Obesity is among the most prevalent nutritional disorders in industrial societies. Approximately 27% of 6-11 year old and 21% of 12-17 year old individuals in the United States are currently obese, and 30-40% of obese adults were obese adolescents. Thirty four million adult Americans are obese. Obesity in adults accounts for over 80% of type II diabetes mellitus, and a substantial fraction of hypertension and disorders of lipid metabolism. Relative distribution of fat (abdominal:pelvic ratio) also plays a role in obesity-related morbidity/mortality. As much as 80% of the risk of obesity and a significant component of distribution of body fat may be due to genetic factors. None of these genetic factors has been identified. In mice, clear examples of Mendelian genetic transmission of obesity have been described and mapped to specific chromosome regions. Many aspects of the phenotype of these animals - most notably excess food intake and high metabolic efficiency - are similar to those encountered in obese humans. In humans, the Prader-Labhart-Willi syndrome (PW) is associated with extreme obesity of early onset. The high homology between relevant portions of the mouse and human genomes, makes it plausible that one or more allelic variants of the human homologues of these mouse genes contributes to obesity in man. We propose to examine human pedigrees in which obesity (as measured by body mass index) is segregating, for linkage to RFLP's from regions of the human genome syntenic with regions of the mouse genome where 5 obesity genes have been mapped, and to RFLP's from 15qll-13 where the P-W locus has been mapped. Measurements of abdominal and hip circumference will also be obtained in these pedigrees. 100 families (1100 individuals) will be characterized from both relatively inbred populations ( e.g. Pima Indians of Arizona; residents of Maracaibo, Venezuela), as well as from families with obesity in urban centers in the USA. Both child and adult probands will be used to identify families segregating an obese phenotype. Lymphoblastoid cell lines will be prepared on members of these pedigrees, creating a genetic resource in perpetuity. Tests for allelic association (linkage disequilibrium) affected sib-pair and genetic linkage analysis will be performed. Ultimately, this genetic resource can also be used to search for loci linked to specific aspects of phenotype using linked clones spanning the genome.
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