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Nutrient-gene interactions in human obesity: implications for dietary guidelines

Deliverables

Large between subject variations in weight loss has been observed for all types of obesity interventions. There is however a lack of knowledge about pre-intervention factors predicting success in various weight loss regimes, and few (if any) have studied the possible interaction between baseline predictors of weight loss and diet type. Based on the NUGENOB study we will are able to identify predictors of weight loss success in 771 obese healthy subjects who can be assumed to resemble the overall obese European population, and who have undergone an intervention which resample the general recommendations in terms of the degree of calorie restriction. The weight loss intervention was a 10-week intervention program consisting of a hypocaloric diet (~ 600 kcal energy deficit per day), either with a low fat content (20-25% fat) or with a medium fat content (40-45% fat). . A large panel of putative predictors are being tested for their association with weight loss, changes in body composition and waist circumference, as well as drop out from the treatment regime. All predictors are tested for possible interaction with diet, i.e. whether specific baseline parameters are associated with better outcome following the moderate fat or the low fat diet. . The panel of putative predictors addressed in this study includes parameters of energy and substrate metabolism and blood parameters (substrates, metabolites and hormones) in fasting, and following a high fat (95 E% from fat) test meal. Additional factors include habitual diet and lifestyle, history of obesity and previous dieting attempts, familial predisposition to obesity; health related quality of life (SF36). The search for predictors of weight loss success is strongly guided by the result of thorough analyses of determinants of postprandial substrate metabolism after the high fat meal. . These findings will improve the ability to predict which subjects will in general be successful in losing weight, and which diet will be optimal for certain subgroups of subjects. Further these findings may guide the assessment of weight loss readiness’ and pinpoint modifiable subject characteristic which may hamper weight loss, and which should be addressed before the weight loss intervention begins in order to optimise the results. . These results will primarily aid clinicians and dieticians treating obese subjects, improving the platform for setting realistic weight loss expectations on the individual level and for tailoring and optimising the diet in accordance with subject characteristic. Further, these results can be implemented in a more targeted search for candidate genes involved in the regulation of energy and body fat balance in obesity. Finally and foremost, these results will aid the >135 millions obese European consumers, who will be able to select and receive more optimised dietary treatment for obesity. . The results pertaining will be disseminated primary in a scientific papers in a peer-reviewed journal. Manuscripts will be submitted se within a few months after the completion of the projects period.
The NUGENOB database includes all data from the NUGENOB study. The data thus provide a thorough set of characteristics from 771 obese and 119 lean European subjects from 8 European cities. From all subjects background information regarding habitual diet and life-style, family history of obesity and related diseases are available. All subjects completed a one-day clinical investigation programme including assessment of fasting energy and substrate metabolism (indirect calorimetry), and plasma levels of obesity related hormones, metabolites and substrates. The one-day investigation included a high-fat test meal (95% energy from fat, energy intake 50% of estimated BMR). 3 hour metabolic response (calorimetry and blood samples) was obtained from all subjects. All obese subjects were randomised to a 10-week intervention programme consisting of a hypocaloric diet (about 600 kcal energy deficit per day), either with a low fat content (20-25% fat) or with a medium fat content (40-45% fat). All subjects were genotyped for a long list of candidate SNPs and haplotypes. Quantitative gene expression of 40 selected genes and microarray-based gene expression profiling was conducted on subcutaneous adipose tissue samples obtained before and after the dietary intervention. However these analyses were only conducted in sub samples of the obese study population. The data are saved in a big databank from which specific data can easily be extracted. All datasets extracted from the databank are anonymous, and thus does not include any type of information that can lead to the identification of the subjects who participated in the study. The database includes following categories of data: - Screening data; - Baseline anthropometrics from clinical investigation day; - Basic and post meal metabolic rate and fat oxidation; - Basic and post meal appetite scores; - Blood values (fasting, 1,2, and 3 h post meal, and fasting week 10): insulin, glucose, free fatty acids, total glycerol, free glycerol, triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol; - Blood values (fasting, 3 h post meal, and fasting week 10): VLDL TAG; - Blood values (fasting at baseline and week 10): leptin, IGF; - Weight and compliance registered weekly throughout the 10-week dietary intervention; - Body composition and fasting blood values obtained at the end of the 10-week dietary intervention; - Food recordings: 3 day habitual diet, 1 day intervention diet at week 2,5, and 7, and 3 day intervention diet at week 10; - Questionnaire data: social variables, physical activity, drinking and smoking habits, weight and dieting history, health and illness, family history of obesity and obesity related diseases, SF-36 qGenotyping data for approximately 40 SNPs in approximately 20 candidate genes for obesity; - Quantitative gene expression data for 35-40 genes (available for 2 x25 subjects). The databank is ready for use for external collaborations as well as supplementary analyses within the NUGENOB project. Target data can easily be extracted from the databank. The data are anonymous, and thus does not include any type of information that can lead to the identification of the subjects who participated in the study. The database will be of major interest for future research projects and is expected to be a cornerstone in several European as well as national research projects. The FP6 Network of Excellence NuGO "European Nutrigenomics Organisation - linking genomics, nutrition and health research" www.nugo.org (coordinated by Ben van Ommen), as well as future projects under the 6th and 7th Framework Program are expected to incorporate the databank and the project as such. In addition, the members of the consortium has build up knowledge regarding the strategies for setting up data storage facilities in multi-centre trails, setting up case report forms for entering the data, data cleaning etc. In order to use the data from the databank a synopsis defining the aim of the project, the samples needed, the analyses planned, the plans for publication etc must be presented to and approved by the NUGENOB Project Steering Committee.
