Gene-diet interactions affect the risk of metabolic diseases, like obesity and type 2 diabetes, but the mechanisms underlying these interactions are not understood. We applied multi-omics approaches to investigate the mechanistic foundations of one of the most consistently replicated gene-diet interactions, that of saturated fat intake (SFA) and APOA2 genotype on obesity, beginning in the Boston Puerto Rican Health Study. We further validated the findings in two additional populations: the Genetics of Lipid Lowering Drugs and Diet Network and the Framingham Heart Study. Transcription and metabolomics analyses were also conducted to determine the relationship between epigenetic status, APOA2 mRNA expression, and blood metabolites. Our findings from three populations of diverse ancestries showed that that epigenetic status of the APOA2 regulatory region was associated with SFA intake and APOA2 -265T&gt;C genotype, leading to differential diet-dependent and genotype-dependent APOA2 expression. As appropriate for a gene-diet interaction linked to the metabolically disruptive condition of obesity, we also uncovered plausible dysregulation of select metabolic pathways. These findings identify potential mechanisms by which this highly reproducible gene-diet interaction influences obesity risk, and contribute new insights to ongoing investigations of the relationship between SFA and human health.

Epigenetic and metabolomic signature of gene-diet interaction on metabolic diseases

256th National Meeting (2018)

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