Epigenome-wide association study of triglyceride postprandial responses to a high-fat dietary challenge

Abstract

Postprandial lipemia (PPL), the increased plasma TG concentration after consuming a high-fat meal, is an independent risk factor for CVD. Individual responses to a meal high in fat vary greatly, depending on genetic and lifestyle factors. However, only a few loci have been associated with TG-PPL response. Heritable epigenomic changes may be significant contributors to the unexplained inter-individual PPL variability. We conducted an epigenome-wide association study on 979 subjects with DNA methylation measured from CD4⁺ T cells, who were challenged with a high-fat meal as a part of the Genetics of Lipid Lowering Drugs and Diet Network study. Eight methylation sites encompassing five genes, LPP, CPT1A, APOA5, SREBF1, and ABCG1, were significantly associated with PPL response at an epigenome-wide level (P < 1.1 × 10^-7), but no methylation site reached epigenome-wide significance after adjusting for baseline TG levels. Higher methylation at LPP, APOA5, SREBF1, and ABCG1, and lower methylation at CPT1A methylation were correlated with an increased TG-PPL response. These PPL-associated methylation sites, also correlated with fasting TG, account for a substantially greater amount of phenotypic variance (14.9%) in PPL and fasting TG (16.3%) when compared with the genetic contribution of loci identified by our previous genome-wide association study (4.5%). In summary, the epigenome is a large contributor to the variation in PPL, and this has the potential to be used to modulate PPL and reduce CVD.

Keywords: DNA methylation; apolipoproteins; atherosclerosis; diet and dietary lipids; dietary fat; lipoproteins; postprandial lipemia; triglycerides.

Fig. 1.

Distribution of P values [−log10(P value)] from the epigenome-wide association analysis with AUC phenotype (n = 979). Eight CpG sites reached epigenome-wide significance P < 1.1 × 10⁻⁷ (above the dashed line).

Fig. 2.

Integrated regional overlap of EWAS signals (open squares) and GWAS signals (solid circles) at the APOA5. The x-axis displays the physical position of CpG sites and SNPs within 50 kb upstream and downstream of the EWAS signal of cg12556569 at APOA5; the y-axis displays −log10(P value) of the association.