The NUGENOB project targets the treatment and prevention of obesity, one of the major health problems in Europe. It is a large-scale project in which the clinical investigations have been conducted in research centres in 8 European cities. In order to standardise the technical procedures a long list of SOPs have been developed. The SOPs covers a long list of procedures related to clinical research in general and specifically to clinical investigation and dietary intervention in obese subjects. The SOPs include: - SOP for anthropometrical measurements and measurement of body composition based on bioelectrical impedance. - A questionnaire addressing lifestyle, smoking and drinking habits, physical activity, history of obesity and previous dieting, familial predisposition to obesity, health related quality of life (SF36). The questionnaire is mainly based on previously published and validated questionnaires, which have been edited into an overall questionnaire and translated from English into French, Spanish, Dutch, Czech, Danish, Swedish. - SOPs related to blood sampling: Obtaining plasma, serum and buffycoat samples, labelling of the samples, and packing of the samples, boxinlays, storage of the samples, shipment of the samples. - Dietary Intervention SOP describing the strategies for conducting a 10-week intervention program consisting of a hypocaloric diet (about 600 kcal energy deficit per day), either with a low fat content (20-25% fat) or with a medium fat content (40-45% fat). The diet was based on local customs, and the subjects themselves purchased all food items. Dietary instructions were reinforced weekly. The SOP includes Guidance for Delivery of Intervention, Required Measurements relating to Dietary Intake (taking a diet history, conducting weighed food record and analysing the data), Proposed Method of achieving Dietary Intervention, Dietary Templates, and Recipe Suggestions. - Needle subcutaneous abdominal adipose tissue biopsy: SOP for taking the biopsy, handling and preparation of the biopsy, shipment of the biopsies. - SOP for preparation of the high fat liquid test meal. - SOP for validating, calibrating and conducting indirect calorimetry (Hood). - SOPs and flowchart of clinical investigation day, including blood sampling, energy and substrate metabolism in fasting and flowing a high fat test meal. - SOP and strategy for randomisation. - SOP for data entry and data transfer into the freeware programme EpiData The SOPs can be used as instrument for standardized implementation of various research procedures in future research projects. In addition aspects of these SOPs may be used as teaching material for pre and postgraduate students, in relation to project planning, method standardisation and formulation and specific methods. In addition aspects of the dietary intervention SOP may be used as a platform aiding clinicians and dieticians treating obese subjects, improving the strategy for implementing dietary recommendations. Any use of these SOPs require permission from the Project Steering Committee of the NUGENOB consortium. The NUGENOB consortium will have the full copyright for these SOPs.
