Location: Boston, Massachusetts2011 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.
3. Progress Report
We have made major progress towards the completion of the first genome wide association study (GWAS) conducted on subjects participating in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. These subjects were receiving a standardized fat load before and after taking the PPARA agonist fenofibrate, which is known to decrease fasting plasma triglyceride levels. This will be the first GWAS conducted for this specific trait, and it will allow us to look at the genetics of lipid metabolism from a perspective never explored before. In the near future, we will complete the statistical analysis and we will begin replication of promising genomic areas in other informative cohorts. Along the same lines, we started the laboratory component of the Boston Puerto Rican Health Study GWAS. Like the one mentioned above, this will be the first GWAS carried out in this specific Hispanic population and it will provide new light on health disparities related to aging-related diseases. As a follow up of our recent discovery involving microRNAs (miRNA) –related genetic variants as risk factors for obesity, we are carrying out genomic search for polymorphisms in miRNA binding sites that will inform us and other researchers about the functionality of many of the targets being discovered in a number of GWAS studies that, so far, remain unexplained. Although further research is necessary, our initial findings suggest that miRNA activity is a possible target for dietary-based weight-loss therapies for obesity. Taken together, our findings and ongoing research provide the foundation to develop a broader biological understanding of obesity and to identify new therapeutic opportunities for the prevention and treatment of obesity. The above indicated ongoing projects in combination with our accomplishments demonstrate the potential success of using genetic information to predict obesity risk and to use more personalized nutritional recommendations towards its prevention. In addition, we have explored both novel and previously known genes in terms of gene environment interactions that could potentially modulate the expression of obesity and other cardiovascular risk factors 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 populations in the USA, Europe and Asia. Moreover, we have extensively demonstrated that genes involved in chronobiology are significantly involved in the risk of obesity and the metabolic syndrome. The knowledge generated from our work will provide the basis for a more successful prevention of chronic disorders impairing healthy aging.