GENETIC EPIDEMIOLOGY OF BLOOD LIPIDS AND OBESITY--NGHS

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DESCRIPTION: (Adapted from Investigator's Abstract) This project has two major objectives. The first is to examine the role of genetic variation in the human homologues of the mouse obese, fat and agouti genes as well as in tumor necrosis factor alpha, cholecystokinin, and neuropeptide Y for the determination of interindividual variation in measures of obesity, measures of body morphology, and changes in adiposity in a large biracial sample of girls participating in the National Heart, Lung, and Blood Institute Growth and Health Study (NGHS). The measures of obesity include BMI and skinfolds, and the measures of body morphology are indicators of regional fat distribution, such as waist/hip ratio. The investigators will identify polymorphic variation at the candidate loci by molecular screening, developing PCR-based assays for genotyping this variation, and estimating allele frequencies at these loci in black and white girls. The association between variation at these loci and measures of adiposity at each annual visit will be examined, as will the changes in adiposity over the entire 9-year follow-up period of the main NGHS. Since the products of several of these obesity candidate genes are putative satiety factors, the investigators also will examine the association of variation at these loci with the total caloric content of each meal as well as with behavioral aspects of eating such as frequency of eating/snacking and the total amount of fat ingested per day. The second major objective is to carry out a detailed analysis of genes involved in maintaining the homeostatic relationship between triglycerides and HDL cholesterol, to further understand the apparent black-white differences in responses of triglyceride and HDL-C levels to increases in adiposity during puberty. The genes of interest are LCAT, CETP, HL and LPL. While adiposity increased to a greater extent in black girls than in white girls from ages 9-10 years to 15-16 years, black girls continue to have higher levels of HDL. There is a significant race-adiposity interaction regarding triglycerides with the levels in black girls increasing to a lesser extent than in white girls who are experiencing the same increase in adiposity. The investigators hypothesize that part of this difference in blood lipid levels may be due to differences in the frequency of variation at the LCAT, CETP, HL, and/or LPL loci. They will test this hypothesis by contrasting the frequencies and allelic effects of variation at these loci in black and white girls. The proposed study is nested within the ongoing NGHS as an ancillary study in the final year of NGHS. This ancillary mechanism offers an opportunity to utilize extensive longitudinal data which encompass anthropometric, dietary, behavioral, and environmental measures collected on this cohort for 10 years. Since the goal of the main NGHS is to investigate racial divergence in adiposity development during pubescence, this database is particularly rich for the investigation of obesity development.