Lai Chao-Qiang, Wojczynski Mary K, Parnell Laurence D, Hidalgo Bertha A, Irvin Marguerite Ryan, Aslibekyan Stella, Province Michael A, Absher Devin M, Arnett Donna K, Ordovás José M
USDA Agricultural Research Service, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.
Department of Genetics, Washington University School of Medicine, St. Louis, MO.
J Lipid Res. 2016 Dec;57(12):2200-2207. doi: 10.1194/jlr.M069948. Epub 2016 Oct 24.
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), 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.
餐后血脂异常（PPL），即摄入高脂餐后血浆甘油三酯（TG）浓度升高，是心血管疾病（CVD）的独立危险因素。个体对高脂餐的反应差异很大，这取决于遗传和生活方式因素。然而，只有少数基因位点与TG-PPL反应相关。可遗传的表观基因组变化可能是个体间PPL差异无法解释的重要原因。我们对979名受试者进行了全表观基因组关联研究，这些受试者的CD4 T细胞进行了DNA甲基化检测，他们作为脂质降低药物和饮食网络研究的一部分接受了高脂餐挑战。在全表观基因组水平上，包含LPP、CPT1A、APOA5、SREBF1和ABCG1五个基因的八个甲基化位点与PPL反应显著相关（P < 1.1×10），但在调整基线TG水平后，没有甲基化位点达到全表观基因组显著性。LPP、APOA5、SREBF1和ABCG1的甲基化水平较高，CPT1A甲基化水平较低与TG-PPL反应增加相关。这些与PPL相关的甲基化位点，也与空腹TG相关，与我们之前全基因组关联研究确定的基因位点的遗传贡献（4.5%）相比，在PPL和空腹TG中占更大比例的表型变异（14.9%）。总之，表观基因组是PPL变异的重要贡献者，这有可能用于调节PPL并降低CVD风险。
