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Abstract：
Lipid traits (total, low-density and high-density lipoprotein cholesterol, and triglycerides) are risk factors for cardiovascular disease. DNA methylation is not only an inherited but also modifiable epigenetic mark that has been related to cardiovascular risk factors. Our aim was to identify loci showing differential DNA methylation related to serum lipid levels. Blood DNA methylation was assessed using the Illumina Human Methylation 450 BeadChip. A two-stage epigenome-wide association study was performed, with a discovery sample in the REGICOR study (n = 645) and validation in the Framingham Offspring Study (n = 2,542). Fourteen CpG sites located in nine genes (SREBF1, SREBF2, PHOSPHO1, SYNGAP1, ABCG1, CPT1A, MYLIP, TXNIP and SLC7A11) and 2 intergenic regions showed differential methylation in association with lipid traits. Six of these genes and 1 intergenic region were new discoveries showing differential methylation related to total cholesterol (SREBF2), HDL-cholesterol (PHOSPHO1, SYNGAP1 and an intergenic region in chromosome 2) and triglycerides (MYLIP, TXNIP and SLC7A11). These CpGs explained 0.7%, 9.5% and 18.9% of the variability of total cholesterol, HDL cholesterol and triglycerides in the Framingham Offspring Study, respectively. The expression of the genes SREBF2 and SREBF1 was inversely associated with methylation of their corresponding CpGs (P-value = 0.0042 and 0.0045, respectively) in participants of the GOLDN study (n = 98). In turn, SREBF1 expression was directly associated with HDL cholesterol (P-value = 0.0429). Genetic variants in SREBF1, PHOSPHO1, ABCG1 and CPT1A were also associated with lipid profile. Further research is warranted to functionally validate these new loci and assess the causality of new and established associations between these differentially methylated loci and lipid metabolism.
摘要：
脂质性状（总，低密度和高密度脂蛋白胆固醇，和甘油三酯）是心血管疾病的危险因素。DNA甲基化不仅是一种遗传的，而且是与心血管危险因素有关的可修饰的表观遗传标记。我们的目的是鉴定显示与血清脂质水平相关的差异DNA甲基化的基因座。使用Illumina人甲基化450BeadChip评估血液DNA甲基化。进行了两阶段全表观基因组关联研究，在REGICOR研究中发现样本(n=645)，在Framingham后代研究中验证(n=2,542)。位于9个基因(SREBF1,SREBF2,PHOSPHO1,SYNGAP1,ABCG1,CPT1A,MYLIP,TXNIP和SLC7A11）和2个基因间区域显示与脂质性状相关的差异甲基化。其中6个基因和1个基因间区域是新发现，显示与总胆固醇（SREBF2）相关的差异甲基化，HDL-胆固醇（PHOSPHO1，SYNGAP1和2号染色体中的一个基因间区域）和甘油三酯（MYLIP，TXNIP和SLC7A11)。这些CpG解释了0.7%，总胆固醇变异性的9.5%和18.9%，Framingham后代研究中的HDL胆固醇和甘油三酯，分别。在GOLDN研究的参与者（n=98）中，SREBF2和SREBF1基因的表达与其相应CpG的甲基化呈负相关（P值分别为0.0042和0.0045）。反过来,SREBF1表达与HDL胆固醇直接相关（P值=0.0429）。SREBF1、PHOSPHO1、ABCG1和CPT1A的遗传变异也与血脂谱相关。需要进一步的研究以在功能上验证这些新基因座，并评估这些差异甲基化基因座与脂质代谢之间新的和已建立的关联的因果关系。