Within two to three years after the completion of the NUGENOB project, the project consortium will explore the options for funding of a booklet to the European clinicians and dieticians treating obesity. A major aim of the NUGENOB project has been to identify the specific mechanisms behind the well know genetic predisposition for developing obesity, and to addressing the inter-individual variation in the response to a fat challenge and long-term hypocaloric low-fat or high-fat dietary intervention in relation to the specific genotypes of the obese subjects. These results will pave the way for development of new obesity taxonomy, in which new modes of classification of subtypes of obesity are based upon their specific genotypes, and the nutrient-gene interaction. The findings will further lead to the development of diagnostic tools, on the basis of the genotyping that can discriminate obese subjects with respect to predicted effectiveness of a long-term hypocaloric low-fat or high-fat dietary intervention allowing accurate targeting of this intervention and delineation of obese subjects in whom other means of intervention are needed. The concept of tailor made treatment based on genotyping is relatively new to the clinicians and dieticians treating obesity, and an solid understanding of the interaction between genetic and environmental factors will be important in order to relate to this concept. In addition the understanding of the role of genetic factors in the development of obesity and in the response to weight loss intervention will aid in setting realistic expectations of success on the individual level. These results will primarily aid clinicians and dieticians treating obese subjects, improving the platform for individualised dietary recommendations and implementation of new tailor made treatment regimes based on gene-environment interaction. In addition these results will aid obese European consumers, who will receive an optimised of obesity.
During the time course of the NUGENOB project a group of scientists have taken the initiative to generating a database of nutrient-sensitive genes expected to play a role in the development of obesity. Many studies pertaining to human as well as animals have addressed this topic, identifying genes for which the expression changes in response to energy restriction or change in diet composition. Generating an integrated overview of these findings will optimise the exploitation and implementation in future research. The aim is to make a database on genes for which there is a known nutrient-gene interaction and a putative role in obesity. The database will include additional information on the nature of the nutrient-gene interaction, and for each gene the database should include additional info on relationship to obesity and related phenotypes, as well as candidate gene variants. The database will include information on genes for which the expression is changed in response to calorie restriction, overfeeding or changes in diet composition (animal and human). Data from published experiments using quantitative gene expression and micro array based gene expression profiling will be included. In addition animal studies investigating the sensitivity or resistance to diet induced obesity in knock-out, knock-in or mutational models will be included. An important feature of the database will be a scoring system, summarizing the evidence for each gene being nutrient –sensitive. The scoring system will work on the overall level, and not involve scoring of individual papers. The system will take into account the number of studies conducted, the number of subjects included, the structure of the studies, etc. Preliminary versions of the database have been and will be used internally in NUGENOB and related FP6 projects in which the NUGENOB consortium will be integrated. When the build up of the database is completed a paper that describes the database including selected examples of candidate nutrient-sensitive genes will be submitted. The database will be launched as a public web-based database, and can be used as an instrument of identifying nutrient-sensitive candidate genes, and for interpreting data from future experiments. The database will be continuously updated and review papers addressing the current knowledge on nutrient-sensitive genes may be published yearly. The database will be of interest for scientists working in the area of obesity and nutrient-gene interaction. In addition the database will be of interest to the pharmaceutical industry and food industries. The FP6 Network of Excellence NuGO "European Nutrigenomics Organisation - linking genomics, nutrition and health research" www.nugo.org (coordinated by Ben van Ommen), as well as future projects under the 6th and 7th Framework Program are expected to incorporate the database. A preliminary version of the database is available in text form. The tools for setting up the actual database have been developed.
Within two to three years after the completion of the NUGENOB project, the project consortium will explore the options for funding of a booklet to the European Consumers. From a historical perspective, it is evident that mankind has for many decades been challenged by an environment of sparse food resources and high demand for physical activity. It has therefore been hypothesized that the selection pressure on genetic variants that favour body fat accumulation has therefore been high. Today mankind, at least in the westernised society, is faced with large food reserves and low physical activity. Thus the lack of fit between our genetic background and our current environment may thus be seen as one of the major causes of obesity. The message that obesity is in part determined by genetic factors is often interpreted by the consumers in such a way that they believe, that when they have these genetic predispositions they are destined to become obese and there is they can do to prevent this. The message could in fact be exactly the opposite. With a genetic predisposition to gain weight in the westernised society characterized by physical inactivity and high variety and accessibility of foods with a high palatability and a high energy density, the development of obesity may indeed be speculated to depend on the lifestyle that the individual creates for him or herself. Disseminating the knowledge gained from the NUGENOB project and other sources of information will guide the individuals with a genetic predisposition to obesity in how to handle and overcome this genetic predisposition, by creating a lifestyle, which prevents the development of obesity, and which promotes maintained weight loss in obese subjects.
