Epigenomics and metabolomics reveal the mechanism of the APOA2 -saturated fat intake interaction affecting obesity

Chao Qiang Lai, Caren E. Smith, Laurence D. Parnell, Yu Chi Lee, Dolores Corella, Paul Hopkins, Bertha A. Hidalgo, Stella Aslibekyan, Michael A. Province, Devin Absher, Donna K. Arnett, Katherine L. Tucker, Jose M. Ordovas

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37 Citations (SciVal)


Background The putative functional variant -265T>C (rs5082) within the APOA2 promoter has shown consistent interactions with saturated fatty acid (SFA) intake to influence the risk of obesity. Objective The aim of this study was to implement an integrative approach to characterize the molecular basis of this interaction. Design We conducted an epigenome-wide scan on 80 participants carrying either the rs5082 CC or TT genotypes and consuming either a low-SFA (<22 g/d) or high-SFA diet (≥22 g/d), matched for age, sex, BMI, and diabetes status in the Boston Puerto Rican Health Study (BPRHS). We then validated the findings in selected participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study (n = 379) and the Framingham Heart Study (FHS) (n = 243). Transcription and metabolomics analyses were conducted to determine the relation between epigenetic status, APOA2 mRNA expression, and blood metabolites. Results In the BPRHS, we identified methylation site cg04436964 as exhibiting significant differences between CC and TT participants consuming a high-SFA diet, but not among those consuming low-SFA. Similar results were observed in the GOLDN Study and the FHS. Additionally, in the FHS, cg04436964 methylation was negatively correlated with APOA2 expression in the blood of participants consuming a high-SFA diet. Furthermore, when consuming a high-SFA diet, CC carriers had lower APOA2 expression than those with the TT genotype. Lastly, metabolomic analysis identified 4 pathways as overrepresented by metabolite differences between CC and TT genotypes with high-SFA intake, including tryptophan and branched-chain amino acid (BCAA) pathways. Interestingly, these pathways were linked to rs5082-specific cg04436964 methylation differences in high-SFA consumers. Conclusions The epigenetic status of the APOA2 regulatory region is associated with SFA intake and APOA2 -265T>C genotype, promoting an APOA2 expression difference between APOA2 genotypes on a high-SFA diet, and modulating BCAA and tryptophan 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 relation between SFA and human health. This study was registered at clinicaltrials.gov as NCT03452787.

Original languageEnglish
Pages (from-to)188-200
Number of pages13
JournalAmerican Journal of Clinical Nutrition
Issue number1
StatePublished - Jul 1 2018

Bibliographical note

Funding Information:
The authors’ responsibilities were as follows—C-QL and JMO: conceived and designed the study; C-QL, CES, LDP, Y-CL, DA, and DC: acquired the data; C-QL, CES, LDP, MAP, and KLT: analyzed and interpreted the data; JMO and C-QL: performed statistical analysis and drafted the manuscript; C-QL, CES, LDP, JMO, and KLT: critically revised the manuscript for intellectual content; JMO, KLT, and DKA: provided funding and supervision; and all authors: read and approved the final manuscript. The Genotype-Tissue Expression Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described here were obtained from the Genotype-Tissue Expression Portal on 10 January 2018. None of the authors had a conflict of interest. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture. The USDA is an equal opportunity provider and employer.

Funding Information:
This work was funded by the US Department of Agriculture, under agreement no. 8050-51000-098-00D, by National Heart, Lung, and Blood Institute grants U01-HL072524-04 and R01HL104135, and NIH grants P01 AG023394, P50 HL105185, and R01 AG027087. CES is supported by K08 HL112845. Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the US Department of Agriculture.

Publisher Copyright:
© 2018 American Society for Nutrition.


  • APOA2
  • branched-chain amino acid metabolism
  • epigenomics
  • gene-diet interaction
  • metabolomics
  • obesity
  • satiety
  • transcription
  • tryptophan metabolism

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics


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