Introduction. An increased energy intake and/or reduced energy expenditure can lead to massive overweight, which has reached epidemic proportions in modern human society. Obesity is associated with numerous health risks, including cardiovascular diseases, diabetes mellitus, and certain types of cancer, reproductive defects and others. Abnormal eating behaviour, e.g., bulimia nervosa and binge eating disorder can be associated with obesity. The evidence of a significant contribution of genetic factors to obesity and eating disorders has recently emerged from study of animal models and single human families. However, the genes for most forms of obesity or for any kind of eating disorders have not yet been identified. Thus, the identification of the genes of pleiotropic pathological effects related to eating behaviour and/or body weight regulation is of significant importance in different disciplines of medical biology.
Goals and Research.
It is planned to identify genes causing or predisposing to obesity and related disorders and elucidate molecular pathways leading to both physiological and behavioural dysfunction in food intake. The specific aims include:
1) the chromosomal locus and corresponding mutant gene will be mapped and isolated for a monogenic form of very severe obesity and bulimia found in a genetic isolate;
2) susceptibility genes are to be identified in several candidate chromosomal regions with a main focus on a major locus on chromosome 10p in a large set of families with suggestive linkage to this region;
3) direct screening of candidate genes for mutations and polymorphisms in individuals with either early or adult onset moderate to severe obesity in geographically and ethnically different populations. The methods of linkage analysis in pedigrees, family- based (parent offspring trio, sib-pair approach, transmission/disequilibrium tests) and population based (case-control) association analysis, fine mapping and positional cloning will be used to accomplish the goals of the proposal. In addition, to investigate the biological effect of the mutant genes the tissues and cells from members of pedigrees with monogenic obesity will be collected. The regulation of gene expression and response to energy metabolism factors will be investigated in these specimens. Justification.
This collaborative proposal is justified by three major conditions.
(1)Experiences of the NIS team (Dr Rogaev E. et al) in strategies of positional cloning of human disease genes and epidemiological, genetic and medical analysis of diseases in human populations (Dr Ginter E. et al and Koshechkin et al); INTAS (Dr Hebebrand group) in genetic, biochemical and endocrinological analysis and (DrSchalling group) in animal models and genetic study of obesity and anorexia. It is planned that Dr Rogaev will contribute strongly to fine mapping and cloning of the candiate-genes in families found by all teams. Dr Hebebrand and Dr Schalling will evaluate many cellular, genetic and biochemical parameters in samples from patients and healthy individuals provided by NIS collaborators;
(2)Unique resources of families and populations will be unified in the consortium. Both NIS and INTAS groups have collected family material and the collection will be extended. The genetic isolate and large families (> 80 individuals in one pedigree) with monogenic obesity and bulimia recently described by the NIS groups are unique in the field. One of the worldwide largest collections of families and sib-pairs with suggestive oligogenic/ poligenic obesity and eating disorders was obtained by the INTAS group. Several chromosomal candidate regions, including a major locus within a 15cM region on chromosome 10p, have been identified. The INTAS group has confirmed the 10p locus. However, to clone the susceptible genes, fine mapping of these loci and consequently, additional families from different ethnic populations are crucial for success;
(3) The genetic association approach in case-control studies requires replication of the results in different populations. The collaborative groups will provide the samples from diverse populations. Significance. Obesity is a frequent disorder with high risk of morbidity and mortality and multiple medical, psychological and socio-economical implications. Identification of the genes and its products will help to elucidate the mechanisms of control of food intake and body mass and make possible the development of diagnostic and specific pharmacological interventions.