|Lai, Chao Qiang|
|SMITH, CAREN - Tufts University|
|LEE, YU-CHI - Tufts University|
|CORELLA, DOLORES - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|HOPKINS, PAUL - University Of Utah|
|HIDALGO, BERTHA - University Of Alabama|
|ASLIBEKYAN, STELLA - University Of Alabama|
|PROVINCE, MICHAEL - Washington University|
|ABSHER, DEVIN - Hudsonalpha Institute For Biotechnology|
|ARNETT, DONNA - University Of Kentucky|
|TUCKER, KATHERINE - University Of Massachusetts|
|ORDOVAS, JOSE - Tufts University|
Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/28/2018
Publication Date: 6/12/2018
Citation: Lai, C., Smith, C.E., Parnell, L.D., Lee, Y., Corella, D., Hopkins, P., Hidalgo, B.A., Aslibekyan, S., Province, M.A., Absher, D.M., Arnett, D.K., Tucker, K.L., Ordovas, J.M. 2018. Epigenomics and metabolomics reveal the mechanism of the APOA2-saturated fat intake interaction affecting obesity. American Journal of Clinical Nutrition. 108:188-200.
Interpretive Summary: Obesity is a product of genetic and environmental factors. Among the latter, diet is a most important one. We refer to these combinations of genetic and dietary factors as ‘gene-diet interactions.' In earlier studies, we found and replicated an interaction between dietary fat and the genetic factor, APOA2 m265, for the outcome of body weight. Specifically, greater consumption of saturated fats (found mostly in foods of animal origin) was associated with greater weight in people who carried this genetic factor. In the current study, we sought to gain an understanding of the biological mechanisms driving this interaction. We selected participants in three cohorts according to this genetic factor and conducted a series of molecular analyses (epigenetics, transcriptomics, and metabolomics). Our analyses identified an epigenetic mark that is associated with saturated fat intake exclusively in subjects who carry this genetic factor. Moreover, this finding was associated with lesser expression of the gene, APOA2, and lower concentrations in blood of metabolites related to appetite control. These discoveries could explain why individuals with this genetic factor, consume more food and have a higher body mass index. These findings increase our understanding of how genetics and diet act together to promote weight gain, and may eventually have implications for dietary recommendations that make use of genetic information.
Technical Abstract: Apolipoprotein A-II (APOA2) is a major constituent of high-density lipoproteins (HDL) with an undefined biological role. A putative functional variant, -265 T>C (rs5082) within the promoter of the APOA2 gene has been shown consistently to interact with saturated fat (SFA) intake to influence risk of obesity in several studies. Our objective was to take an integrative omics approach to gain insight into the molecular basis of this interaction. First, we conducted an epigenome-wide scan on 40 participants carrying the rs5082 CC genotype consuming either a low (<22 g/d, n=20) or a high (>/=22 g/d, n=20) SFA diet, and on 40 participants with the TT genotype, matched for SFA intake, age, gender, and diabetes status. We identified a methylation site (cg04436964) mapping about 26 kb upstream of the APOA2 gene that exhibited differential differences between CC and TT participants consuming the high SFA diet, but not among those consuming the low SFA diet. We then validated these findings in two independent populations (Framingham Heart Study, n=243; and the GOLDN study, n=379). Next, using transcriptomic analysis of whole blood, we then showed that methylation at cg04436964 is negatively correlated with APOA2 expression in participants consuming a high SFA diet. Furthermore, CC carriers had a lower expression of APOA2 compared to those with the TT genotype in a high SFA diet, whereas APOA2 expression did not differ by genotype in subjects consuming a low SFA diet. Finally, metabolomics analysis identified four pathways that were overrepresented in metabolite differences between CC and TT genotype under high SFA intake. Among them, two pathways (tryptophan and branched chain amino acids) were linked to cg0443694 differences between the CC and the TT genotypes in participants consuming a high SFA diet. Our results strongly support that epigenetic status of APOA2 is associated with SFA intake and APOA2-265T>C genotype, leading to APOA2 expression difference between APOA2 genotype in a high SFA diet, and modulating the kynurenine pathway of tryptophan metabolism and branched chain amino acid metabolism. These findings support 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.