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Background: The Agouti-related protein (AGRP), an appetite modulator, induces hyperphagia when administered intracerebroventricularly or when overexpressed in transgenic mice. Exogenous administration of AGRP in rodents predisposes to high fat and high sugar intakes. Objective: The objective was to examine the potential associations of 2 ethnic-specific polymorphisms in the AGRP gene (Ala67Thr in whites and - 38C>T in blacks) in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study. Design: We examined the effect of the 2 polymorphisms in the AGRP gene on self-reported macronutrient intakes in 478 white and 272 black participants in the HERITAGE Family Study. Results: Both AGRP polymorphisms showed a significant association with energy intake. In whites, a smaller proportion of total energy was derived from fat by the Ala67Thr heterozygotes ([bar.X] [+ or -] SEM: 29.4 [+ or -] 0.7%) than by the Ala67Ala homozygotes (31.5 [+ or -] 0.5%; P = 0.009), mainly because of a lower intake of saturated (P = 0.06) and monounsaturated (P = 0.01) fats by the Ala67Thr heterozygotes. The percentage of energy from carbohydrates was 2.6% greater in the Ala67Thr heterozygotes (55.1 [+ or -] 1.1%) than in the Ala67Ala homozygotes (52.5 [+ or -] 0.6%; P = 0.03). In blacks, protein intake was associated with the -38C>T promoter polymorphism. T/T homozygotes had a significantly lower protein intake than did the C-allele carriers (C/C: 16.8 [+ or -] 0.4%; C/T: 17.2 [+ or -] 0.2%; T/T: 15.4 [+ or -] 0.7%; P = 0.04). No significant differences in total energy and alcohol intakes existed between genotype groups in blacks or whites. Conclusions: The present study suggests that 2 ethnic-specific AGRP variants, previously shown to be associated with leanness in the HERITAGE Family Study, are also associated with macronutrient intake. KEY WORDS Agouti-related protein, AGRP, Ala67Thr, -38C>T, energy intake, macronutrient intake, food-frequency questionnaire, Quebec Family Study

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