2007 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.
1) The individual response to a dietary fat challenge and to a PPARA activator is
modulated by genetic variation at the APOA5 gene locus.
Apolipoprotein A5 (APOA5) is a key determinant of plasma triglyceride(TG)
concentrations which is a significant risk factor for cardiovascular disease. This is especially important in terms of the amounts of TG carried in partially metabolized chylomicrons (also known as lipoprotein remnants). Genetic variation at the APOA5 locus could be responsible for some of the observed differences in postprandial response of these atherogenic lipoproteins following a fat-rich meal as well as in response to fenofibrate therapy. We examined the association between APOA5 polymorphisms (-1131T>C and 56C>G) and TG and HDL-C response to fenofibrate and a postprandial lipid challenge in 791 men and women. After 3-week drug treatment, APOA5 56G carriers displayed significant decrease in TG, and increase in HDL-C levels relative to their basal values in the fasting state when compared with noncarriers. In the postprandial lipemia after a fat load, the 56G carriers showed a significant decrease in the area under curve for TG and increase for HDL-C than the noncarriers. On the other hand, subjects with different APOA5-1131T>C genotypes showed no significant response to fenofibrate intervention. Our study suggests that the APOA5 56G carriers benefited more from the fenofibrate
treatment than noncarriers in lowering plasma TG and increasing HDL-C levels and can provide important leads towards personalized dietary recommendations and other type of therapies aimed to decrease the risk of cardiovascular diseases.
This accomplishment addresses NP107 Human Nutrition Component 6-Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle.
2) A common polymorphism in the APOA5 gene identifies subjects who don’t
increase their body mass index when consuming diets enriched in fat.
Diet is an important environmental factor interacting with our genes to modulate the likelihood of developing lipid disorders and, consequently, cardiovascular disease risk. Obesity is one of those risk factors and an integral component of the
metabolic syndrome. We have examined the interaction between common polymorphisms in the regulatory region of the apolipoprotein A5 gene (APOA5) (ApoA5-1131T>C) and the coding region [56C>G (S19W)] and the macronutrient intake(total fat, carbohydrate, and protein) in their relation to the body mass index (BMI) and obesity risk in 1,073 men and 1,207 women participating in the Framingham Offspring Study. We found for the first time a significant interaction between the APOA5 -1131T>C single-nucleotide polymorphism (SNP) and total fat intake for BMI. In subjects homozygous for the -1131T major allele, body mass index (BMI) increased as total fat intake increased. Conversely, this increase was not present in carriers of the -1131C minor allele. When specific fatty acid groups were analyzed, monounsaturated fatty acids showed the highest statistical significance for these interactions. In summary, the APOA5-1131T>C SNP, which is present in approximately 13% of this population, modulates the effect of fat intake on BMI. These data contribute to the identification of a segment of the population that could consume a wide variety of diets without having detrimental effects on their BMI. This is especially important considering that these subjects are at higher risk of cardiovascular disease if they become obese. These findings underscore the importance of dietary recommendations tailored to specific population groups or to
individuals based on their genetic makeup and provides strength to the future
feasibility of Nutrigenetics. This accomplishment addresses NP107 Human Nutrition Component 6-Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle.
3) A polymorphism in the APOA2 gene determines dietary intake and obesity
The prevalence of obesity and overweight continues to increase; currently, an
estimated 66% of adult Americans fit within these categories. This trend is unprecedented in U.S. history and is an important underlying cause of many related
disorders, including cardiovascular disease, Type 2 diabetes and several cancers, as well as escalating health care costs. Reduction of excess weight is difficult to
achieve and even harder to sustain, and there is critical need for effective, proven methods for the primary prevention of weight gain. Therefore, there is need to explore genetic, dietary, biological, behavioral, and environmental factors
influencing the development and consequences of obesity and related disorders across the lifespan. We studied the association between a functional apolipoprotein (APOA2) promoter polymorphism (-265T>C) and plasma lipids (fasting and postprandial), anthropometric variables, and food intake in 514 men and 564 women who participated in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. We observed that individuals homozygous for the -265C allele had statistically higher BMI than did carriers of the T allele. Consistently, the risk for obesity in homozygous for the -265C allele compared with carriers of the minor -256T allele almost doubled. Interestingly, total energy intake in CC individuals was statistically higher than in T allele carriers. Likewise, total fat and protein intakes were statistically higher in CC individuals, whereas the intake of carbohydrates was lower. Therefore, we found a new polymorphism at the APOA2 gene that was consistently associated with food consumption and obesity. Our findings support for the first time a role for APOA2 in regulating dietary intake and the risk of diet-induced obesity. This accomplishment addresses NP107 Human Nutrition Component 6-Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle.
4) Identification of novel genetic targets for the metabolic syndrome using bioinformatic analyses.
Computational and bioinformatic analysis of the human genome revealed novel targets relevant to cardiovascular disease (CVD) risk. The genetic contribution to risk of cardiovascular disease is incompletely described. Many genes pertinent to CVD risk are regulated by transcription factors that respond to constituents of the diet. Thus, a bioinformatic scan of the genome was conducted looking for genes with population-specific differences in rates of transcription and whose mRNA levels are linked to genetic markers that reside in binding sites of transcription factors that are important to the response to diet. Several novel targets were identified and preliminary data suggest these genes have regulatory roles for body-mass index, inflammation and serum triglyceride levels. Importantly, this accelerated approach to identification of genetic contributors to CVD risk and obesity has proven capable and provides for a further description of the interplay between genes and nutrition. This accomplishment addresses NP107 Human Nutrition Component 6-Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle.
5) Identifying candidate genes affecting Drosophila life span by integrating microarray gene expression analysis and quantitative trait loci mapping.
The current increase in life expectancy observed in industrialized societies underscores the need to achieve a better understanding of the aging process that
could help the development of effective strategies to achieve healthy aging. This
will require not only identifying aging-related genes, but also understanding how their effects are modulated by environmental factors, such as dietary intake and life style. We investigated gene expression changes between two strains of Drosophila (Oregon and 2b) for which quantitative trait loci (QTLs); stretches of DNA that are closely linked to the genes that underlie the life span, were previously identified. Males and females from both strains at young and old ages were analyzed for whole genome RNA expression using Affymetrix microarrays. Of the more than 8000 genes detected, we focused on the 354 genes that exhibited significant changes in gene expression both with age and between strains. We used these genes to integrate the analysis of microarray gene expression data, bioinformatics, and the results of genetic mapping studies reported previously, to identify 49 longevity candidate genes and four pathways that could potentially be responsible for regulating life span and involved in the process of aging in Drosophila and humans. This study demonstrated a new and powerful approach by combining QTL mapping (genetics), genomics, and bioinformatics to identify candidate genes that could affect the rate of aging in Drosophila. A similar approach could be used to identify relevant genes and pathways in humans and to investigate whether nutritional factors could modify their expression and provide recommendations to promote healthier aging. This accomplishment addresses NP107 Human Nutrition Component 6-Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle.
5.Significant Activities that Support Special Target Populations
|Number of patent applications filed||3|
|Number of non-peer reviewed presentations and proceedings||48|
|Number of newspaper articles and other presentations for non-science audiences||200|