2010 Annual Report
1a.Objectives (from AD-416)
1. Identify new human genes involved in the homeostasis of lipid metabolism using
genome-wide association studies and bioinformatics.
2. Identify candidate genes for overweight and obesity in humans with special emphasis on those modulating the risk for the metabolic syndrome.
3. Identify genetic factors determining differential susceptibility towards chronic disorders in response to a Western-type diet and lifestyle in humans with differing ethnic backgrounds.
4. Identify new longevity genes and describe their modulation by nutritional and environmental factors in animals and humans.
1b.Approach (from AD-416)
Because the predisposition to most common ailments affecting healthy aging and the responses of the individual to nutrients both contain a strong genetic component, our approach aims to uncover sets of genes involved in the predisposition to alterations in fasting and non fasting lipid metabolism and obesity and 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 from different ethnic groups 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
and dyslipidemia, often precursors to cardiovascular disease and diabetes. Cardiovascular candidate genes, both those previously described in the literature as well as those we identify through new genetic technologies and 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, fiber) 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 in silico analysis of animal models of aging and longevity. Candidate aging genes will then be studied in human populations.
This report documents research conducted under a Specific Cooperative Agreement between ARS and the TUFTS UNIVERSITY. Additional details for the research can be found in the report for the parent project 1950-51520-010-00D, NUTRITION, CARDIOVASCULAR HEALTH AND GENOMICS. Within the reporting period the project has had significant progress. A major accomplishment of the project has been the identification of 95 genes, 59 of them novel genes, involved in the metabolism of blood lipids, which are major Cardiovascular Heart Disease (CHD) risk factors, using state-of-the-art genetic information from over 100,000 individuals, the largest genetic study ever reported. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and impact lipid traits in multiple non-European populations (East Asians, South Asians, and African Americans). Moreover, we demonstrated that several of the new genes were also associated with coronary artery disease (CAD), highlighting potential targets for new therapies.
Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
The above indicated accomplishment demonstrates the potential success of using genetic information to predict disease risk; however, as previously indicated, our knowledge of the genes implicated in CHD risk is still limited and more comprehensive knowledge in this area is needed in order to create diagnostic tools with the required specificity and sensitivity to be used in the general population.
In addition, we have explored both novel and previously known genes in terms of gene environment interactions that could potentially modulate the expression of the risk phenotype in the population. More specifically, we have demonstrated for the first time the replication of a gene diet interaction involving obesity and the APOA2 gene in three large US populations. The knowledge generated from our work will provide the basis for a more successful prevention of chronic disorders impairing healthy aging.
Moreover, we have made significant advances towards the completion of the first ever genome wide association study (GWAS) aiming to investigate the genetic basis of postprandial lipid response to diet, and developed novel and faster statistical approaches to analyze the massive amount of data generated by these analyses.
For publications related to this project, see parent project# 1950-51520-012-00D.
New method for the statistical analysis of massive amounts of genetic data. Genetic studies represent the new frontier in Biology and Medicine and their application to large populations allow the generation of vast amounts of data and their analysis and interpretation will allow new discoveries in basic and applied research. However, current statistical approaches are extremely resource intensive requiring powerful mainframe computers and long periods of processing time. This major limitation is impairing the progress of this most important area of translational research. Therefore, ARS-funded researchers from Tufts University in Boston, in collaboration with other ARS scientists have developed a combination of new statistical technique that overcomes current technical challenges. This new technology has been successfully tested and implemented using genomic information from datasets in humans, dog and maize. This approach dramatically reduced computing time from years to days without compromising the quality of the results. This development will increase vastly the capacity to carry out and analyze larger datasets in order to accelerate the path of discovery in biomedical research.
A common genetic variant in the APOA2 gene determines dietary intake and obesity The prevalence of obesity and overweight continues to increase to a level without precedent in U.S. history and is an important underlying cause of many related disorders, as well as escalating health care costs. Therefore, there is critical need for effective, proven methods for the primary prevention of weight gain. However, we don’t have the tools to predict the individual risk as well as responses to therapeutic recommendations. Therefore, ARS-funded researchers from Tufts University in Boston conducted a large study to investigate the role of a functional genetic variant, known as APOA2 -265T>C, in the regulation of food intake and body weight. Three independent populations in the United States were examined: the Framingham Offspring Study (1454 whites), the Genetics of Lipid Lowering Drugs and Diet Network Study (1078 whites), and Boston-Puerto Rican Centers on Population Health and Health Disparities Study (930 Hispanics of Caribbean origin). The results of this study show that people carrying the genetic variant at the APOA2 gene developed obesity only in the presence of a high saturated fat diet. This was true for the three populations and this is the first time that such replication is achieved across populations in research involving gene and diet interactions. This finding will contribute to the identification of individuals susceptible to diet-induced obesity. Moreover, it will guide the implementation of tailored dietary recommendations to specifically quench their increased predisposition to obesity and cardiovascular diseases.
Genes under pressure: adding a new twist to the gene-disease relationship Combining human genome data from disparate sources, ARS-funded researchers from Tufts University in Boston, in collaboration with ARS scientists have identified a select set of genes that both have been implicated in nutrition-based diseases, such as heart disease and type 2 diabetes, and are under genetic pressure. This latter feature indicates these genes are changing in response to differences in diet, environment or lifestyle choices. These results help to fill a gap in our understanding of why blanket recommendations from doctors, nutritionists and other health-care officials do not succeed for all patients. Specifically, we are now able to focus on a core set of heart disease and type 2 diabetes genes which are most likely to respond to diet, exercise and other lifestyle choices in a manner specific to an individual’s unique genetic makeup. Furthermore, these results can then be used to develop disease-prevention strategies that are tailored to the individual, strategies that call for specific diets or exercise plans.
Discovery of new genes associated with blood lipids in humans. Blood lipid concentrations are heritable risk factors for cardiovascular disease (CVD), but most of their heritability remains unexplained. This hampers the ability to predict an individual’s risk for CVD and consequently to successfully prevent this disease. To fill this gap, ARS-funded researchers from Tufts University in Boston, in collaboration with an international consortium, have thoroughly analyzed the genomes of over 100,000 individuals of European ancestry. This is the largest and more comprehensive study ever conducted to elucidate the genetic basis of cardiovascular risk factors. We identified 95 distinct genes reproducibly associated with lipoprotein concentrations, including 59 genes that were found to be significant for the first time. Moreover, we have shown that some of these genes have a significant impact in blood lipid levels in non-European populations (East Asians, South Asians and African Americans). These discoveries provide the foundation to develop a broader and deeper understanding of lipoprotein metabolism and to identify new preventive and therapeutic opportunities for the prevention of CVD.