The NUGENOB biobank includes: - Serum and plasma samples taken in the fasting state, and every hour during a 3-hour period following a high-fat test meal (95% of energy from fat, energy content equal to 50% estimated BMR) in 771 obese and 119 lean subjects. In obese subjects fasting serum and plasma samples were obtained following a 10-week intervention program consisting of a hypocaloric diet (~ 600 kcal energy deficit per day), either with a low fat content (20-25% fat) or with a medium fat content (40-45% fat). - Purified DNA in 96-well master plates (two sets) from all but 10 of the 771 obese and 119 lean subjects. Buffy coat samples from all but ~120 of the 771 obese and 119 lean subjects. Extracted mRNA from abdominal subcutaneous adipose tissue biopsies obtained in fasting before and after the 10-week dietary intervention in ~ 700 obese subjects. mRNA from biopsies obtained 3 hours after the test meal in a small group of obese subjects and mRNA from biopsies obtained in a small group of lean subjects. The biobank is ready for use for future collaborations as well as supplementary analyses within the NUGENOB project. A standardised set-up for the storage of the samples has been developed. All samples have been stored under optimal conditions, and are labelled with anonymous id-codes identifying project, research centre and subjects ID. The biobank will be of major interest for future research projects and is expected to be a cornerstone in several European as well as national research projects. The biobank will be of major interest for future research projects and is expected to be a cornerstone in several European as well as national research projects. The FP6 Network of Excellence NuGO "European Nutrigenomics Organisation - linking genomics, nutrition and health research" www.nugo.org (coordinated by Ben van Ommen), as well as future projects under the 6th and 7th Framework Program are expected to incorporate the biobank and the project as such. In order to use the samples from the biobank a synopsis defining the aim of the project, the samples needed, the analyses planned, the plans for publication must be presented to and approved by the NUGENOB Project Steering Committee.
Through the planning and the conducting of the NUGENOB project the consortium members have gained an detailed insight into the overall role of genetic and environmental factors in human obesity, an in dept knowledge regarding the current knowledge on nutrient-sensitive genes, the strategies for identifying nutrient sensitive genes, and the strategies for implementing these findings in the treatment and prevention of obesity. The current knowledge on these topics has been summarized in the book chapter "Nutrient-gene interactions in the control of obesity" written by C Verdich, K Clement, and TIA Sorensen. This book chapter will be published in the books "Functional foods: ageing and degenerative disease" and "Food, diet and obesity" by Woodhead Publishing. The book chapters will be of relevance for clinicians, scientist and industries working in the field of obesity research. The book chapter "Nutrient-gene interactions in the control of obesity" in Woodhead Publishing books was finalised in October 2003. This version will be printed in the book "Functional foods: ageing and degenerative disease" expected to be published in June 2004. The text will be updated before submission for the book "Food, diet and obesity".
Within two to three years after the completion of the NUGENOB project the project consortium will explore the options for funding of a booklet to the European pharmaceutical and food industry and other industries developing product related to the diagnosing or treatment of obesity. A major aim of the NUGENOB project is to identify the specific mechanisms behind the well know genetic predisposition for developing obesity, and to address the inter-individual variation in the response to a fat challenge and long-term hypocaloric low-fat or moderate-fat dietary intervention in relation to the specific genotypes of the obese subjects. These results will pave the way for development of a new obesity taxonomy, in which new modes of classification of subtypes of obesity are based upon their specific genotypes, and the nutrient-gene interaction. The findings will further lead to the development of diagnostic tools, on the basis of the genotyping that can discriminate obese subjects with respect to effectiveness of a long-term hypocaloric low-fat or moderate-fat dietary intervention allowing accurate targeting of this intervention and delineation of obese subjects in whom other means of intervention are needed. Providing the industry with updated knowledge related to the role of genetic factors and the gene environment interaction in obesity can inspire and guide the pharmaceutical industry in the testing of anti-obesity drugs, by integrating the knowledge on the role of genetic factors in the individual response to the treatment, undertaking a pharmaco-genomic approach. In addition these results can inspire and guide the pharmaceutical industry in the identification of new drug targets for obesity treatment. For the food industry, increased knowledge about the interaction between nutritional aspects and genetic factors and the possibility of tailor made treatment regimes may lay the ground for a production of a broader variety of ready-made foods and other products to be included in weight loss interventions.
