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.
1. Discovery of a new epigenetic mechanism associated with obesity risk in humans. The prevalence of obesity and overweight continues to increase to unprecedented levels and is an important driver of many related disorders, as well as escalating health care costs. Consequently, there is critical need for effective methods for the prevention of weight gain; however, we cannot predict either obesity risk or response to therapeutic recommendations. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, investigated whether genetic variants found on genes expressed in the fat cell (adipocyte) were associated with obesity risk in human populations. They investigated whether obesity risk was modulated by interactions between gene variants and dietary fat. These investigators demonstrated that a specific gene variant (rs8887) on a gene known as PERILIPIN 4 (PLIN4) was associated with fatness ( adipiosity). Moreover, this association was modified by consumption of omega-3 polyunsaturated fatty acids; demonstrating that genetic predisposition towards obesity can be eliminated using specific nutrients. Further investigation of these findings revealed a novel mechanism involving a new family of small non-coding RNAs known as microRNAs (miRNAs). These results show that the PLIN4 gene and its interaction with dietary fatty acids modulate obesity risk through a novel regulatory mechanism and underscores the need to study both genetic (gene variants) as well as epigenetic (i.e., miRNAs) mechanisms. 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 prevent obesity and cardiovascular diseases.
2. A Database of Gene-Environment Interactions Pertaining to Cardiovascular Risk Factors. As the role of the environment – diet, exercise, alcohol and tobacco use and sleep among others – is given a more prominent role in modifying the relationship between genetic variants and clinical measures of disease, consideration of gene-environment (GxE) interactions is a must. To facilitate incorporation of GxE interactions into single-gene and genome-wide association studies, ARS-funded researchers and ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, have compiled from the literature a database of GxE interactions relevant to nutrition, blood lipids, cardiovascular disease and type 2 diabetes. This database will serve as an important resource to researchers in genetics and nutrition in order to gain an understanding of which points in the human genome are sensitive to variations in diet, physical activity and alcohol use, among other lifestyle choices. Furthermore, this GxE database has been designed with future integration into a larger database of nutritional phenotypes in mind. This development will increase vastly the capacity to build new information related to gene by diet interactions and will accelerate the path of discovery in nutritional research.
3. The Lactase (LCT) Gene Determines Obesity and its Modulation by Dairy Products. 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 at JMUSDA-HNRCA at Tufts University, Boston, MA, conducted a study to investigate the association of a variant in the Lactase gene (LCT-13910C>T) with obesity and its modulation by dairy products. This polymorphism has been strongly associated with lactase persistence (LP) in populations of European origin and it is emerging as a new candidate gene for obesity. The findings from this research show that individuals with a form of the LCT gene known as CC had lower weight, Body Mass Index, waist circumference and obesity risk as compared with other forms of this gene. However, these associations were found to be significant only among those consuming moderate or high lactose intakes (>8 g/day). In conclusion, this genetic polymorphism was strongly associated with BMI and obesity and modulated by lactose intake. 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 including dairy products.
4. The Human Biological Clock Modulates Behavior and Obesity Risk. There is increasing evidence supporting that poor sleep and nutritional practices can desynchronize the body's biological clocks, known as circadian rhythms. This is particularly true for the clock that regulates glucose and insulin, two hormones that when out of balance, are closely associated with weight gain and heart disease. Consequently, ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, conducted a study to investigate whether the Circadian Locomotor Output Cycles Kaput (CLOCK) gene, an essential element of the human biological clock, is involved in metabolic regulation. The aim was to investigate the behavioral (sleep duration, eating patterns and chronobiological characteristics) and hormonal (plasma ghrelin and leptin concentrations) factors which could be involved in obesity risk and successful weight loss. The results of this research show an association between a gene variant in the CLOCK gene, known as CLOCK 3111T/C, and weight loss following diet and behavioral therapy. Specifically, carriers of the genetic variant were more resistant to weight loss than individuals who did not carry the mutation. In addition, the data show that those subjects had shorter sleep duration; higher plasma ghrelin concentrations; delayed breakfast time; evening preference and less compliance with weigh loss program. In conclusion, sleep reduction, alteration of eating behaviors and evening preference driven by variation at the CLOCK gene could be affecting weight and weight loss. These results support the influence of the CLOCK gene on a broad range of variables linked with human behaviors and that behavioral modification and dietary changes must be an intrinsic component of preventive and therapeutic approaches in the fight against obesity.