Obesity is a major cause of morbidity and mortality in the USA and worldwide. Identification of genes increasing susceptibility to obesity would impact public health by providing basic biological and clinical data about development and treatment of obesity and by advising specific lifestyle changes in at-risk individuals. Obesity is a complex disease with clear genetic and environmental risk factors, however few actual genes leading to this increased risk have been identified and the underlying mechanisms by which obesity develops remain obscure. Our broad long-term objectives are to identify genetic variants increasing susceptibility to body mass index, adiposity, and weight gain and to characterize the interactions between these genetic variants and behavioral factors. We propose to study a large sample of Filipino women for which detailed anthropometric, environmental, diet and physical activity data have been collected for the past 22 years as part of the Cebu Longitudinal Health and Nutrition Survey (CLHNS). In the current application, we propose genetic analysis of the quantitative and longitudinal traits of body mass index, adiposity, and weight gain using selected genes in the CLHNS women. We will select and prioritize genes based on functional data, cis-acting expression quantitative trait loci correlated with obesity in mice, and prior evidence of association in other human populations. Recent technical advances in high-throughput genotyping, single nucleotide polymorphism (SNP) discovery and haplotype map (HapMap) construction provide unprecedented tools enabling more thorough analysis of selected genes than was previously possible. We propose to perform in- depth association analysis of 12,000 SNPs in 720 selected genes by evaluating common and likely functional SNPs in a large, well-characterized sample set of 1896 women. We will evaluate association with longitudinal measures of weight gain and we will evaluate interactions between genetic variants, diet composition and physical activity measures. Promising associations will be evaluated in other large cohort studies, to identify the most likely susceptibility variants. We strongly believe that a detailed study of genetic factors and their interactions is an essential step to identifying targeted obesity prevention strategies and treatments.
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