The NUGENOB project has included a thorough search for candidate obesity and nutrient sensitive genes and gene variants. The genes have been identified by linkage analyses, genome wide scan, association studies, by studying changes in gene expression in adipose tissue in response to energy restriction and varying fat content of the diet, and finally by bioinformatics search. Several candidate genes and gene variants have been identified. The majority of the results are still unpublished, although three papers have been published before the end of the project period. These results can be exploited in future research projects addressing the role of these genes and gene variants in obesity and type II diabetes. Further identification of novel candidate genes for obesity holds the perspective of identifying new drug targets for the pharmacological treatment of obesity. The results will be of major interest for the scientific community in obesity research as well as to the pharmaceutical industry. Five papers have been published before the end of the project period. The identification of candidate genes and gene variants were undertaken by: Professor, Dr.Med.Sci. Oluf Borbye Pedersen, Steno Diabetes Center, Novo Nordisk A/S Denmark Niels Steensens Vej 2, DK-2820 Gentofte, Denmark Professor Philippe Froguel, MD, Ph D. Head of the Department of Human Genetics, Institute of Biology, CNRS 8090, Institut Pasteur de Lille, 1 rue Calmette, 59000 Lille, France.
Large between subject variations in weight loss has been observed for all types of obesity interventions. The response to weight loss intervention, as well as obesity per se, is recognised as a complex trait, determined by interplay between genetic and environmental factors. Studies in monozygotic twins, subjected to strictly controlled dietary intervention have illustrated the importance of genetic factors. However, only few specific gene variants have yet been identified as factors contributing to between-subject differences in weight loss. In addition the relatively low number of subjects included has limited previous studies. In the NUGENOB project 771 obese healthy subjects were randomised to a 10-week intervention program consisting of a hypocaloric diet (~ 600 kcal energy deficit per day), either with a low fat content (20-25% fat) or with a medium fat content (40-45% fat). All subjects have been genotyped for ~ 40 candidate gene variants in more than 20 genes assumed to be associated with obesity. The candidate genes have been selected based on their association with obesity (studies conducted within the framework of NUGENOB and bioinformatics). The identification of candidate genes has further been supported by studies of quantitative gene expression and gene expression profiling, identifying genes for which the expression is changed in response to the dietary intervention, and which show differential changes in expression in response to the two dietary regimens. The study will lead to the identification of specific gene variants affecting the overall weight loss success and showing an interaction with diet. In the future it will be possible to sub classify obesity according to genetic variation which have shown to play a role in the development of obesity and in the response to controlled weight loss intervention. Genotyping will then serve as a diagnostic tool in obesity, and genotype profiling will be an instrument for optimising the treatment, for instance diet composition during energy restriction, and for setting realistic weight loss expectations on the individual level. These results will primarily aid clinicians and dieticians treating obese subjects, improving the platform for dietary recommendations and other treatment regimens. Secondly, these results may be of interest for the industry producing customized chips for rapid and efficient genotyping as a diagnostic tool and as an instrument for tailoring and optimising dietary intervention. Thirdly these results may guide the way to the developing of new drugs used in the treatment of obesity. The results will guide future research in the identification of the specific pathways involved in the weight gain and weight loss, and in the identification of the specific mechanisms underlying the well documented role of genetic factors in response to dietary weight loss intervention. Finally and foremost, these results will aid the >135 millions obese European consumers, who will be able to select and receive more optimised dietary treatment for obesity. The results will be disseminated primary in scientific papers in a peer-reviewed journal. Manuscripts will be submitted se within a few months after the completion of the projects period.
Weight loss, weight loss composition, changes in fasting blood parameters, and dropout rate during a 10-week intervention program consisting of a hypocaloric diet (~ 600 kcal energy deficit per day), either with a low fat content (20-25% fat) or with a medium fat content (40-45% fat) is available for 771 obese subjects from 8 European cities. The diet was based on local customs, and the subjects themselves purchased all food items. Dietary instructions were reinforced weekly. The possible differences in the response to the two diets with respect to weight loss, weight loss composition (i.e. loss of fat mass or lean body mass), and changes in waist circumference are addressed. Further the effect of the two diets on insulin resistance, and blood lipids is addressed. These results can provide the basis for future standard recommendations for dietary intervention regimes in the treatment of obesity. The results will indicate whether an energy restricted diet of either low or the medium fat content is superior in promoting weight loss, fat loss, changes in waist circumference, and changes in insulin sensitivity and blood lipids. The results may lay the ground for specific recommendations for weight loss intervention in obese subjects with dyslipidaemia, insulin resistance, and abdominal obesity, which are all parameters associated with obesity related co-morbidities. These results will primarily aid clinicians and dieticians treating obese subjects, improving the platform for dietary recommendations. Secondly these results may be of interest for the food industry producing ready-made foods to be included in weight loss interventions. The results will guide the future research regarding the role of diet composition in weight loss. Finally and foremost, these results will aid the >135 million obese European consumers, who will be able to select and receive more optimised dietary treatment for obesity. The results will be disseminated primary in a scientific papers in a peer-reviewed journal. A manuscript was submitted several months prior to the completion of the project period, and is expected to be accepted for publication within a few months after the completion of the projects period.
