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There is limited evidence on the role of genetic and environmental factors in the etiology of childhood obesity, a major health problem worldwide.The Gene-Diet Attica Investigation on childhood obesity (GENDAI) evaluates the contributions to and pivotal interactions of genetic, dietary and physical activity variables on children's weight. We describe the design, methodology, and present preliminary data. So far, 920 participants have been enrolled and the final projected sample is 1000 fifth-and sixth-grade students from selected elementary schools in Attica (10–14 years). In this school-based cross-sectional study, more than 400 variables describing anthropometric, dietary, clinical, genetic, sociodemographic and other lifestyle characteristics were collected from participating children and their families.Increased body mass index was identified in 39.3% of subjects (30.5% overweight and 8.8% obese), with males presenting a more unfavorable metabolic profile, i.e., higher blood lipids, glucose, and insulin, compared to females. Normal-weight children had a significant advantage when compared to all children of increased weight in terms of lipid profile and insulin, as well as behaviors examined. Specifically, normal-weight children exhibited less skipping of meals and less sedentary activities.The overall high prevalence of overweight and obesity in the current population is significant and underscores the need for environmental and genetic information that will shed light on the phenomenon of childhood obesity.