among women. However, the burden of this disease is not fully represented by the mortality figures. About one-fourth of the US population suffers from these diseases and account for 6 million hospitalizations each year. As the population ages the cost of these diseases to Health Care Systems in the US increases. The estimated cost in 2001 - including health care expenditures and lost productivity, was nearly $300 billion. The research program relates to the ARS Human Nutrition National Program 107 component 2: Diet, Genetics, Lifestyle, and the Prevention of Obesity and Disease. By addressing the individuality of the nutritional needs based on genetics, this research contributes to component 1: Nutrient Requirements. By examining the impact of genetic knowledge of the behavioral aspects of the individuals, this work impacts the components 3:Nutrition Monitoring and 5: Health Promoting Intervention Strategies for Targeted Populations. Finally, the understanding of the molecular mechanisms of nutrients and their interaction with different gene variants, we can contribute to the understanding of component 7: Bioavailability of Nutrients and Food Components. 2.List the milestones (indicators of progress) from your Project Plan. A. Identification of cardiovascular disease risk markers at candidate genes B. Identification of novel genes involved in cardiovascular disease risk C. Analysis of gene-gene interactions D. Analysis of gene-diet interactions in populations E. Analysis of gene-diet interactions in the postprandial state F. Identify genes associated with longevity 3.Milestones: A. List the milestones that were scheduled to be addressed in FY 2004. It is not possible to know at this time the number of genes implicated in cardiovascular disease risk and longevity, and the number of genetic variants that will be informative in risk prediction (milestones A, B, F). Therefore, the milestones are accomplished by providing new information aimed to answer these questions in the long term. This also applies to the gene-gene and gene-diet interactions (Milestones C-E). During FY2004 we proposed to: 1. Begin genotyping to identify new candidate genes and genetic variants involved with cardiovascular risk in several populations. This has been accomplished for each of the proposed milestones (A,B,D,E). 2. Begin the analyses of gene-gene and gene-diet interactions. This has been accomplished as planned for Milestones C and D. 3. Begin the bioinformatic approach to identify new genes involved in CVD and longevity. This has been accomplished for milestones B and F. B.The following projects will be accomplished over the next three years: Years 1 and 2 (FY2005-06): 1. Extend our current gene by diet interactions studies to examine common polymorphisms at genes involved in lipoprotein metabolism that are also regulated by hormones and are modified by overweight and obesity. This project aims to increase our understanding of the genetic basis underlying the individual variability in response to dietary intervention, but also to provide information about the gender-related differences in response to diets. We will collaborate with the Framingham Heart Study and with other population studies exposed to different dietary habits Years 1 - 5 (FY2005-08): 2. Investigate the genetic basis of obesity and to understand the interaction between genetics and dietary factors. Extend our current search of candidate genes for cardiovascular disease risk to include those associated with overweight and obesity, with special emphasis on those that may modulate the risk for the metabolic syndrome, one of the most common phenotypes present in people at risk for cardiovascular disease and that is present in an extremely high percent of the US population. We will collaborate with the Framingham Heart Study and with other population studies. The complexity and relevance of this task is such that will require intensive research during the next five years. Years 1-3 (FY2005-07): 3. Most studies have examined how individuals belonging to a relatively homogenous ethnic group (i.e., whites) respond to differences in environment (i.e., diet). We plan to examine the impact of gene-diet interaction on blood lipid levels and cardiovascular disease risk by examining the effects of a homogeneous environment over subjects with different genetic backgrounds. For this study, we have identified a population in which three different ethnic groups with vastly different disease rates share a common environment. We will study the genetic factors that determine the differences in disease in response to a Western type lifestyle and changes in dietary habits. 4. We will conduct intervention studies to demonstrate the validity of the findings that we have reported in epidemiological studies. We will select subjects based on specific genotypes and place them on different diet phases to examine in a more controlled environment, whether the differences in response based on their genetic information are significant and in agreement with those that we have observed in population studies. We will make a special effort to concentrate some of these studies on minorities. This is important based on the especially negative impact that westernization of life styles, especially diet, is having in these populations. 5. We will establish animal models of prolonged survival to identify those genes that are differentially expressed in those that have a normal lifespan and in those with a prolonged lifespan. The genes identified using these models will be then examined in humans for polymorphisms and for differences in gene expression in those cases in which the site of expression allows for this kind of studies. Establishment of the models will take place on year 1. Examination of the impact of the relevant genes on human longevity will take place during years 2 and 3. 6. We will search for new genes involved in the homeostasis of lipid metabolism, with emphasis on levels of high-density lipoproteins. High levels of these lipoprotein particles have been associated in the past with the ¿longevity syndrome¿. We have already from a genome wide scan identified several human chromosomal regions that appear to be promising to find new and relevant genes that could be regulated by dietary factors and determine cardiovascular risk. Gene mapping will occur during year 1. Characterization of their impact on aging on populations will be accomplished during years 2 and 3. Year 2 (FY2006): 7. In our search for genes involved in healthy aging and prolonged survival, we will study survivors among subjects with low life expectancy and high disease rates. We have selected familial hypercholesterolemia, a genetic disorder associated with a 25-fold increased risk of premature cardiovascular disease. Some subjects carrying the mutations predisposing for this disease are able to survive disease-free for many years. Therefore, we will examine the genetic and environmental factors that determine the extended disease-free survival in comparison with those who develop the disease at an early age. This effort will be initiated during year 2. 4.What were the most significant accomplishments this past year? This project was recently established following completion of the Office of Scientific Quality Review process. Please see the report for 1950-51520-007-00D. Nutrition, Cardiovascular Health and Genomics. 5.Describe the major accomplishments over the life of the project, including their predicted or actual impact. This project was recently established following completion of the Office of Scientific Quality Review process. Please see the report for 1950-51520-007-00D Nutrition, Cardiovascular Health and Genomics. 6.What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end-user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? This project was recently established following completion of the Office of Scientific Quality Review process. Please see the report for 1950-51520-007-00D Nutrition, Cardiovascular Health and Genomics. 7.List your most important publications in the popular press and presentations to organizations and articles written about your work. This project was recently established following completion of the Office of Scientific Quality Review process. Please see the report for 1950-51520-007-00D Nutrition, Cardiovascular Health and Genomics.