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.

DNA methylation in human lipid metabolism and related diseases

“…Lai et al [ 40 ] showed that eight methylation sites encompassing different genes LPP encoding lipoma-preferred partner, APOA5 encoding apolipoprotein A-V, SREBF1 , ABCG1 , and CPT1A were associated with triglyceride postprandial responses (TG-PPL), an independent CVD risk factor, after consuming a high-fat meal [ 40 ]. These genes had been previously found to be associated with triglyceride and/or HDL-C levels [ 15 , 23 ▪▪ , 24 ▪ , 25 , 38 ▪▪ ].…”

The challenge of detecting genotype-by-methylation interaction: GAW20

“…The GOLDN study was designed with 2 arms: a high-fat meal challenge and fenofibrate treatment for 3 weeks to identify genetic determinants of lipid response to 2 interventions. A total of 1053 individuals met all eligibility requirements, while the data in use for lipids at visits 1 and 2, at the start of the trial, and at visits 3 and 4, at the end of the trial, that have genotype and methylation were smaller [ 8 – 12 ]. The GAW20 simulated data [ 7 ] followed the structure of real data, by simulating the effects of a lipid-lowering medication in interaction with methylation by affecting TG levels.…”

Critical Role of the Human ATP-Binding Cassette G1 Transporter in Cardiometabolic Diseases

“…The association of DNA methylation at ABCG1 locus in whole blood DNA with plasma TG and HDL-C levels was replicated in several studies recapitulated in Table 1 which were conducted in the Botnia prospective study (cg06500161, TG, n = 258) [ 80 ], the Rotterdam study (cg06500161, TG and HDL-C, n = 1485) [ 78 ], the Framingham heart study (FHS) and prospective investigation of the vasculature in uppsala seniors study (PIVUS) (cg06500161, TG and HDL-C, cg27243685 and cg01176028, TG, n = 2036) [ 79 ] and in Canadian familial hypercholesterolemia patients (CpGC3, TG, HDL-C and TC, n = 98) [ 81 ]. In addition, Lai et al reported that methylation of the ABCG1 CpG site (cg06500161) in blood CD4 + T cells from 979 subjects of the genetics of lipid lowering drugs and diet network (GOLDN) study was significantly associated with postprandial hypertriglyceridemia (PPHT) after consumption of a high-fat test meal [ 82 ]. Indeed, an increased methylation at ABCG1 was correlated with an increased PPHT response.…”