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
This progress report includes the work of a subordinate project at the HNRCA funded through a Specific Cooperative Agreement with TUFTS UNIVERSITY. For further information and progress report, see 1950-51520-012-01S (Nutrition, Cardiovascular Health and Genomics).
1. Discovery of a new epigenetic mechanism associated with obesity risk in humans. 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. Consequently, 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, investigated whether genetic variants found on genes expressed in the adipocyte were associated with obesity risk in human populations. Moreover, 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) demonstrated significant association with adiposity. Moreover, this association was dependent on the dietary intake of omega-3 polyunsaturated fatty acids; supporting the notion that genetic predisposition towards obesity can be eliminated using targeted nutritional advice. Investigation of the molecular basis of these findings revealed a new mechanism involving a new family of molecules known as microRNAs (miRNAs). These results show that common variation at the PLIN4 gene and its interaction with dietary fatty acids modulates obesity related phenotypes, and this is due to the creation on this gene of a new miRNA regulatory site which represents a new mechanism in human obesity research and underscores the need to study both genetic (gene variants) as well as epigenetic (i.e., miRNAs) mechanisms.
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 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. Over 550 such interactions have been incorporated into a single database, along with over 1430 instances where a lack of statistical significance was found. 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, BMI, 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 scientific evidence supporting that poor sleep and nutritional practices can desynchronize the body's biological clocks, also 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, heart disease and diabetes. Sleep deficit has also been found to elevate levels of cortisol, a hormone that among other things regulates how the body uses energy; elevated cortisol levels have been linked to insulin resistance and a higher BMI. Along these lines, 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 and 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.
Huang, T., Tucker, K., Lee, Y., Crott, J., Parnell, L.D., Shen, J., Smith, C., Ordovas, J., Li, D., Lai, C. 2011. Interactions between genetic variants of methionine metabolism genes and lifestyle affect plasma homocysteine concentrations in the Boston Puerto Rican Population. Molecular Nutrition and Food Research. DOI: 10.1017/S1368980011000140.