Changes in Gene expression in subcutaneous abdominal adipose tissue in response to energy restricted diets with either medium or low fat content Changes in gene expression in subcutaneous abdominal adipose tissue in response to 10 week energy restricted diet (- 600 kcal/d) with either moderate or low fat content was examined in sub-samples of the NUGENOB study population. Quantitative gene expression for 40 genes related to signal transduction, glucose and lipid metabolism, mitochondria function and energy metabolism, transcription factors and co-factors were examined in 25 subjects from each diet group. Gene expression profiling was examined in 10-13 female subjects for each of the diet groups using a commercial Affymetrix chip (Affymetrix Inc., Santa Clara, CA, USA) with approximately 8,500 genes. In addition gene expression in response to energy restriction with low fat content in the diet was examined in 12 women using a custom made chip containing 600-700 genes related to the regulation of energy balance and fat metabolism. The results will be published in 3-5 papers in peer reviewed scientific journals. The results of these analyses can further be exploited in testing of the association between genotype, gene expression and at risk phenotypes. In addition, the data may be used to explore the association between changes in gene expression and previous or subsequent changes in body weight, based on the changes in weight prior to or following the dietary intervention. Such exploitation is expected to be undertaken within the NUGENOB consortium. In addition, the data on changes in gene expression can be linked to changes in blood variables analysed within the NUGENOB project, or in relation to future collaboration with other research entities. Purified adipose tissue RNA obtained at baseline and after the 10 week dietary intervention is available for most of the subjects who completed the intervention. Thus, more large scale analyses of changes in gene expression in subpopulations of subjects with specific phenotypic or genotypic profile can be made, provided that financial support can be obtained. The identification of nutrient-sensitive genes, for which the expression changes in response to energy restriction and changes in dietary fat content is expected to lead to the identification of new candidate genes/pathways involved in the regulation of adipose tissue fat accumulation and lipolysis, signal transduction, lipid and glucose metabolism etc. Further these results may lead to the identification of markers/determinants of weight loss. The results on changes in adipose tissue gene expression in response to energy restriction and changes in dietary fat content, the possibility of linking data on gene expression to genotypic and phenotypic characteristics and the possibility of conducting additional analyses based on the biobank of purified adipose tissue mRNA will be of major interest for future research projects and is expected to be a cornerstone in several European as well as national research projects. The FP6 Network of Excellence NuGO "European Nutrigenomics Organisation - linking genomics, nutrition and health research" http://www.nugo.org (coordinated by Ben van Ommen), as well as future projects under the 6th and 7th Framework Program are expected to incorporate the results on gene expression and nutrient-sensitive genes derived from the NUGENOB project, and to consider exploding the options for making additional analyses based on the mRNA biobank. Further identification of novel candidate genes and candidate pathways involved in the development of obesity holds the perspective of identifying new drug targets for the pharmacological treatment of obesity. The results will be of major interest for the scientific community in obesity research as well as to the pharmaceutical industry. Purified adipose tissue RNA obtained at baseline and after the 10 week dietary intervention is available for most of the subject who completed the intervention. Thus, more large scaled analyses of changes in gene expression in subpopulations of subjects with specific phenotypic or genotypic profile can be made, provided that financial support can be obtained. The gene expression analyses were undertaken by: Dominique Langin, D.V.M., Ph.D.Directeur de recherches, INSERM U317,Institut Louis Bugnard Bat. L3, CHU Rangueil, F-31403 Toulouse Cedex 4 Professor, Dr.Med. Peter Arner, The Lipid Laboratory at the Dept. of Medicine Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden.