2008 Annual Report 1a.Objectives (from AD-416) To identify genetic markers for assessment of cardiovascular health related to plasma lipoprotein levels, diabetes and obesity and evaluate, the effects of specific gene-gene interactions in common metabolic pathways. 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. To identify genes newly associated with cardiovascular health and overall longevity and determine their expression response to dietary intervention using animal models of aging. 1b.Approach (from AD-416) 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 technics, both in ongoing studies of free-living populations and in the metabolic ward (intervention studies). 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. 3.Progress Report This project includes the work of one subordinate project at the HNRCA funded through a Specific Cooperative Agreement with Tufts University. For further information and progress report see 1950-51520-010-02S, Nutrition and Genomics. 4.Accomplishments 1. Discovery of new genes associated with blood lipids in humans. High blood concentrations of low-density lipoprotein (LDL), triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, are known risk factors for cardiovascular disease. Blood lipid concentrations are heritable, but most of their heritability remains unexplained by known genes and gene variants. More complete knowledge will be crucial to develop better disease prevention strategies. Using cutting edge technical and analytical approaches, we have thoroughly analyzed the genomes of about 9000 subjects and replicated promising findings in about 19,000 additional individuals. Our data reveal that common single nucleotide polymorphisms (SNPs) at six new genes are reproducibly associated with LDL cholesterol, HDL cholesterol, and/or triglycerides. These findings represent advancement in our understanding of the genetics of plasma lipids and underscore the benefits of the new genetic technologies and worldwide collaborations. Understanding the molecular, cellular and clinical consequences of the new genes will provide the basis for new preventive measures in the population as well as for new therapies and clinical care. This addresses Component 6 (Prevention of Obesity and Disease: Relationship between Diet, Genetics and Lifestyle) of the NP107 Human Nutrition Action Plan. 2. Non-fasting plasma lipid metabolism is related to variation at the perilipin (PLIN) gene. The relationship between the after-meal response to changes in blood lipids, a risk factor for coronary heart disease, and genetic differences in the perilipin gene family has not been fully investigated. We investigated whether genetic variation in the PLIN gene relates to individual variability in lipid profiles during the after-meal period. Data from subjects of two populations-USA and Spain- consistently showed that carriers of one form of the PLIN gene displayed lower after-meal levels of triglyceride-rich lipoproteins than did subjects carrying the most common form of the gene. The impact of this study is three-fold: PLIN contributes to the regulation of dietary fat metabolism; a segment of the population has been identified that is better able to handle dietary fat with a lower risk of obesity and lower atherogenic risk; hence PLIN is now a target for dietary and drug intervention to reduce cardiovascular disease risk. This addresses Component 6 (Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle) of the NP107 Human Nutrition Action Plan. 3. Variation at the PPGARC1A gene is associated with DNA damage, diabetes, and cardiovascular diseases in Hispanics. Diabetes is an age-related disease and a major risk factor for cardiovascular disease (CVD). Over 23% of the US population, 60 years or older have diabetes, and the numbers are even higher in African American, Asian, Native American, and Hispanic populations. The mechanisms underlying the development of diabetes are not well understood and strategies for effective prevention of this disesae are lacking. We examined DNA damage using a reliable technique that measures urinary 8-hydroxydeoxyguanosine (8-OHdG) concentration and related this measurement with nine genetic variants at the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PPARGC1A) gene, DNA damage, diabetes, and CVD in Puerto Ricans living in the Boston area. Two PPARGC1A variants associated significantly with diabetes whereas carriers of variants of 2 other PPARGC1A polymorphisms had lower DNA damage and lower prevalence of CVD. Moreover, we found that physical activity correlated negatively with DNA damage. It is plausible that sedentary lifestyle combined with genetic risk contribute to the high prevalence of diabetes in Hispanics. Our finding support that the PPARGC1A gene influences development of diabetes and CVD via DNA damage. Increasing physical activity is a potential strategy to slow DNA damage, thereby decreasing the risk of CVD for individuals with diabetes. This addresses Component 6 (Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle) of the NP017 Human Nutrition Action Plan. 6.Technology Transfer Number of Newspaper Articles and Other Presentations for Non-Science Audiences 1