Variation in dietary intake and DNA methylation: The possibility of a remnant thrifty epigenotype in populations remaining at…

Anthropologists hypothesize a human 'thrifty genotype' allowed ancestral populations to store energy when food was bountiful and survive famine. LEP, which produces leptin, an adipocyte-synthesized protein regulating appetite, energy storage and expenditure, is a major candidate gene; however, no allelic variant of LEP seems to explain the range of leptin expression among populations. DNA methylation responds to nutritional programming, potentially modulating gene expression to provide flexibility of adaptive responses in unstable nutritional environments. We hypothesize differential epigenetic signatures among populations suggest a 'thrifty epigenotype.' We examine the relationship of dietary intake to DNA methylation percentage at functional CpG sites (4 & 7) of LEP core promoter (C/EBPαTBS and TATA) and serum leptin levels in 182 individuals from two distinct populations: Siberian Buryat and Kansas Mennonite. Serum leptin is higher in females than males and lower in indigenous Buryat (M2.54/Fe7.3ng/ml) than US Mennonite (M6.4/Fe 16.0ng/ml). Mean percent DNA methylation at functional CpGs is greater in Buryat (62/38) than Mennonite (55/35) (p<0.001 for all per Mann-Whitney U). Macronutrient percent of diet was greater in carbohydrate and protein for Mennonite and higher in fat for Buryat. After log transforming appropriate variables, dietary percent of macronutrients were correlated with DNA methylation, with results significant in Buryat only. Percent of dietary protein correlates with functional CpGs (r=.375/p=0.006 and r= .409/p=0.003). Serum leptin correlates with percent fat and negatively with percent carbohydrate in Buryat only (r=.330/p=0.017 and r=-.367/p=0.008 respectively). LEP methylation correlating with differential energy intake in Buryat only implies a remnant thrifty epigenotype. Funding: Wenner Gren Foundation for Anthropological Research, Western Washington University, and State of Kansas Attorney Settlement Fund.